Nuclear Receptor Nur77 Facilitates Melanoma Cell Survival under Metabolic Stress by Protecting Fatty Acid Oxidation.

Fatty acid oxidation (FAO) is crucial for cells to overcome metabolic stress by providing ATP and NADPH. However, the mechanism by which FAO is regulated in tumors remains elusive. Here we show that Nur77 is required for the metabolic adaptation of melanoma cells by protecting FAO. Glucose deprivation activates ERK2 to phosphorylate and induce Nur77 translocation to the mitochondria, where Nur77 binds to TPß, a rate-limiting enzyme in FAO. Although TPß activity is normally inhibited by oxidation under glucose deprivation, the Nur77-TPß association results in Nur77 self-sacrifice to protect TPß from oxidation. FAO is therefore able to maintain NADPH and ATP levels and prevent ROS increase and cell death. The Nur77-TPß interaction further promotes melanoma metastasis by facilitating circulating melanoma cell survival. This study demonstrates a novel regulatory function of Nur77 with linkage of the FAO-NADPH-ROS pathway during metabolic stress, suggesting Nur77 as a potential therapeutic target in melanoma.

Blocking PPARγ interaction facilitates Nur77 interdiction of fatty acid uptake and suppresses breast cancer progression.

Nuclear receptor Nur77 participates in multiple metabolic regulations and plays paradoxical roles in tumorigeneses. Herein, we demonstrated that the knockout of Nur77 stimulated mammary tumor development in two mouse models, which would be reversed by a specific reexpression of Nur77 in mammary tissues. Mechanistically, Nur77 interacted and recruited corepressors, the SWI/SNF complex, to the promoters of CD36 and FABP4 to suppress their transcriptions, which hampered the fatty acid uptake, leading to the inhibition of cell proliferation. Peroxisome proliferator-activated receptor-γ (PPARγ) played an antagonistic role in this process through binding to Nur77 to facilitate ubiquitin ligase Trim13-mediated ubiquitination and degradation of Nur77. Cocrystallographic and functional analysis revealed that Csn-B, a Nur77-targeting compound, promoted the formation of Nur77 homodimer to prevent PPARγ binding by steric hindrance, thereby strengthening the Nur77's inhibitory role in breast cancer. Therefore, our study reveals a regulatory function of Nur77 in breast cancer via impeding fatty acid uptake.

Associations of Social Capital with Mental Disorder Prevalence, Severity, and Comorbidity among U.S. Adolescents.

OBJECTIVE: To examine cross-sectional associations between social capital constructs and 1) adolescent lifetime mental disorders, 2) severity of functional impairment, and 3) psychiatric comorbidity. METHOD: Data were from the National Comorbidity Survey Adolescent Supplement, a nationally representative mental health survey of 6,483 U.S. adolescents aged 13-18 years. Information from fully-structured diagnostic interviews, including adolescent and caregiver reports, was used to measure seven social capital constructs and lifetime DSM-IV mental disorders (mood, anxiety, behavior, substance use and eating disorder classes). Disorder severity was divided into severe vs. mild/moderate. Comorbidity was measured as the number of different classes of lifetime mental disorders. RESULTS: Adjusted for socio-demographics and caregivers' mental health, the most consistent associations with adolescent mental disorder were for supportive friendships (any disorder OR = 0.95, 95%CI = 0.91-0.99), family cohesion (OR = 0.81, 95%CI = 0.75-0.86), school bonding (OR = 0.76, 95%CI = 0.71-0.81), and extracurricular participation (OR = 0.90, 95%CI = 0.86-0.95), although results differed by disorder class. Caregiver-reported neighborhood trust and reciprocity and caregiver community involvement were less consistently associated with mental disorder. Medium levels of adolescent-reported affiliation with neighbors was associated with lower odds of mood (OR = 0.81, 95%CI = 0.66-0.98) and anxiety (OR = 0.78, 95%CI = 0.64-0.96) disorder, while high levels were associated with higher odds of behavior disorder (OR = 1.47, 95%CI = 1.16-1.87). Several associations were stronger for severe vs. mild/moderate disorder and with increasing comorbidity. CONCLUSION: Although we cannot infer causality, our findings support the notion that improving actual and/or perceived social capital, especially regarding friendships, family, and school, (e.g., through multimodal interventions) could aid in the prevention and treatment of both individual adolescent mental disorders and psychiatric comorbidity.

