Allosteric Activators of Protein Phosphatase 2A Display Broad Antitumor Activity Mediated by Dephosphorylation of MYBL2.

Protein phosphatase 2A (PP2A) enzymes can suppress tumors, but they are often inactivated in human cancers overexpressing inhibitory proteins. Here, we identify a class of small-molecule iHAPs (improved heterocyclic activators of PP2A) that kill leukemia cells by allosterically assembling a specific heterotrimeric PP2A holoenzyme consisting of PPP2R1A (scaffold), PPP2R5E (B56ε, regulatory), and PPP2CA (catalytic) subunits. One compound, iHAP1, activates this complex but does not inhibit dopamine receptor D2, a mediator of neurologic toxicity induced by perphenazine and related neuroleptics. The PP2A complex activated by iHAP1 dephosphorylates the MYBL2 transcription factor on Ser241, causing irreversible arrest of leukemia and other cancer cells in prometaphase. In contrast, SMAPs, a separate class of compounds, activate PP2A holoenzymes containing a different regulatory subunit, do not dephosphorylate MYBL2, and arrest tumor cells in G1 phase. Our findings demonstrate that small molecules can serve as allosteric switches to activate distinct PP2A complexes with unique substrates.

Validity of the DSM-5 Mixed Features Specifier Interview.

OBJECTIVES: To examine the reliability and validity of a semi-structured interview assessing the features of the DSM-5 mixed features specifier. Our goal was to develop an instrument that could be used for both diagnostic and severity measurement purposes. METHODS: Four hundred fifty-nine psychiatric patients in a depressive episode were interviewed by a trained diagnostic rater who administered semi-structured interviews including the DSM-5 Mixed Features Specifier Interview (DMSI). We examined the inter-rater reliability and psychometric properties of the DMSI. The patients were rated on clinician rating scales of depression, anxiety, and irritability, and measures of psychosocial functioning, suicidality, and family history of bipolar disorder. RESULTS: The DMSI had excellent joint-interview interrater reliability. More than twice as many patients met the DSM-5 mixed features specifier criteria during the week before the assessment than for the majority of the episode (9.4% vs. 3.9%). DMSI total scores were more highly correlated with a clinician-rated measure of manic symptoms than with measures of depression and anxiety. More patients with bipolar depression met the mixed features specifier than patients with MDD. Amongst patients with MDD, those with mixed features more frequently had a family history of bipolar disorder, were more frequently diagnosed with anxiety disorders, attention deficit disorder, and borderline personality disorder, more frequently had attempted suicide, and were more severely depressed, anxious, and irritable. CONCLUSION: The DMSI is a reliable and valid measure of the presence of the DSM-5 mixed features specifier in depressed patients as well as the severity of the features of the specifier.

Synthetic lethal targeting of TET2-mutant haematopoietic stem and progenitor cells by XPO1 inhibitors.

TET2 inactivating mutations serve as initiating genetic lesions in the transformation of haematopoietic stem and progenitor cells (HSPCs). In this study, we analysed known drugs in zebrafish embryos for their ability to selectively kill tet2-mutant HSPCs in vivo. We found that the exportin 1 (XPO1) inhibitors, selinexor and eltanexor, selectively kill tet2-mutant HSPCs. In serial replating colony assays, these small molecules were selectively active in killing murine Tet2-deficient Lineage-, Sca1+, Kit+ (LSK) cells, and also TET2-inactivated human acute myeloid leukaemia (AML) cells. Selective killing of TET2-mutant HSPCs and human AML cells by these inhibitors was due to increased levels of apoptosis, without evidence of DNA damage based on increased γH2AX expression. The finding that TET2 loss renders HSPCs and AML cells selectively susceptible to cell death induced by XPO1 inhibitors provides preclinical evidence of the selective activity of these drugs, justifying further clinical studies of these small molecules for the treatment of TET2-mutant haematopoietic malignancies, and to suppress clonal expansion in age-related TET2-mutant clonal haematopoiesis.

The hidden borderline patient: patients with borderline personality disorder who do not engage in recurrent suicidal or self-injurious behavior.

