Interoceptive brain network mechanisms of mindfulness-based training in healthy adolescents.

Introduction: This study evaluated changes in the white matter of the brain and psychological health variables, resulting from a neuroscience-based mindfulness intervention, the Training for Awareness, Resilience, and Action (TARA), in a population of healthy adolescents. Methods: A total of 100 healthy adolescents (57 female, age ranges 14-18 years) were randomized into the 12-week TARA intervention or a waitlist-control group. All participants were imaged with diffusion MRI to quantify white matter connectivity between brain regions. Imaging occurred at baseline/randomization and after 12 weeks of baseline (pre- and post-intervention in the TARA group). We hypothesized that structural connectivity in the striatum and interoceptive networks would increase following the TARA intervention, and that, this increased connectivity would relate to psychological health metrics from the Strengths and Difficulties Questionnaire (SDQ) and the Insomnia Severity Index (ISI). The TARA intervention and all assessments, except for the MRIs, were fully remotely delivered using secure telehealth platforms and online electronic data capture systems. Results: The TARA intervention showed high consistency, tolerability, safety, recruitment, fidelity, adherence, and retention. After 12 weeks, the TARA group, but not controls, also demonstrated significantly improved sleep quality (p = 0.02), and changes in the right putamen node strength were related to this improved sleep quality (r = -0.42, p = 0.006). Similarly, the TARA group, but not controls, had significantly increased right insula node strength related to improved emotional well-being (r = -0.31, p = 0.04). Finally, we used the network-based statistics to identify a white matter interoception network that strengthened following TARA (p = 0.009). Discussion: These results suggest that the TARA mindfulness-based intervention in healthy adolescents is feasible and safe, and it may act to increase structural connectivity strength in interoceptive brain regions. Furthermore, these white matter changes are associated with improved adolescent sleep quality and emotional well-being. Our results suggest that TARA could be a promising fully remotely delivered intervention for improving psychological well-being in adolescents. As our findings suggest that TARA affects brain regions in healthy adolescents, which are also known to be altered during depression in adolescents, future studies will examine the effects of TARA on depressed adolescents. Clinical trial registration: https://clinicaltrials.gov/study/NCT04254796.

Examining putamen resting-state connectivity markers of suicide attempt history in depressed adolescents.

Introduction: Suicide is a current leading cause of death in adolescents and young adults. The neurobiological underpinnings of suicide risk in youth, however, remain unclear and a brain-based model is lacking. In adult samples, current models highlight deficient serotonin release as a potential suicide biomarker, and in particular, involvement of serotonergic dysfunction in relation to the putamen and suicidal behavior. Less is known about associations among striatal regions and relative suicidal risk across development. The current study examined putamen connectivity in depressed adolescents with (AT) and without history of a suicide attempt (NAT), specifically using resting-state functional magnetic resonance imaging (fMRI) to evaluate patterns in resting-state functional connectivity (RSFC). We hypothesized the AT group would exhibit lower striatal RSFC compared to the NAT group, and lower striatal RSFC would associate with greater suicidal ideation severity and/or lethality of attempt. Methods: We examined whole-brain RSFC of six putamen regions in 17 adolescents with depression and NAT (MAge [SD] = 16.4[0.3], 41% male) and 13 with AT (MAge [SD] = 16.2[0.3], 31% male). Results: Only the dorsal rostral striatum showed a statistically significant bilateral between-group difference in RSFC with the superior frontal gyrus and supplementary motor area, with higher RSFC in the group without a suicide attempt compared to those with attempt history (voxel-wise p<.001, cluster-wise p<.01). No significant associations were found between any putamen RSFC patterns and suicidal ideation severity or lethality of attempts among those who had attempted. Discussion: The results align with recent adult literature and have interesting theoretical and clinical implications. A possible interpretation of the results is a mismatch of the serotonin transport to putamen and to the supplementary motor area and the resulting reduced functional connectivity between the two areas in adolescents with attempt history. The obtained results can be used to enhance the diathesis-stress model and the Emotional paiN and social Disconnect (END) model of adolescent suicidality by adding the putamen. We also speculate that connectivity between putamen and the supplementary motor area may in the future be used as a valuable biomarker of treatment efficacy and possibly prediction of treatment outcome.