Headache and mental disorders in a nationally representative sample of American youth.

The objective of this study is to examine the association between headache and mental disorders in a nationally representative sample of American youth. We used the National Comorbidity Survey-Adolescent Supplement to assess sex-specific prevalence of lifetime migraine and non-migraine headache using modified International Headache Society criteria and examine associations between headache subtypes and DSM-IV mental disorders. Adolescent report (n = 10,123) was used to identify headache subtypes and anxiety, mood, eating, and substance use disorders. ADHD and behavior disorder were based on parent report (n = 6483). Multivariate logistic regression analyses controlling for key demographic characteristics were used to examine associations between headache and mental disorders. Headache was endorsed by 26.9% (SE = 0.7) of the total sample and was more prevalent among females. Youth with headache were more than twice as likely (OR 2.74, 95% CI 1.94-3.83) to meet criteria for a DSM-IV disorder. Migraine, particularly with aura, was associated with depression and anxiety (adjusted OR 1.90-2.90) and with multiple classes of disorders. Adolescent headache, particularly migraine, is associated with anxiety, mood, and behavior disorders in a nationally representative sample of US youth. Headache is highly prevalent among youth with mental disorders, and youth with headache should be assessed for comorbid depression and anxiety that may influence treatment, severity, and course of both headache and mental disorders.

Meta-analysis of protein intake on the effect of Crohn's disease and ulcerative colitis.

BACKGROUND AND PURPOSE: published studies have assessed the effect of protein intake on Crohn's disease (CD) and ulcerative colitis (UC). However, the results were inconsistent. To provide a more precise estimation, a meta-analysis was performed to evaluate the association of protein intake in Crohn's disease and ulcerative colitis. METHODS: the PubMed, Chinese National Knowledge Infrastructure databases (CNKI), and Wanfang databases were searched to identify relevant studies. The summarized results of the relative risk (RR) with the corresponding 95 % confidence intervals (CI) were calculated using a random effects model. RESULTS: the final analysis included a total of nine articles. Nine studies reported on protein intake for the risk of UC and five studies reported on protein intake for the risk of CD. Overall, based on current studies, no significant association was found between protein intake and the risk of UC (RR = 1.13, 95 % CI = 0.82-1.55) or CD (RR = 1.18, 95 % CI = 0.51-2.74). A significant change was not found in the stratified analysis by study design and geographic location. CONCLUSIONS: in conclusion, the present meta-analysis suggested that dietary protein intake did not show a significant effect on the risk of UC or CD.

Direct synthesis of 2,3,5-trisubstituted pyrroles via copper-mediated one-pot multicomponent reaction.

We have developed a copper-mediated one-pot synthesis of 2,3,5-trisubstituted pyrroles from 1,3-dicarbonyl compounds and acrylates using ammonium acetate as a nitrogen source. The reaction achieves C-C and C-N bond formation and provides an efficient approach to access highly functionalized pyrroles without further raw material preparation. This method is operationally simple, compatible with a wide range of functional groups, and provides the target products in moderate to good yields.

Validation of the Ask Suicide-Screening Questions for Adult Medical Inpatients: A Brief Tool for All Ages.