BACKGROUND: Despite the significant psychosocial morbidity associated with borderline personality disorder (BPD), its underrecognition is a significant clinical problem. BPD is likely underdiagnosed, in part, because patients with BPD usually present with chief complaints associated with mood, anxiety, and substance use disorders. When patients with BPD do not exhibit self-harm behavior, we suspect that BPD is less likely to recognized. An important question is whether the absence of this criterion, which might attenuate the likelihood of recognizing and diagnosing the disorder, identifies a subgroup of patients with BPD who are 'less borderline' than patients with BPD who do not manifest this criterion. METHODS: Psychiatric outpatients were evaluated with a semi-structured diagnostic interview for DSM-IV BPD, 390 of whom were diagnosed with BPD. We compared the demographic and clinical characteristics of patients with BPD who do and do not engage in repeated suicidal and self-harm behavior. RESULTS: Approximately half of the patients with BPD did not meet the suicidality/self-injury diagnostic criterion for the disorder. There were no differences between the patients who did and did not meet this criterion in occupational impairment, likelihood of receiving disability payments, impairment in social functioning, level of educational achievement, comorbid psychiatric disorders, history of childhood trauma, or severity of depression, anxiety, or anger upon presentation for treatment. CONCLUSIONS: Repeated self-injurious and suicidal behavior is not synonymous with BPD. It is critical for clinicians to be aware that the absence of repeated self-injury and suicide threats/gestures or attempts does not rule out the diagnosis of BPD.

Validation of hierarchical taxonomy in a clinical sample.

BACKGROUND: Quantitatively derived dimensional models of psychopathology enjoy overwhelming empirical support, and a large and active community of psychopathology researchers has been establishing an empirically based dimensional hierarchical taxonomy of psychopathology (or HiTOP) as a strong candidate replacement for the current categorical classification system. The hierarchical nature of this taxonomy implies that different levels of resolution are likely to be optimal for different purposes. Our aim was to identify which level of detail is likely to provide optimal validity and explanatory power with regard to relevant clinical variables. METHODS: In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services project, we used data from a sample of 2900 psychiatric outpatients to compare different levels from a bass-ackwards model of psychopathology in relation to psychosocial impairment across different domains (global functioning, inability to work, social functioning, suicidal ideation, history of suicide attempts, history of psychiatric hospitalization). RESULTS: All functioning indices were significantly associated with general psychopathology, but more complex levels provided significant incremental validity. The optimal level of complexity varied across functioning indices, suggesting that there is no single 'best' level for understanding relations between psychopathology and functioning. CONCLUSIONS: Results support the hierarchical organization of psychopathology dimensions with regard to validity considerations and downstream implications for applied assessment. It would be fruitful to develop and implement measurement of these dimensions at the appropriate level for the purpose at hand. These findings can be used to guide HiTOP-consistent assessment in other research and clinical settings.

Borderline personality disorder symptom networks across adolescent and adult clinical samples: examining symptom centrality and replicability.

BACKGROUND: Numerous theories posit different core features to borderline personality disorder (BPD). Recent advances in network analysis provide a method of examining the relative centrality of BPD symptoms, as well as examine the replicability of findings across samples. Additionally, despite the increase in research supporting the validity of BPD in adolescents, clinicians are reluctant to diagnose BPD in adolescents. Establishing the replicability of the syndrome across adolescents and adults informs clinical practice and research. This study examined the stability of BPD symptom networks and centrality of symptoms across samples varying in age and clinical characteristics. METHODS: Cross-sectional analyses of BPD symptoms from semi-structured diagnostic interviews from the Collaborative Longitudinal Study of Personality Disorders (CLPS), the Methods to Improve Diagnostic Assessment and Service (MIDAS) study, and an adolescent clinical sample. Network attributes, including edge (partial association) strength and node (symptom) expected influence, were compared. RESULTS: The three networks were largely similar and strongly correlated. Affective instability and identity disturbance emerged as relatively central symptoms across the three samples, and relationship difficulties across adult networks. Differences in network attributes were more evident between networks varying both in age and in BPD symptom severity level. CONCLUSIONS: Findings highlight the relative importance of affective, identity, and relationship symptoms, consistent with several leading theories of BPD. The network structure of BPD symptoms appears generally replicable across multiple large samples including adolescents and adults, providing further support for the validity of the diagnosis across these developmental phases.