Epigenetic Effects of Resveratrol on Oncogenic Signaling in Breast Cancer.

The crosstalk between oncogenic signaling pathways plays a crucial role in driving cancer development. We previously demonstrated that dietary polyphenols, specifically resveratrol (RSV) and other stilbenoids, epigenetically target oncogenes for silencing via DNA hypermethylation in breast cancer. In the present study, we identify signal transduction regulators among RSV-hypermethylated targets and investigate the functional role of RSV-mediated DNA hypermethylation in the regulation of Hedgehog and Wnt signaling. Non-invasive ER-positive MCF-7 and highly invasive triple-negative MCF10CA1a human breast cancer cell lines were used as experimental models. Upon 9-day exposure to 15 µM RSV, pyrosequencing and qRT-PCR were performed to assess DNA methylation and expression of GLI2 and WNT4, which are upstream regulators of the Hedgehog and Wnt pathways, respectively. Our results showed that RSV led to a DNA methylation increase within GLI2 and WNT4 enhancers, which was accompanied by decreases in gene expression. Consistently, we observed the downregulation of genes downstream of the Hedgehog and Wnt signaling, including common targets shared by both pathways, CCND1 and CYR61. Further analysis using chromatin immunoprecipitation identified increased H3K27 trimethylation and decreased H3K9 and H3K27 acetylation, along with abolishing OCT1 transcription factor binding. Those changes indicate a transcriptionally silent chromatin state at GLI2 and WNT4 enhancers. The inhibition of the Wnt signal transduction was confirmed using a phospho-antibody array that demonstrated suppression of positive and stimulation of negative Wnt regulators. In conclusion, our results provide scientific evidence for dietary polyphenols as epigenetics-modulating agents that act to re-methylate and silence oncogenes, reducing the oncogenic signal transduction. Targeting such an action could be an effective strategy in breast cancer prevention and/or adjuvant therapy.

Novel Oppositional Defiant Disorder or Conduct Disorder 24 Months After Traumatic Brain Injury in Children and Adolescents.

OBJECTIVE: The authors sought to identify predictive factors of new-onset or novel oppositional defiant disorder or conduct disorder assessed 24 months after traumatic brain injury (TBI). METHODS: Children ages 5 to 14 years who had experienced TBI were recruited from consecutive hospital admissions. Soon after injury, participants were assessed for preinjury characteristics, including psychiatric disorders, socioeconomic status (SES), psychosocial adversity, and family function, and the presence and location of lesions were documented by MRI. Psychiatric outcomes, including novel oppositional defiant disorder or conduct disorder, were assessed 24 months after injury. RESULTS: Of the children without preinjury oppositional defiant disorder, conduct disorder, or disruptive behavior disorder not otherwise specified who were recruited in this study, 165 were included in this sample; 95 of these children returned for the 24-month assessment. Multiple imputation was used to address attrition. The prevalence of novel oppositional defiant disorder or conduct disorder was 23.7 out of 165 (14%). In univariable analyses, novel oppositional defiant disorder or conduct disorder was significantly associated with psychosocial adversity (p=0.049) and frontal white matter lesions (p=0.016) and was marginally but not significantly associated with SES. In the final multipredictor model, frontal white matter lesions were significantly associated with novel oppositional defiant disorder or conduct disorder (p=0.021), and psychosocial adversity score was marginally but not significantly associated with the outcome. The odds ratio of novel oppositional defiant disorder or conduct disorder among the children with versus those without novel depressive disorder was significantly higher for girls than boys (p=0.025), and the odds ratio of novel oppositional defiant disorder or conduct disorder among the children with versus those without novel attention-deficit hyperactivity disorder (ADHD) was significantly higher for boys than girls (p=0.006). CONCLUSION: Approximately 14% of children with TBI developed oppositional defiant disorder or conduct disorder. The risk for novel oppositional defiant disorder or conduct disorder can be understood from a biopsychosocial perspective. Sex differences were evident for comorbid novel depressive disorder and comorbid novel ADHD.

