Precise control of the balance between protein phosphorylation, catalyzed by protein kinases, and protein dephosphorylation, catalyzed by protein phosphatases, is essential for cellular homeostasis. Dysregulation of this balance leads to pathophysiological states, driving diseases such as cancer, heart disease, and diabetes. Aberrant phosphorylation of components of the pathways that control cell growth and cell survival are particularly prevalent in cancer. One of the most studied tumor suppressors in these pathways is the lipid phosphatase PTEN (phosphatase and tensin homolog deleted on chromosome ten), which dephosphorylates the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3), thus preventing activation of the oncogenic kinase AKT (v-akt murine thymoma viral oncogene homolog). In 2005, the discovery of a family of protein phosphatases whose members directly dephosphorylate and inactivate AKT introduced a new negative regulator of the phosphoinositide 3-kinase (PI3K) oncogenic pathway. Pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) isozymes comprise a novel tumor suppressor family whose two members, PHLPP1 and PHLPP2, are deleted as frequently as PTEN in cancers such as those of the prostate. PHLPP is thus a novel therapeutic target to suppress oncogenic pathways and is a potential candidate biomarker to stratify patients for the appropriate targeted therapeutics. This review discusses the role of PHLPP in terminating AKT signaling and how pharmacological intervention would impact this pathway.

While total errors on the Benton Visual Retention Test (BVRT) are known to increase in normal aging, there is little information on changes for specific error types. We examined the differential increase in seven specific error categories for 2,000 participants in the Baltimore Longitudinal Study of Aging. Cross-sectional analyses indicated that all errors increased with age, but differences between age groups in error profiles suggested relatively greater age effects for distortions, omissions, and rotations. There were also significant gender differences in error profiles, reflecting increased rotation and omission errors in females. Longitudinal analyses of age changes for a subset of 673 participants with three BVRT assessments were consistent with the cross-sectional data and indicated intra-individual increases with age in distortions, omissions, and rotations. While women made more omission errors, men showed steeper increases in omission errors with age. These findings suggest that cerebral aging impacts all categories of BVRT errors but has differential effects on particular error types.

Atypical antipsychotics (AT) and stress are related to weight gain in individuals with severe mental illness. This cross-sectional study examines AT use, stressful life events, and baseline weight in a sample of youth at clinical high risk for psychosis. Results showed that dependent and desirable life events moderated the relationship between AT use and weight after controlling for demographic factors and selective serotonin reuptake inhibitor antidepressant (AD) use. The relation of AD and weight was explored as a secondary analysis and showed no relation between AD use and weight. Further, stress did not moderate the relationship between AD medication and weight after controlling for antipsychotic use. Results suggest that stress exposure may exacerbate the relationship between ATs and increased weight in clinical high-risk populations. Findings have implications for the development of interventions to address psychosocial factors that worsen or buffer the adverse effects of antipsychotic medication on weight.

Huntington's disease (HD) is characterized by the accumulation of a pathogenic protein, Huntingtin (Htt), that contains an abnormal polyglutamine expansion. Here, we report that a pathogenic fragment of Htt (Httex1p) can be modified either by small ubiquitin-like modifier (SUMO)-1 or by ubiquitin on identical lysine residues. In cultured cells, SUMOylation stabilizes Httex1p, reduces its ability to form aggregates, and promotes its capacity to repress transcription. In a Drosophila model of HD, SUMOylation of Httex1p exacerbates neurodegeneration, whereas ubiquitination of Httex1p abrogates neurodegeneration. Lysine mutations that prevent both SUMOylation and ubiquitination of Httex1p reduce HD pathology, indicating that the contribution of SUMOylation to HD pathology extends beyond preventing Htt ubiquitination and degradation.

Background

Studies of biomarkers of hypothalamic-pituitary-adrenal activity indicate that psychotic disorders are associated with elevated cortisol. This study examined cortisol levels in healthy control subjects and individuals who met clinical high-risk (CHR) criteria for psychosis. It was hypothesized that cortisol levels would be 1) elevated in the CHR group relative to control subjects, 2) positively correlated with symptom severity, and 3) most elevated in CHR patients who transition to psychotic level severity.

Methods

Baseline assessments were conducted at eight centers in the North American Prodrome Longitudinal Study. The present CHR sample included 256 individuals meeting the Scale for Prodromal Symptoms criteria and 141 control subjects, all of whom underwent baseline assessment and measurement of salivary cortisol.

Results

Consistent with previous reports, there was an effect of age on cortisol, with increases through the adolescent/early adult years. Analysis of covariance showed a main effect of diagnostic group, with the CHR group showing higher cortisol. There were modest, positive correlations of cortisol with baseline symptom severity, and analysis of covariance revealed higher baseline cortisol in those who transitioned to psychotic level symptoms when compared with healthy control subjects and CHR subjects who remitted.