BACKGROUND: Few brief suicide risk screening instruments are validated for use in both adult and pediatric medical populations. Using the pediatric Ask Suicide-Screening Questions (ASQ) development study as a model, this study aimed to determine whether the ASQ is a valid suicide risk-screening instrument for use among adults medical patients, as well as to evaluate a set of other potential screening questions for use in adults. METHODS: Adult patients hospitalized on inpatient medical/surgical units from 4 hospitals were recruited to participate in a cross-sectional instrument-validation study. The 4-item ASQ and other candidate items were compared against the 25-item, previously validated Adult Suicidal Ideation Questionnaire as the criterion standard. RESULTS: A total of 727 adult medical inpatients completed the screening process. Compared with the Adult Suicidal Ideation Questionnaire, the ASQ performed best among the full set of candidate items, demonstrating strong psychometric properties, with a sensitivity of 100% (95% confidence interval = 90%-100%), a specificity of 89% (95% confidence interval = 86%-91%), and a negative predictive value of 100% (95% confidence interval = 99%-100%). A total of 4.8% (35/727) of the participants screened positive for suicide risk based on the standard criterion Adult Suicidal Ideation Questionnaire. CONCLUSIONS: The ASQ is a valid and brief suicide risk-screening tool for use among adults. Screening medical/surgical inpatients for suicide risk can be performed effectively for both adult and pediatric patients using this brief, primary screener.

Physical-Mental Comorbidity of Pediatric Migraine in the Philadelphia Neurodevelopmental Cohort.

OBJECTIVE: To examine the associations between headaches and migraine with physical and mental disorders in a large pediatric registry. STUDY DESIGN: In total, 9329 youth aged 8-21 years from the Philadelphia Neurodevelopmental Cohort were included. Physical conditions, including headache, were ascertained from electronic medical records and in-person interviews. Modified International Classification of Headache Disorders (ICHD-II) criteria were used to classify migraine symptoms. Forty-two other physical conditions were classified into 14 classes of medical disorders. Mental disorders were assessed using an abbreviated version of the Kiddie-Schedule for Affective Disorders and Schizophrenia. RESULTS: Lifetime prevalence of any headache was 45.5%, and of migraine was 22.6%. Any headache was associated with a broad range of physical disorders, attention-deficit/hyperactivity disorder (OR 1.2 [95% CI 1.1-1.4]), and behavior disorders (1.3 [1.1-1.5]). Youth with migraine had greater odds of specific physical conditions and mental disorders, including respiratory, neurologic/central nervous system, developmental, anxiety, behavior, and mood disorders than those with nonmigraine headache (OR ranged from 1.3 to 1.9). CONCLUSIONS: Comorbidity between headaches with a range of physical conditions that have been associated with adult migraine demonstrates that multimorbidity occurs early in development. Comorbidity may be an important index of heterogeneity of migraine that can guide clinical management, genetic investigation, and future research on shared pathophysiology with other disorders.

Parenting style and mental disorders in a nationally representative sample of US adolescents.

PURPOSE: We examined associations between parenting style and past-year mental disorders in a nationally representative cross-sectional survey of US adolescents and whether the associations differed by adolescent demographic characteristics. METHODS: The sample included 6483 adolescents aged 13-18 years who were interviewed for a full range of DSM-IV mental disorders. Parenting style was assessed by adolescent-reported maternal and paternal care and control using items from the Parental Bonding Instrument. We controlled for socio-demographics, parental history of mental disorders, stressful life events, sexual violence, inter-parental conflict, and household composition. We also tested for two-way interactions between parental care and control and adolescent age, sex, and race/ethnicity. RESULTS: In adjusted models, high maternal care was associated with lower odds of depressive, eating, and behavioral disorders, and high maternal control was associated with greater odds of depressive, anxiety, eating, and behavioral disorders. High paternal care was associated with lower odds of social phobia and alcohol abuse/dependence. High paternal control was associated with greater odds of agoraphobia and alcohol abuse/dependence but with lower odds of attention-deficit/hyperactivity disorder. Associations of maternal and paternal control with anxiety disorders and substance abuse/dependence differed by sex. High paternal care was associated with lower odds of anxiety disorders only among Hispanics and non-Hispanic blacks. CONCLUSIONS: Perceived parental care and control were associated with adolescent mental disorders after controlling for multiple potential confounders. Differential patterns of association were found according to adolescent sex and race/ethnicity. Findings have implications for prevention and intervention programs that incorporate familial contextual factors.

Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation.