A Systematic Review of MRI Studies and the "Emotional paiN and social Disconnect (END)" Brain Model of Suicidal Behavior in Youth.

Introduction: Risk of suicidal ideation and suicidal behaviors greatly increases during adolescence, and rates have risen dramatically over the past two decades. However, few risk factors or biomarkers predictive of suicidal ideation or attempted suicide have been identified in adolescents. Neuroimaging correlates hold potential for early identification of adolescents at increased risk of suicidality and risk stratification for those at high risk of suicide attempt. Methods: In this systematic review, we evaluated neural regions and networks associated with suicidal ideation and suicide attempt in adolescents derived from magnetic resonance imaging (MRI) studies. A total of 28 articles were included in this review. Results: After descriptively synthesizing the literature, we propose the Emotional paiN and social Disconnect (END) model of adolescent suicidality and present two key neural circuits: (1) the emotional/mental pain circuit and (2) the social disconnect/distortion circuit. In the END model, the emotional pain circuit-consisting of the cerebellum, amygdala, and hippocampus-shows similar aberrations in adolescents with suicidal ideation as in those with a history of a suicide attempt (but to a smaller degree). The social disconnect circuit is unique to adolescent suicide attempters and includes the lateral orbitofrontal cortex (OFC), the temporal gyri, and the connections between them. Conclusion: Our proposed END brain model of suicidal behavior in youth, if confirmed by future prospective studies, can have implications for clinical goals of early detection, risk stratification, and intervention development. Treatments that target emotional pain and social disconnect may be ideal interventions for reducing suicidality in adolescents.

Evaluation of major depressive disorder using 7 Tesla phase sensitive neuroimaging before and after mindfulness-based cognitive therapy.

OBJECTIVE: We applied 7 Tesla phase sensitive imaging to evaluate the impact of brain iron levels on depression severity and cognitive function in individuals with major depressive disorder (MDD) treated with mindfulness-based cognitive therapy (MBCT). METHODS: Seventeen unmedicated MDD participants underwent MRI, evaluation of depression severity, and cognitive testing before and after receiving MBCT, compared to fourteen healthy controls (HC). Local field shift (LFS) values, measures of brain iron levels, were derived from phase images in the putamen, caudate, globus pallidus (GP), anterior cingulate cortex (ACC) and thalamus. RESULTS: Compared to the HC group, the MDD group had significantly lower baseline LFS (indicative of higher iron) in the left GP and left putamen and had a higher number of subjects with impairment in a test of information processing speed. In the MDD group, lower LFS values in the left and right ACC, right putamen, right GP, and right thalamus were significantly associated with depression severity; and lower LFS in the right GP was correlated with worse performance on measures of attention. All MBCT participants experienced depression relief. MBCT treatment also significantly improved executive function and attention. MBCT participants with lower baseline LFS values in the right caudate experienced significantly greater improvement in depression severity with treatment; and those with lower LFS values in the right ACC, right caudate, and right GB at baseline performed better on measures of verbal learning and memory after MBCT. CONCLUSIONS: Our study highlights the potential contribution of subtle differences in brain iron to MDD symptoms and their successful treatment.

How Obstructed Action Efficacy Impacts Reward-Based Decision Making in Adolescent Depression: An fMRI Study.