Sulfopin is a covalent inhibitor of Pin1 that blocks Myc-driven tumors in vivo.

The peptidyl-prolyl isomerase, Pin1, is exploited in cancer to activate oncogenes and inactivate tumor suppressors. However, despite considerable efforts, Pin1 has remained an elusive drug target. Here, we screened an electrophilic fragment library to identify covalent inhibitors targeting Pin1's active site Cys113, leading to the development of Sulfopin, a nanomolar Pin1 inhibitor. Sulfopin is highly selective, as validated by two independent chemoproteomics methods, achieves potent cellular and in vivo target engagement and phenocopies Pin1 genetic knockout. Pin1 inhibition had only a modest effect on cancer cell line viability. Nevertheless, Sulfopin induced downregulation of c-Myc target genes, reduced tumor progression and conferred survival benefit in murine and zebrafish models of MYCN-driven neuroblastoma, and in a murine model of pancreatic cancer. Our results demonstrate that Sulfopin is a chemical probe suitable for assessment of Pin1-dependent pharmacology in cells and in vivo, and that Pin1 warrants further investigation as a potential cancer drug target.

Depressed patients who do not believe they deserve to get better: Prevalence, clinical characteristics, and treatment outcomes.

BACKGROUND: The aim of the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project was to examine the demographic and clinical features that distinguished depressed patients who did and did not indicate they deserved to feel better. METHODS: A total of 490 depressed patients completed a clinical history questionnaire that included a question about whether the patient thought they deserved to feel better, as well as a self-report questionnaire assessing symptoms, positive mental health, coping ability, functioning, and well-being. RESULTS: Approximately 20% of patients indicated they were unsure or undeserving of feeling better. Patients who did not believe they deserved to get better reported more cognitive symptoms of depression, were more likely to drop out of treatment due to nonattendance, more pessimistic about outcomes upon treatment initiation, more frequently reported suicidal ideation, more frequently reported a history of multiple suicide attempts, and experienced less improvement in their depressive symptoms during treatment. CONCLUSIONS: A meaningful number of depressed patients seeking treatment did not assert that they deserved to feel better. Efforts to treat individuals who do not believe they deserve to feel better may be less productive if this perspective is not addressed.

Better than we think: Is the treatment of depressed patients more effective than we think?

BACKGROUND: Most studies of depression treatment rely on measures of symptom severity to evaluate outcome. We hypothesized that many patients would consider themselves to have benefitted significantly from treatment despite not being considered a responder according to a measure of depression symptom severity (ie, 50% reduction in symptom score). METHODS: In our study, 854 patients with major depressive disorder completed the Remission from Depression Questionnaire, a self-report measure that assesses several constructs patients consider to be relevant for assessing treatment outcome. At discharge, patients completed the Patient Global Rating of Improvement (PGI) to gauge effectiveness of treatment. RESULTS: Less than 40% of patients were responders on the depressive symptom subscale, whereas two-thirds of the sample were PGI responders. Among patients who were PGI responders but nonresponders on the depression symptoms scale, more than one-half were responders on at least 1 of 4 nonsymptom domains (functioning, quality of life, coping ability, positive mental health). CONCLUSIONS: A patient-centered approach to evaluating outcome goes beyond an assessment of symptoms. When viewed from a broader perspective, the results of our study suggest that patients with depression benefit more from treatment than is suggested by only examining outcome from a symptom-based perspective.

Levels of Anger Severity in Psychiatric Patients.

ABSTRACT: Given anger's clinical relevance and adverse impact on functioning, there is a need to examine diagnostically heterogeneous individuals at different levels of anger severity to provide a basis for considering anger severity in clinical research and practice. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services project, we examined the validity of severity classifications based on the Clinically Useful Anger Outcome Scale (CUANGOS) in 1738 clinically heterogeneous psychiatric outpatients. We compared patients reporting no, mild, moderate, or severe anger with regard to demographics, psychosocial morbidity, functioning, and life satisfaction. Increasing anger severity was associated with elevated clinician-rated psychosocial morbidity and poorer self-rated functioning and life satisfaction. Results demonstrate that assessing anger severity yields crucial information about psychosocial functioning and morbidity. This provides additional validity evidence for self-reported anger in general and the CUANGOS in particular, in that the CUANGOS can validly distinguish among meaningfully different anger severity levels.