Sepsis, a hyperinflammatory response that can result in multiple organ dysfunctions, is a leading cause of mortality from infection. Here, we show that orphan nuclear receptor Nur77 (also known as TR3) can enhance resistance to lipopolysaccharide (LPS)-induced sepsis in mice by inhibiting NF-κB activity and suppressing aberrant cytokine production. Nur77 directly associates with p65 to block its binding to the κB element. However, this function of Nur77 is countered by the LPS-activated p38α phosphorylation of Nur77. Dampening the interaction between Nur77 and p38α would favor Nur77 suppression of the hyperinflammatory response. A compound, n-pentyl 2-[3,5-dihydroxy-2-(1-nonanoyl) phenyl]acetate, screened from a Nur77-biased library, blocked the Nur77-p38α interaction by targeting the ligand-binding domain of Nur77 and restored the suppression of the hyperinflammatory response through Nur77 inhibition of NF-κB. This study associates the nuclear receptor with immune homeostasis and implicates a new therapeutic strategy to treat hyperinflammatory responses by targeting a p38α substrate to modulate p38α-regulated functions.

School Start Time and Adolescent Sleep Patterns: Results From the U.S. National Comorbidity Survey--Adolescent Supplement.

OBJECTIVES: We estimated associations between school start time and adolescent weeknight bedtime, weeknight sleep duration, and weekend compensatory sleep and assessed whether associations differ by age, sex, or urbanicity. METHODS: We used a subsample of a nationally representative, cross-sectional survey of 7308 students aged 13 to 18 years attending 245 schools to estimate associations of school start time, reported by school principals, with weeknight bedtime and sleep duration and weekend compensatory sleep, reported during adolescent face-to-face interviews. RESULTS: Start time was positively associated with weeknight bedtime. Associations between start time and weeknight sleep duration were nonlinear and were strongest for start times of 8:00 am and earlier. Associations differed by sex and urbanicity, with the strongest association among boys in major metropolitan counties. Start time was negatively associated with sleep duration among boys in nonurban counties. Start time was not associated with weekend compensatory sleep. CONCLUSIONS: Positive overall associations between school start time and adolescent sleep duration at the national level support recent policy recommendations for delaying school start times. However, the impact of start time delays may differ by sex and urbanicity.

The orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPK.

Liver kinase B1 (LKB1) has important roles in governing energy homeostasis by regulating the activity of the energy sensor kinase AMP-activated protein kinase (AMPK). The regulation of LKB1 function, however, is still poorly understood. Here we demonstrate that the orphan nuclear receptor Nur77 binds and sequesters LKB1 in the nucleus, thereby attenuating AMPK activation. This Nur77 function is antagonized by the chemical compound ethyl 2-[2,3,4-trimethoxy-6-(1-octanoyl)phenyl]acetate (TMPA), which interacts with Nur77 with high affinity and at specific sites. TMPA binding of Nur77 results in the release and shuttling of LKB1 to the cytoplasm to phosphorylate AMPKα. Moreover, TMPA effectively reduces blood glucose and alleviates insulin resistance in type II db/db and high-fat diet- and streptozotocin-induced diabetic mice but not in diabetic littermates with the Nur77 gene knocked out. This study attains a mechanistic understanding of the regulation of LKB1-AMPK axis and implicates Nur77 as a new and amenable target for the design and development of therapeutics to treat metabolic diseases.

A case of penile squamous cell carcinoma treated with a combination of antiepidermal growth factor receptor antibody and chemotherapy.

Our previous study showed that the features of epidermal growth factor receptor (EGFR)-RAS signaling in penile squamous cell carcinoma (SCC) suggested potential benefits of anti-EGFR monoclonal antibodies (mAbs) for penile SCC. Here, we report, for the first time, a combination of nimotuzumab (an EGFR mAb) with chemotherapy that resulted in a partial response in a 44-year-old patient with penile SCC, who developed bilateral inguinal node metastasis after primary partial penile amputation. The literature of case reports of anti-EGFR mAbs in penile SCC was also reviewed.

Efficacy of percutaneous mechanical thrombus removal in acute lower extremity deep venous thrombosis.