OBJECTIVE: Disruption of reward seeking behavior by unforeseen obstacles can promote negative affect, including frustration and irritability, in adolescents. Repeated experiences of obstructed reward may in fact contribute to the development of depression in adolescents. However, the neurocognitive mechanisms whereby goal disruption impacts reward processing in adolescent depression have not yet been characterized. The present study addresses this gap by using neuroimaging and a novel paradigm to assess how incidental action obstruction impacts reward-based decision making. METHOD: We assessed 62 unmedicated adolescents with major depressive disorder (MDD; mean age = 15.6 years, SD = 1.4 years, 67% female participants) and 68 matched healthy control participants (mean age = 15.3 years, SD = 1.4 years, 50% female participants) using functional magnetic resonance imaging (fMRI) while they played a card game in which they had to guess between 2 options to earn points, in low- and high-stake conditions. Functioning of button presses through which they made decisions was intermittently blocked, thereby blocking action efficacy. RESULTS: Participants with MDD made fewer button press repetitions in response to action efficacy obstruction, which was more apparent in the low-stake condition (rate ratio =0.85, p = .034). During response repetition across stake conditions, MDDs exhibited higher activation in regions in the ventromedial prefrontal cortex, caudate, and putamen (F1,125 = 16.4-25.6, df=1,125; p values <.001; Hedges g = 0.85-0.98). CONCLUSION: Adolescents with depression tend to exhibit less flexible behavioral orientation in the face of blocked action efficacy, and abnormalities in neural systems critical to regulating negative affect during reward-based decision making. This research highlights possible mechanisms relevant to understanding and treating affective dysregulation in adolescent depression.

Novel Psychiatric Disorder 6 Months After Traumatic Brain Injury in Children and Adolescents.

OBJECTIVE: To investigate the factors predictive of novel psychiatric disorders in the interval 0-6 months following traumatic brain injury (TBI). METHODS: Children ages 5-14 years consecutively hospitalized for mild to severe TBI at five hospitals were recruited. Participants were evaluated at baseline (soon after injury) for pre-injury characteristics including psychiatric disorders, socioeconomic status (SES), psychosocial adversity, family function, family psychiatric history, and adaptive function. In addition to the psychosocial variables, injury severity and lesion location detected with acquisition of a research MRI were measured to develop a biopsychosocial predictive model for development of novel psychiatric disorders. Psychiatric outcome, including occurrence of a novel psychiatric disorder, was assessed 6 months after the injury. RESULTS: The recruited sample numbered 177 children, and 141 children (80%) returned for the six-month assessment. Of the 141 children, 58 (41%) developed a novel psychiatric disorder. In univariable analyses, novel psychiatric disorder was significantly associated with lower SES, higher psychosocial adversity, and lesions in frontal lobe locations, such as frontal white matter, superior frontal gyrus, inferior frontal gyrus, and orbital gyrus. Multivariable analyses found that novel psychiatric disorder was independently and significantly associated with frontal-lobe white matter, superior frontal gyrus, and orbital gyrus lesions. CONCLUSION: The results demonstrate that occurrence of novel psychiatric disorders following pediatric TBI requiring hospitalization is common and has identifiable psychosocial and specific biological predictors. However, only the lesion predictors were independently related to this adverse psychiatric outcome.

The gut microbiota, HPA axis, and brain in adolescent-onset depression: Probiotics as a novel treatment.

Stress-associated disruptions in the development of frontolimbic regions may play a critical role in the emergence of adolescent-onset depression. These regions are particularly sensitive to Hypothalamic-Pituitary-Adrenal (HPA) axis signaling. The HPA axis is hyperactive in adolescent depression, and interventions that attenuate such hyperactivity hold promise as potential treatments. The Microbiome-Gut-Brain (MGB) axis is an important pathway through which stress dysregulates HPA-axis activity and thus exerts deleterious effects on the adolescent brain. Probiotic agents, which alter the gut microbiota composition by introducing bacterial strains with beneficial physiological effects, normalize aberrant HPA-axis activity and reduce depressive symptoms in both animal studies and adult clinical trials. While the potential utility of such agents in treating or preventing adolescent depression remains largely unexplored, recent data suggest the existence of an adolescent sensitive window during which probiotics may be especially efficacious in reducing depressive symptoms compared to effects observed in adult populations. In this review, we outline evidence that probiotic use may attenuate stress effects on frontolimbic development, providing a novel means of improving depressive symptoms among adolescent populations.