Conclusions

The present findings add to accumulating evidence of heightened cortisol secretion in CHR individuals. The findings also indicate nonspecific associations between cortisol levels and symptom severity, as well as symptom progression. The role of hypothalamic-pituitary-adrenal activity in prediction of conversion to psychosis and its relation with other biomarkers of risk should receive attention in future research.

Growth factor receptor levels are aberrantly high in diverse cancers, driving the proliferation and survival of tumor cells. Understanding the molecular basis for this aberrant elevation has profound clinical implications. Here we show that the pleckstrin homology domain leucine-rich repeat protein phosphatase (PHLPP) suppresses receptor tyrosine kinase (RTK) signaling output by a previously unidentified epigenetic mechanism unrelated to its previously described function as the hydrophobic motif phosphatase for the protein kinase AKT, protein kinase C, and S6 kinase. Specifically, we show that nuclear-localized PHLPP suppresses histone phosphorylation and acetylation, in turn suppressing the transcription of diverse growth factor receptors, including the EGF receptor. These data uncover a much broader role for PHLPP in regulation of growth factor signaling beyond its direct inactivation of AKT: By suppressing RTK levels, PHLPP dampens the downstream signaling output of two major oncogenic pathways, the PI3 kinase/AKT and the Rat sarcoma (RAS)/ERK pathways. Our data are consistent with a model in which PHLPP modifies the histone code to control the transcription of RTKs.

Cancer cells from a primary tumor can disseminate to other tissues, remaining dormant and clinically undetectable for many years. Little is known about the cues that cause these dormant cells to awaken, resume proliferating, and develop into metastases. Studying mouse models, we found that sustained lung inflammation caused by tobacco smoke exposure or nasal instillation of lipopolysaccharide converted disseminated, dormant cancer cells to aggressively growing metastases. Sustained inflammation induced the formation of neutrophil extracellular traps (NETs), and these were required for awakening dormant cancer. Mechanistic analysis revealed that two NET-associated proteases, neutrophil elastase and matrix metalloproteinase 9, sequentially cleaved laminin. The proteolytically remodeled laminin induced proliferation of dormant cancer cells by activating integrin α3β1 signaling. Antibodies against NET-remodeled laminin prevented awakening of dormant cells. Therapies aimed at preventing dormant cell awakening could potentially prolong the survival of cancer patients.

There is inconsistent evidence for increased stress exposure among individuals at clinical high risk (CHR) for psychosis. Yet similar to patients with a diagnosed psychotic illness, the preponderance of evidence suggests that CHR individuals tend to experience stressful life events (LE) and daily hassles (DH) as more subjectively stressful than healthy individuals. The present study utilizes data from the North American Prodrome Longitudinal Study Phase 2 (NAPLS-2) to test the hypotheses that (1) CHR individuals manifest higher self-reported stress in response to both LE and DH when compared to healthy controls (HC), (2) group differences in self-reported stress increase with age, (3) baseline self-reported stress is associated with follow-up clinical status, and (4) there is a sensitization effect of LE on the response to DH. In contrast to some previous research, the present findings indicate that the CHR group (N=314) reported exposure to more LE when compared to the HC group (N=162). As predicted, CHR participants rated events as more stressful, and those who progressed to psychosis reported a greater frequency of LE and greater stress from events compared to those whose prodromal symptoms remitted. There was also some evidence of stress-sensitization; those who experienced more stress from LE rated current DH as more stressful. The results indicate that the "prodromal" phase is a period of heightened stress and stress sensitivity, and elevated cumulative lifetime exposure to stressful events may increase reactions to current stressors.

Mounting evidence indicates that the nervous system plays a central role in cancer pathogenesis. In turn, cancers and cancer therapies can alter nervous system form and function. This Commentary seeks to describe the burgeoning field of cancer neuroscience and encourage multidisciplinary collaboration for the study of cancer-nervous system interactions.

It is now well established that the utilization of standardized clinical criteria can enhance prediction of psychosis. These criteria are primarily concerned with the presence and severity of attenuated positive symptoms. Because these symptom criteria are used to derive algorithms for designating clinical high risk (CHR) status and for maximizing prediction of psychosis risk, it is important to know whether the symptom ratings vary as a function of demographic factors that have previously been linked with symptoms in diagnosed psychotic patients. Using a sample of 356 CHR individuals from the NAPLS-II multi-site study, we examined the relation of three sex, age, and educational level, with the severity of attenuated positive symptom scores from the Scale of Prodromal Symptoms (SOPS). Demographic factors accounted for little of the variance in symptom ratings (5-6%). Older CHR individuals manifested more severe suspiciousness, and female CHR participants reported more unusual perceptual experiences than male participants. Contrary to prediction, higher educational level was associated with more severe ratings of unusual thought content, but less severe perceptual abnormalities. Overall, sex, age and education were modestly related to unusual thought content and perceptual abnormalities, only, suggesting minimal implication for designating CHR status and predicting psychosis-risk.