LIN28B regulates transcription and potentiates MYCN-induced neuroblastoma through binding to ZNF143 at target gene promotors.

LIN28B is highly expressed in neuroblastoma and promotes tumorigenesis, at least, in part, through inhibition of let-7 microRNA biogenesis. Here, we report that overexpression of either wild-type (WT) LIN28B or a LIN28B mutant that is unable to inhibit let-7 processing increases the penetrance of MYCN-induced neuroblastoma, potentiates the invasion and migration of transformed sympathetic neuroblasts, and drives distant metastases in vivo. Genome-wide chromatin immunoprecipitation coupled with massively parallel DNA sequencing (ChIP-seq) and coimmunoprecipitation experiments show that LIN28B binds active gene promoters in neuroblastoma cells through protein-protein interaction with the sequence-specific zinc-finger transcription factor ZNF143 and activates the expression of downstream targets, including transcription factors forming the adrenergic core regulatory circuitry that controls the malignant cell state in neuroblastoma as well as GSK3B and L1CAM that are involved in neuronal cell adhesion and migration. These findings reveal an unexpected let-7-independent function of LIN28B in transcriptional regulation during neuroblastoma pathogenesis.

Focusing Narrowly on Model Fit in Factor Analysis Can Mask Construct Heterogeneity and Model Misspecification: Applied Demonstrations across Sample and Assessment Types.

This study builds upon research indicating that focusing narrowly on model fit when evaluating factor analytic models can lead to problematic inferences regarding the nature of item sets, as well as how models should be applied to inform measure development and validation. To advance research in this area, we present concrete examples relevant to researchers in clinical, personality, and related subfields highlighting two specific scenarios when an overreliance on model fit may be problematic. Specifically, we present data analytic examples showing that focusing narrowly on model fit may lead to (a) incorrect conclusions that heterogeneous item sets reflect narrower homogeneous constructs and (b) the retention of potentially problematic items when developing assessment measures. We use both interview data from adult outpatients (N = 2,149) and self-report data from adults recruited online (N = 547) to demonstrate the importance of these issues across sample types and assessment methods. Following demonstrations with these data, we make recommendations focusing on how other model characteristics (e.g., factor loading patterns; carefully considering the content and nature of factor indicators) should be considered in addition to information provided by model fit indices when evaluating factor analytic models.

Treatment engagement of depressed patients with and without psychosis in a partial hospital program: Dropout, symptom reduction, and satisfaction.

BACKGROUND: The ways patients with psychosis and depression engage in therapeutic treatment is not well understood. To determine if an intensive outpatient psychotherapy program could benefit patients experiencing psychotic symptoms, it is important to know how these individuals engage with psychotherapeutic treatment. METHODS: The present study from the Rhode Island Hospital Methods to Improve Diagnostic Assessment and Services (MIDAS) project compared dropout rates, treatment response, and satisfaction among 219 individuals with psychosis and major depressive disorder (MDD) to 2,545 individuals with MDD at a general, Acceptance and Commitment Therapy-based partial hospital program (PHP). RESULTS: Those with psychosis were significantly less likely to complete treatment. Approximately one-fifth of all patients experienced at least a 50% reduction in depressive and anxiety symptoms. The vast majority of patients with psychosis were highly satisfied with treatment. CONCLUSIONS: Findings suggest patients with psychosis have a higher risk of premature dropout. Patients with psychosis demonstrated a reduction in symptoms during PHP treatment and self-reported high satisfaction with treatment. This study calls for the implementation of practices to reduce premature dropout for patients with psychosis, and for future research on the effectiveness of general psychiatric treatment for those with psychotic symptoms.

Emotion regulation difficulties link trait resilience and symptoms of depression and anxiety in psychiatric outpatients.