A meta-analysis of brain morphometric aberrations in adolescents who experienced childhood trauma.

Introduction: Childhood trauma is known to have dramatic effects on the risks for developing psychiatric disorders and increased suicidality. We conducted a meta-analysis of whole brain voxel-based morphometry (VBM) correlates of childhood trauma in adolescents exposed to childhood maltreatment (N = 379) and unexposed controls (N = 348). Methods: Anisotropic effect size-signed differential mapping (AES-SDM) was utilized to synthesize the studies. Results: We observed increased volume amongst adolescents with a history of childhood trauma in regions that are involved in motor functions and language production: left precentral gyrus, including part of the left inferior frontal gyrus, left fibers of the body of corpus callosum, and left postcentral gyrus. We observed decreased volume amongst adolescents with a history of childhood trauma in regions that are involved in language processing and/or sensory processing: bilateral cerebellum, bilateral middle temporal gyrus, left rostrum of corpus callosum, and bilateral supramarginal gyrus. Discussion: We suggest that these morphometric differences may be reflective of impaired motor development and increased sensory sensitivity and hypervigilance in adolescents with experiences of childhood trauma. Our results differ from meta-analytical findings in adults with history of childhood trauma and may contribute to a better understanding of neural mechanisms of childhood trauma, prediction of neurodevelopmental outcomes, and development of more effective and personalized therapies.

Resting state brain subnetwork relates to prosociality and compassion in adolescents.

Adolescence is a crucial time for social development, especially for helping (prosocial) and compassionate behaviors; yet brain networks involved in adolescent prosociality and compassion currently remain underexplored. Here, we sought to evaluate a recently proposed domain-general developmental (Do-GooD) network model of prosocial cognition by relating adolescent functional and structural brain networks with prosocial and compassionate disposition. We acquired resting state fMRI and diffusion MRI from 95 adolescents (ages 14-19 years; 46 males; 49 females) along with self-report questionnaires assessing prosociality and compassion. We then applied the Network-Based Statistic (NBS) to inductively investigate whether there is a significant subnetwork related to prosociality and compassion while controlling for age and sex. Based on the Do-GooD model, we expected that this subnetwork would involve connectivity to the ventromedial prefrontal cortex (VMPFC) from three domain-general networks, the default mode network (DMN), the salience network, and the control network, as well as from the DMN to the mirror neuron systems. NBS revealed a significant functional (but not structural) subnetwork related to prosociality and compassion connecting 31 regions (p = 0.02), showing DMN and DLPFC connectivity to the VMPFC; DMN connectivity to mirror neuron systems; and connectivity between the DMN and cerebellum. These findings largely support and extend the Do-GooD model of prosocial cognition in adolescents by further illuminating network-based relationships that have the potential to advance our understanding of brain mechanisms of prosociality.

Policing of Drug Safety Information Dissemination Under the False Claims Act.

On July 25, 2017, the second largest multi-million dollar settlement was pursued with the assistance of the Department of Justice and alleging inappropriate marketing strategies utilized by the pharmaceutical industry came to an end.

DNA hypermethylation of Kiss1r promoter and reduction of hepatic Kiss1r in female rats with type 2 diabetes.