BACKGROUND: Acute lower extremity deep venous thrombosis (LEDVT) is a common vascular emergency with significant morbidity risks, including post-thrombotic syndrome (PTS) and pulmonary embolism. Traditional treatments like catheter-directed thrombolysis (CDT) often result in variable success rates and complications. AIM: To investigate the therapeutic efficacy of percutaneous mechanical thrombus removal in acute LEDVT. METHODS: A retrospective analysis was performed to examine 58 hospitalised patients with acute LEDVT between August 2019 and August 2022. The patients were categorised into the percutaneous mechanical thrombectomy (PMT) group (n = 24) and CDT group (n = 32). The follow-up, safety and treatment outcomes were compared between the two groups. The main observational indexes were venous patency score, thrombus removal effect, complications, hospitalisation duration and PTS. RESULTS: The venous patency score was 9.04 ± 1.40 in the PMT group and 8.81 ± 1.60 in the CDT group, and the thrombus clearance rate was 100% in both groups. The complication rate was 8.33% in the PMT group and 34.84% in the CDT group, and the difference was statistically significant (P < 0.05). The average hospitalisation duration was 6.54 ± 2.48 days in the PMT group and 8.14 ± 3.56 days in the CDT group. The incidence of PTS was lower in the PMT group than in the CDT group; however, the difference was not statistically significant (P < 0.05). CONCLUSION: Compared with CDT, treatment of LEDVT via PMT was associated with a better thrombus clearance rate, clinical therapeutic effect and PTS prevention function, but the difference was not statistically significant. Moreover, PMT was associated with a reduced urokinase dosage, shortened hospitalisation duration and reduced incidence of complications, such as infections and small haemorrhages. These results indicate that PMT has substantial beneficial effects in the treatment of LEDVT.

Correlates of cannabis use and cannabis use disorder among adolescents with major depressive disorder and bipolar disorder in the National Comorbidity Survey-Adolescent Supplement (NCS-A).

BACKGROUND: Despite evidence regarding prevalence and correlates of cannabis use (CU) and cannabis use disorder (CUD) in major depressive disorder (MDD) and bipolar disorder (BD) in adults, little is known about this topic among adolescents. METHODS: Data is from the 2001-2004 National Comorbidity Survey-Adolescent Supplement, an in-person, cross-sectional epidemiologic survey of mental disorders. Participants included adolescents, ages 13-18 years, with MDD (n = 354 with CU, n = 70 with CUD, n = 688 with no CU), BD (n = 79 with CU, n = 32 with CUD, n = 184 with no CU), or adolescents without mood disorders (n = 1413 with CU, n = 333 with CUD, n = 6970 with no CU). Analyses examined prevalence and correlates of CU and CUD within MDD and BD groups. RESULTS: CU was most prevalent in adolescents with MDD followed by adolescents with BD then controls. CUD was most prevalent in adolescents with BD followed by adolescents with MDD then controls. In covariate-adjusted ordinal logistic regression models, within MDD and BD, CU and CUD groups had significantly higher odds of lifetime suicidal ideation/attempts, as well as other significant indicators of clinical severity. LIMITATIONS: Based on changes in cannabis acceptance, potency, and availability in the two decades since this study was conducted, present findings may underestimate adverse cannabis associations. CONCLUSION: CU and CUD are both associated with adverse clinical characteristics in a community-based sample of adolescents with MDD and BD. Evidence that risks of cannabis use extend across the spectrum of use is important for adolescents with MDD and BD, in whom cannabis-related consequences tend to be more severe.

Association of IL­6 and MMP­3 gene polymorphisms with adolescent idiopathic scoliosis: A systematic review and meta­analysis.