BACKGROUND: Despite negative associations of trait resilience with depression and anxiety symptoms, the mechanisms by which resilience may buffer against these symptoms remain underexplored. This study investigated emotion regulation difficulties as a potential link in the relationship between trait resilience and depression and anxiety severity in psychiatric outpatients (N = 353). METHODS: Participants diagnosed with primary depression or anxiety disorders were evaluated prior to treatment initiation with the Connor-Davidson Resilience Scale, Difficulties in Emotion Regulation Scale (DERS), Clinically Useful Depression Outcome Scale (CUDOS), and Clinically Useful Anxiety Outcome Scale (CUXOS). RESULTS: In the depression sample, the effect of resilience on CUDOS scores was fully mediated by total DERS scores. In the anxiety sample, the effect of resilience on CUXOS scores was partially mediated by total DERS scores. Exploratory parallel mediation analyses showed only the DERS subscale strategies had a significant effect on CUDOS scores, while only goals had a significant effect on CUXOS scores. CONCLUSIONS: Emotion regulation difficulties are a mediator of trait resilience in psychiatric outpatients. For patients seeking treatment for depression, difficulties with accessing emotion regulation strategies may be particularly relevant, while difficulties meeting one's goals may be most relevant for patients seeking treatment for anxiety.

Loss of atrx cooperates with p53-deficiency to promote the development of sarcomas and other malignancies.

The SWI/SNF-family chromatin remodeling protein ATRX is a tumor suppressor in sarcomas, gliomas and other malignancies. Its loss of function facilitates the alternative lengthening of telomeres (ALT) pathway in tumor cells, while it also affects Polycomb repressive complex 2 (PRC2) silencing of its target genes. To further define the role of inactivating ATRX mutations in carcinogenesis, we knocked out atrx in our previously reported p53/nf1-deficient zebrafish line that develops malignant peripheral nerve sheath tumors and gliomas. Complete inactivation of atrx using CRISPR/Cas9 was lethal in developing fish and resulted in an alpha-thalassemia-like phenotype including reduced alpha-globin expression. In p53/nf1-deficient zebrafish neither peripheral nerve sheath tumors nor gliomas showed accelerated onset in atrx+/- fish, but these fish developed various tumors that were not observed in their atrx+/+ siblings, including epithelioid sarcoma, angiosarcoma, undifferentiated pleomorphic sarcoma and rare types of carcinoma. These cancer types are included in the AACR Genie database of human tumors associated with mutant ATRX, indicating that our zebrafish model reliably mimics a role for ATRX-loss in the early pathogenesis of these human cancer types. RNA-seq of p53/nf1- and p53/nf1/atrx-deficient tumors revealed that down-regulation of telomerase accompanied ALT-mediated lengthening of the telomeres in atrx-mutant samples. Moreover, inactivating mutations in atrx disturbed PRC2-target gene silencing, indicating a connection between ATRX loss and PRC2 dysfunction in cancer development.

Exploring the Optimal Factor Structure of the Five Facet Mindfulness Questionnaire: Associations Between Mindfulness Facets and Dimensions of Psychopathology.

Recent studies of the Five Facet Mindfulness Questionnaire (FFMQ) and its condensed version (FFMQ-SF) fail to replicate the initially proposed five-factor structure in clinical samples. Failure to adequately understand the dimensionality of common mindfulness measures within clinical samples, therefore, represents an important gap in the current literature. The increasing popularity of mindfulness-based interventions warrants further investigation of differential associations between facets of mindfulness and different forms of psychopathology. We examined (a) the underlying structure of the FFMQ and FFMQ-SF, and (b) associations between FFMQ and FFMQ-SF facets and dimensions of psychopathology (i.e., internalizing and substance use disorders) in two large clinical samples (N = 2,779). Results from bass-ackwards analyses suggested similarly defensible five- and six-factor model solutions in terms of fit. The five-factor model was optimal when factoring in parsimony. Exploratory structural equation modeling revealed that all FFMQ facets with the exception of observe were negatively associated with the internalizing factor. Associations with substance use disorders were more complex. In both samples, five-factor FFMQ and FFMQ-SF models were determined to best represent these data. Whereas deficits in all FFMQ facets with the exception of observe correspond with lower internalizing psychopathology, a more nuanced association was observed with substance use disorders.