Kisspeptin, produced from the brain and peripheral tissues, may constitute an important link in metabolic regulation in response to external cues, such as diet. The kisspeptin system is well described in the brain. However, its function and regulation in the peripheral tissues, especially in relation to metabolic disease and sex differences, remain to be elucidated. As Kiss1 and Kiss1r, encoding for kisspeptin and kisspeptin receptors, respectively, are altered by overnutrition/fasting and regulated by DNA methylation during puberty and cancer, epigenetic mechanisms in metabolic disorders are highly probable. In the present study, we experimentally induced type 2 diabetes mellitus (DM2) in female Wistar rats using high-fat diet/streptozocin. We analysed expression and DNA methylation of Kiss1 and Kiss1r in the peripheral tissues, using quantitative-reverse-transcription PCR (qRT-PCR) and pyrosequencing. We discovered differential expression of Kiss1 and Kiss1r in peripheral organs in DM2 females, as compared with healthy controls, and the profile differed from patterns reported earlier in males. DM2 in females was linked to the increased Kiss1 mRNA in the liver and increased Kiss1r mRNA in the liver and adipose tissue. However, Kiss1r promoter was hypermethylated in the liver, suggesting gene silencing. Indeed, the increase in DNA methylation of Kiss1r promoter was accompanied by a reduction in Kiss1r protein, implying epigenetic or translational gene repression. Our results deliver novel evidence for tissue-specific differences in Kiss1 and Kiss1r expression in peripheral organs in DM2 females and suggest DNA methylation as a player in regulation of the hepatic kisspeptin system in DM2.

Real-world overall survival of patients receiving cetuximab in later lines of treatment for metastatic colorectal cancer.

Aim: To examine characteristics of and treatment duration and real-world overall survival (rwOS) in patients receiving cetuximab as second-line (2L) or third-line (3L) treatment for metastatic colorectal cancer. Materials & methods: This was a retrospective study of 1096 and 684 patients in 2L and 3L cohorts, respectively. Results: The most common cetuximab-based regimens were cetuximab + folinic acid, fluorouracil and irinotecan (2L: 44%; 3L: 32%) and cetuximab + irinotecan (2L: 28%; 3L: 35%). Kaplan-Meier survival estimates and stepwise Cox regression model analysis demonstrated median treatment duration and rwOS of 3.7 and 14.4 months, respectively, in patients receiving treatment in the 2L cohort. In the 3L cohort, treatment duration was 3.3 months and rwOS was 12.0 months. Conclusion: This large real-world study provides evidence of rwOS in patients with metastatic colorectal cancer receiving cetuximab-based regimens as 2L or 3L treatment.

In this retrospective study, the authors examined baseline characteristics of and treatment duration and real-world overall survival (rwOS) in 1096 and 684 patients with metastatic colorectal cancer receiving cetuximab as second-line (2L) and third-line (3L) treatment, respectively. The most common cetuximab-based regimens were cetuximab + folinic acid, fluorouracil and irinotecan (2L: 44%; 3L: 32%) and cetuximab + irinotecan (2L: 28%; 3L: 35%). Median treatment duration and rwOS were 3.7 and 14.4 months, respectively, in patients receiving treatment in the 2L cohort. In the 3L cohort, median treatment duration was 3.3 months and rwOS was 12.0 months. This large real-world study provides evidence of rwOS in patients with metastatic colorectal cancer receiving cetuximab-based regimens as 2L or 3L treatment.

A Feasibility Study of a Remotely-Delivered Mindfulness-Based Training for Adolescents During the COVID-19 Pandemic.

Social distancing, home confinement, economic challenges, and COVID-19-related illness and deaths during the COVID-19 pandemic can significantly affect mental health in youth. One promising approach to reduce anxiety and depression in adolescents is the neuroscience-based mindfulness intervention Training for Awareness, Resilience, and Action (TARA). The objective of this individually randomized waitlist-controlled trial (RCT) was (1) to test the feasibility of TARA, delivered partially over Zoom, and (2) to assess changes in the emotional wellbeing in healthy adolescents between the ages of 14-18 years old during the COVID-19 pandemic. METHODS: Twenty-one healthy adolescents were randomized to the TARA intervention or to the waitlist control group in February 2020, just before the start of the pandemic. The TARA group intervention was delivered in person for the first five sessions and remotely over Zoom for the remaining seven sessions due to the pandemic. The participants' acceptability of TARA was assessed weekly using the Child Session Rating Scale (CSRS). The primary outcome was the emotional wellbeing measured using emotional symptoms subscale of the Strengths and Difficulties Questionnaire (SDQ) pre/post-TARA. We also explored weekly changes in TARA participants' wellbeing using the Child Outcome Rating Scale (CORS). RESULTS: The overall session rating in TARA participants improved after the switch to Zoom (Cohen's d = 1.2, p = 0.008). The results of the two-way ANOVA showed no statistically significant difference in the change of the SDQ emotional symptoms during the 12 weeks between the TARA group and waitlist-control group (timepoint × group interaction: F = 0.77, p = 0.38). The exploratory analysis using the CORS in the TARA participants showed a significant improvement in their functioning over the weeks of training. CONCLUSION: Our results support the feasibility of TARA delivered over Zoom. While our primary outcome did not provide support for the improvement of the emotional wellbeing with TARA compared to a passive control group, our exploratory analysis in the intervention group indicated an improved functioning over the weeks of TARA training. The important general positive impact of this study lies in the possibility of offering a neuroscience-based mindfulness intervention remotely to youth living in remote areas and for all youth during pandemic times.