The pathogenesis of adolescent idiopathic scoliosis (AIS) remains unclear. It has been found that interleukin-6 (IL-6) rs1800795 locus and matrix metalloproteinase-3 (MMP-3) rs3025058 locus gene polymorphisms may be associated with AIS susceptibility, which has been controversial and needs to be further confirmed by updated meta-analysis. The aim of the present study was to investigate the association of MMP-3 rs3025058 and IL-6 rs1800795 single nucleotide polymorphisms (SNPs) with susceptibility to AIS. All relevant articles that met the criteria were retrieved and included, and the publication dates were limited from January 2005 to December 2023. The allele frequencies and different genotype frequencies of IL-6 rs1800795 and MMP-3 rs3025058 loci in each study were extracted and statistically analyzed by ReviewManager 5.4 software, and the odds ratio (OR) and 95% confidence interval (95% CI) of different genetic models were calculated. The results of the meta-analysis showed that there was no significant association between the gene polymorphism of IL-6 rs1800795 locus and the pathogenesis of AIS. The allele 5A and genotype 5A5A of MMP-3 rs3025058 SNP were associated with AIS susceptibility (5A vs. 6A, OR=1.18; 95% CI, 1.04-1.33; 5A5A vs. 6A6A, OR=1.65; 95% CI, 1.23-2.21; and 5A5A vs. 5A6A + 6A6A, OR=1.54; 95% CI, 1.19-1.99). Results of subgroup analysis revealed that the allele 5A and genotype 5A5A of MMP-3 rs3025058 SNP were associated with AIS susceptibility in the Caucasian population, and the susceptibility of AIS was associated with the genotype 5A5A of MMP-3 rs3025058 SNP in an Asian population. There was no significant association between the gene polymorphism of IL-6 rs1800795 locus and the pathogenesis of AIS, while the allele 5A of MMP-3 rs3025058 locus was associated with the susceptibility to AIS, especially in the Caucasian population.

Nodular regenerative hyperplasia in common variable immunodeficiency.

PURPOSE: Patients with Common Variable Immunodeficiency (CVID) are subject to the development of a liver disease syndrome known as nodular regenerative hyperplasia (NRH). The purpose of this study was to define the characteristics and course of this complication of CVID. METHODS: CVID patients were evaluated by retrospective and prospective clinical course review. Liver biopsy specimens were evaluated for evidence of NRH and studied via RT-PCR for cytokine analysis. RESULTS: NRH in our CVID patient population occurred in approximately 5 % of the 261 patients in our total CVID study group, initially presenting in most cases with an elevated alkaline phosphatase level. While in some patients the disease remained static, in a larger proportion a more severe disease developed characterized by portal hypertension, the latter leading to hypersplenism with neutropenia and thrombocytopenia and, in some cases, to ascites. In addition, a substantial proportion of patients either developed or presented initially with an autoimmune hepatitis-like (AIH-like) liver disease that resulted in severe liver dysfunction and, in most cases to death due to infections. The liver histologic findings in these AIH-like patients were characterized by underlying NRH pattern with superimposed interface hepatitis, lymphocytic infiltration and fibrosis. Immunologic studies of biopsies of NRH patients demonstrated the presence of infiltrating T cells producing IFN-γ, suggesting that the NRH is due to an autoimmune process. CONCLUSION: Overall, these studies provide evidence that NRH may not be benign but, can be a severe and potentially fatal disease complication of CVID that merits close monitoring and intervention.

Cannabis Use Is Associated With Depression Severity and Suicidality in the National Comorbidity Survey-Adolescent Supplement.