Sudden gains and treatment outcomes among depressed individuals in a partial hospitalization programme.

Sudden gains commonly occur among patients receiving psychotherapy for depression and have been found to consistently predict better treatment outcomes. However, the majority of prior research has examined sudden gains primarily in weekly or biweekly treatment settings. Individuals were divided into two groups: those who experienced at least one sudden gain and those who did not. Rates of sudden gain occurrence, pretreatment factors and posttreatment outcomes were examined between the two groups. Over 60% of this sample experienced at least one sudden gain, the majority of which occurred during the first 3 days of treatment. Sudden gains were associated with significantly lower baseline depression and anxiety severity. Patients who experienced sudden gains reported significantly greater improvement in depressive and anxiety symptoms, coping skills, functioning, positive mental health and well-being at treatment termination. This study was conducted in a single location with a relatively homogeneous sample. Due to a lack of follow-up data, we were unable to determine if treatment outcomes were sustained after treatment termination. The assessment timeline of the depressive symptoms differs between baseline and daily scales, which may have affected the number of observed sudden gains after the initial treatment day. The proportion of sudden gains in this study is higher than those found in outpatient settings, demonstrating that this phenomenon may commonly occur among depressed patients in acute treatment. These results suggest that the mechanisms by which sudden gains occur may be reinforced by daily, intensive treatment.

Judgment towards emotions as a mediator of the relationship between emotional eating and depression symptoms in bariatric surgery candidates.

PURPOSE: Emotional eating is common in bariatric surgery candidates, and often is associated with depression and poorer weight loss outcomes following surgery. However, less is known about other modifiable risk factors that may link depression and emotional eating. The aim of the current study was to examine facets of mindfulness as potential mediators of the relationship between emotional eating and depression severity in bariatric surgery candidates. METHODS: Bariatric surgery candidates (n = 743) were referred by their surgeons for a comprehensive psychiatric pre-surgical evaluation that included self-report questionnaires assessing depression severity, emotional overeating, and facets of mindfulness. Mediation effects were examined for each mindfulness facet based on prior research. RESULTS: Only the nonjudging mindfulness facet significantly mediated the relationship between emotional eating and depression, suggesting that greater emotional eating may be associated with greater depression severity through higher levels of judgement towards thoughts and emotions. A reverse mediation analysis showed that depression severity was not a significant mediator of the relationship between nonjudging and emotional eating. CONCLUSION: Fostering a nonjudgmental stance towards thoughts and feelings may be helpful in improving eating habits that would support greater post-surgical success. Other clinical and research implications are discussed. LEVEL OF EVIDENCE: Level V, descriptive study.

Patients with borderline personality disorder and bipolar disorder: a descriptive and comparative study.

BACKGROUND: Bipolar disorder and borderline personality disorder (BPD) are each significant public health problems. It has been frequently noted that distinguishing BPD from bipolar disorder is challenging. Consequently, reviews and commentaries have focused on differential diagnosis and identifying clinical features to distinguish the two disorders. While there is a burgeoning literature comparing patients with BPD and bipolar disorder, much less research has characterized patients with both disorders. In the current report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, we compare psychiatric outpatients with both BPD and bipolar disorder to patients with BPD without bipolar disorder and patients with bipolar disorder without BPD. METHODS: Psychiatric outpatients presenting for treatment were evaluated with semi-structured interviews. The focus of the current study is the 517 patients with both BPD and bipolar disorder (n = 59), BPD without bipolar disorder (n = 330), and bipolar disorder without BPD (n = 128). RESULTS: Compared to patients with bipolar disorder, the patients with bipolar disorder and BPD had more comorbid disorders, psychopathology in their first-degree relatives, childhood trauma, suicidality, hospitalizations, time unemployed, and likelihood of receiving disability payments. The added presence of bipolar disorder in patients with BPD was associated with more posttraumatic stress disorder in the patients as well as their family, more bipolar disorder and substance use disorders in their relatives, more childhood trauma, unemployment, disability, suicide attempts, and hospitalizations. CONCLUSIONS: Patients with both bipolar disorder and BPD have more severe psychosocial morbidity than patients with only one of these disorders.