Epigenetic aberrations of gene expression in a rat model of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is mostly triggered by environmental and life-style factors and may involve epigenetic aberrations. However, a comprehensive documentation of the link between the dysregulated epigenome, transcriptome, and liver carcinogenesis is lacking. In the present study, Fischer-344 rats were fed a choline-deficient (CDAA, cancer group) or choline-sufficient (CSAA, healthy group) L-amino acid-defined diet. At the end of 52 weeks, transcriptomic alterations in livers of rats with HCC tumours and healthy livers were investigated by RNA sequencing. DNA methylation and gene expression were assessed by pyrosequencing and quantitative reverse-transcription PCR (qRT-PCR), respectively. We discovered 1,848 genes that were significantly differentially expressed in livers of rats with HCC tumours (CDAA) as compared with healthy livers (CSAA). Upregulated genes in the CDAA group were associated with cancer-related functions, whereas macronutrient metabolic processes were enriched by downregulated genes. Changes of highest magnitude were detected in numerous upregulated genes that govern key oncogenic signalling pathways, including Notch, Wnt, Hedgehog, and extracellular matrix degradation. We further detected perturbations in DNA methylating and demethylating enzymes, which was reflected in decreased global DNA methylation and increased global DNA hydroxymethylation. Four selected upregulated candidates, Mmp12, Jag1, Wnt4, and Smo, demonstrated promoter hypomethylation with the most profound decrease in Mmp12. MMP12 was also strongly overexpressed and hypomethylated in human HCC HepG2 cells as compared with primary hepatocytes, which coincided with binding of Ten-eleven translocation 1 (TET1). Our findings provide comprehensive evidence for gene expression changes and dysregulated epigenome in HCC pathogenesis, potentially revealing novel targets for HCC prevention/treatment.

A Domain-General Developmental "Do-GooD" Network Model of Prosocial Cognition in Adolescence: A Systematic Review.

Adolescence is a period of substantial neural and social development, and prosocial decisions are beneficial to personal well-being, the well-being of others, and the functioning of society. Advances in network neuroscience call for a systematic synthesis and reappraisal of prosocial neural correlates during adolescent development. In this systematic review, we aim to outline the progress made in this field, identify the similarities between study results, and propose a model for prosocial cognition in adolescents to young adults. A total of 25 articles were included in this review. After reviewing and synthesizing the literature, we propose a DOmain-General Developmental "Do-GooD" network model of prosocial cognition that aligns with the reviewed literature, accounts for development, and combines elements of the value-based decision-making model with distinct value contributions from the default mode network, salience network, and control network. We offer predictions to test the "Do-GooD" model and propose new future directions for studying prosocial behavior and its development during adolescence, which in turn may lead to improving education and the development of better health interventions for adolescents.

Novel Oppositional Defiant Disorder 12 Months After Traumatic Brain Injury in Children and Adolescents.