Objective: To investigate the association of cannabis use with major depression and suicidal behavior in adolescence. Method: Data are from the National Comorbidity Survey-Adolescent Supplement N=10,123, a nationally representative survey of adolescents aged 13 to 18 years. Weighted logistic regression and ordinal regression analyses of major depression and suicidal behavior outcomes were conducted on cannabis variables, incorporating sociodemographic characteristics. Results: Adolescents with lifetime cannabis use have 2.07 times higher odds of mild/moderate (adjusted odds ratio [aOR]; 95% CI=1.69, 2.53) and 3.32 times higher odds of severe major depressive disorder (MDD; aOR; 95% CI=2.31, 4.75). Cannabis use (aOR 6.90, 95% CI=4.67,10.19), mild/moderate MDD (aOR 4.10, 95% CI=2.82, 5.98), and severe MDD (aOR 13.97, 95% CI = 7.59, 25.70) were associated with higher odds of suicide attempt. Past 12-month cannabis use (aOR 3.70, 95% CI = 2.16, 6.32), mild/moderate major depressive episodes (MDE) (aOR 7.85, 95% CI=3.59, 17.17), and severe MDE (aOR 36.36, 95% CI=13.68,96.64) were associated with higher odds of suicide attempt. The frequency of past 12-month cannabis use was associated with higher odds of suicide attempt and with MDE severity, with higher odds among individuals who use cannabis 3 or more days than among individuals who use cannabis less frequently, suggesting a dose effect. Among cannabis users, older age of onset of cannabis use was associated with lower odds of suicidal behaviors. Conclusion: Cannabis use is associated with higher odds of depression and depression severity in adolescence. Furthermore, depression and cannabis use are independently associated with higher odds of suicide attempt. Diversity & Inclusion Statement: We worked to ensure sex and gender balance in the recruitment of human participants. We worked to ensure race, ethnic, and/or other types of diversity in the recruitment of human participants. The author list of this paper includes contributors from the location and/or community where the research was conducted who participated in the data collection, design, analysis, and/or interpretation of the work. One or more of the authors of this paper self-identifies as a member of one or more historically underrepresented racial and/or ethnic groups in science. We actively worked to promote sex and gender balance in our author group. We actively worked to promote inclusion of historically underrepresented racial and/or ethnic groups in science in our author group.

Assessing the Validity of the Ask Suicide-Screening Questions in Black Youth.

BACKGROUND: Given the increasing rates of suicide and nonfatal suicide attempts among Black youth in the United States, it is crucial that screening tools are valid in identifying Black youth at risk of suicide. OBJECTIVE: This study assessed the validity of the Ask Suicide-Screening Questions (ASQ) among Black youth. METHODS: This analysis used pooled data from 3 ASQ validation studies of pediatric medical patients aged 10-21 years. All participants completed the ASQ and the gold standard Suicidal Ideation Questionnaire. RESULTS: Of the 1083 participants, 330 (30.5%) were non-Hispanic Black and 753 (69.5%) were non-Hispanic White. ASQ psychometric properties for Black and White participants were equivalent (sensitivity = 94% vs. 90.9%; specificity = 91.4% vs. 91.8%, respectively). CONCLUSIONS: There were no significant differences in ASQ psychometric properties between Black and White youth, indicating that the ASQ is valid for screening Black youth at risk of suicide.

Orphan receptor TR3 participates in cisplatin-induced apoptosis via Chk2 phosphorylation to repress intestinal tumorigenesis.

Cisplatin is a widely used antitumor agent that induces aggressive cancer cell death via triggering cellular proteins involved in apoptosis. Here, we demonstrate that cisplatin effectively induces orphan nuclear receptor TR3 phosphorylation by activating Chk2 kinase activity and promoting cross talk between these two proteins, thereby contributing to the repression of intestinal tumorigenesis via apoptosis. Mechanistic analysis has demonstrated that Chk2-induced phosphorylation enables TR3 to bind to its response elements on the promoters of the BRE and RNF-7 genes, leading to the negative regulation of these two anti-apoptotic genes. Furthermore, the induction of apoptosis by cisplatin is mediated by TR3, and knockdown of TR3 reduces cisplatin-induced apoptosis in colon cancer cells by 27%. The role of TR3 in cisplatin chemotherapy is further clarified in mouse models. In Apc(min/+) mice, cisplatin inhibits intestinal tumorigenesis by 70% in a TR3 phosphorylation-dependent manner; however, the loss of TR3 function in Apc(min/+)/TR3(-/-) mice leads to the failure of cisplatin-induced repression of tumorigenesis. Consistently, xenografts derived from TR3 knockdown colon cancer cells are insensitive to cisplatin treatment, whereas a significant curative effect (50% inhibition) is observed in xenografts with functional TR3. Taken together, our study reveals a novel cross talk between Chk2 and TR3 and sheds light on the mechanism of cisplatin-induced apoptosis through TR3. Therefore, TR3 may be a new target of cisplatin for colon cancer therapy.