OBJECTIVE: The investigators examined the factors predictive of novel oppositional defiant disorder in the 6-12 months following traumatic brain injury (TBI). METHODS: Children ages 5-14 years old who experienced a TBI were recruited from consecutive admissions to five hospitals. Participants were evaluated soon after injury (baseline) for preinjury characteristics, including psychiatric disorders, adaptive function, family function, psychosocial adversity, family psychiatric history, socioeconomic status, and injury severity, to develop a biopsychosocial predictive model for development of novel oppositional defiant disorder. MRI analyses were conducted to examine potential brain lesions. Psychiatric outcome, including that of novel oppositional defiant disorder, was assessed 12 months after injury. RESULTS: Although 177 children were recruited for the study, 120 children without preinjury oppositional defiant disorder, conduct disorder, or disruptive behavior disorder not otherwise specified (DBD NOS) returned for the 12-month assessment. Of these 120 children, seven (5.8%) exhibited novel oppositional defiant disorder, and none developed conduct disorder or DBD NOS in the 6-12 months postinjury. Novel oppositional defiant disorder was significantly associated with lower socioeconomic status, higher psychosocial adversity, and lower preinjury adaptive functioning. CONCLUSIONS: These results demonstrate that novel oppositional defiant disorder following TBI selectively and negatively affects an identifiable group of children. Both proximal (preinjury adaptive function) and distal (socioeconomic status and psychosocial adversity) psychosocial variables significantly increase risk for this outcome.

Characteristics and Clinical Outcomes of Patients With Relapsed/Refractory Diffuse Large B-cell Lymphoma Who Received At Least 3 Lines of Therapies.

INTRODUCTION: The treatment landscape for diffuse large B-cell lymphoma (DLBCL) has recently changed. We examined characteristics and clinical outcomes of DLBCL patients who initiated a third (3L) and fourth (4L) line of therapy during a contemporary time frame. MATERIALS AND METHODS: Adult patients diagnosed with DLBCL who received ≥ 3L after January 1, 2014 were selected from the COTA database. Patients were grouped into cohorts by 3L or 4L initiation and further stratified by type of treatment received: chemotherapy or chemoimmunotherapy (CT/CIT), targeted therapy (TT), chimeric antigen receptor T cells (CAR-T), or salvage therapy consolidated with hematopoietic cell transplant (HCT). Patient characteristics, response rates, and overall survival (OS) were examined. RESULTS: Among adult patients with relapsed/refractory (r/r) DLBCL, 212 (mean age; 61.8 years; 59.0% male) received their 3L and 127 (mean age: 61.0 years; 61.4% male) their 4L. Among those treated with their 3L and 4L, 55.2% and 50.4%, respectively, received CT/CIT; 26.9% and 34.6% received TT. The complete response rate of 3L patients was 9.4% for CT/CIT, 10.5% for TT, and 60% for CAR-T. Similar findings were seen with 4L patients (CT/CIT: 6.3%; TT: 15.9%; CAR-T: 53.8%). For those who received pharmacological treatment in 3L and 4L, median OS times were 7.7 and 4.4 months, respectively. Median OS times of patients who received cell-based therapies (CAR-T/HCT) were not reached. CONCLUSION: In this study, a majority of r/r DLBCL patients were treated with CT/CIT or TT in 3L and 4L settings and had poor clinical outcomes, underscoring the need for more effective treatments.

Requirements and Study Designs for U.S. Regulatory Approval of Influenza Home Tests.

Home testing for infectious disease has come to the forefront during the COVID-19 pandemic. There is now considerable commercial interest in developing complete home tests for a variety of viral and bacterial pathogens. However, the regulatory science around home infectious disease test approval and procedures that test manufacturers and laboratory professionals will need to follow have not yet been formalized by the U.S. Food and Drug Administration (FDA), with the exception of Emergency Use Authorization (EUA) guidance for COVID-19 tests. We describe the state of home-based testing for influenza with a focus on sample-to-result home tests, discuss the various regulatory pathways by which these products can reach populations, and provide recommendations for study designs, patient samples, and other important features necessary to gain market access. These recommendations have potential application for home use tests being developed for other viral respiratory infections, such as COVID-19, as guidance moves from EUA designation into 510(k) requirements.