Biomarkers are most frequently proteins that are measured in the blood. Their development largely relies on antibody creation to test the protein candidate performance in blood samples of diseased versus non-diseased patients. The creation of such antibody assays has been a bottleneck in biomarker progress due to the cost, extensive time and effort required to complete the task. Targeted proteomics is an emerging technology that is playing an increasingly important role to facilitate disease biomarker development. In this study, we applied a SRM-based targeted proteomics platform to directly detect candidate biomarker proteins in plasma to evaluate their clinical utility for pancreatic cancer detection. The characterization of these protein candidates used a clinically well-characterized cohort that included plasma samples from patients with pancreatic cancer, chronic pancreatitis and healthy age-matched controls. Three of the five candidate proteins, including gelsolin, lumican and tissue inhibitor of metalloproteinase 1, demonstrated an AUC value greater than 0.75 in distinguishing pancreatic cancer from the controls. In addition, we provide an analysis of the reproducibility, accuracy, and robustness of the SRM-based proteomics platform. This information addresses important technical issues that could aid in the adoption of the targeted proteomics platform for practical clinical utility.

The objective of this manuscript is to report associations between baseline depressive severity and (1) baseline sociodemographic and clinical characteristics, (2) treatment outcomes, and (3) differential outcomes for three treatment groups. Six hundred and sixty-five outpatients with nonpsychotic, major depressive disorder were prospectively randomized to treatment with either a selective serotonin reuptake inhibitor (SSRI) monotherapy (escitalopram plus placebo) or one of two antidepressant medication combinations (bupropion-sustained release plus escitalopram, or venlafaxine-extended release plus mirtazapine). For purposes of these analyses, participants were divided into four groups based on baseline severity by the 16-item Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR16) total score: mild (0–10) [N=81], moderate (11–15) [N=238], severe (16–20) [N=260] and very severe (21–27) [N=67]. Treatment outcomes at 12 and 28 weeks were compared among the four severity groups. A history of childhood neglect and/or abuse was strongly associated with the severity of adult depression (1/2 of participants in the very severy group versus 1/5–1/4 of those in the mild group reported abuse and/or neglect). The degree of suicidality (e.g., 15/.4% of the very severe group ever attempted suicide versus none in the mild group), the number of suicide attempts (e.g., mean of .41 +/− 1.99 suicide attempts in the severe group versus o.o +/−0.0 in the mild group) and severity of suicidality (e.g., 9.2% of participants in very severe group had a plan or made a gesture versus 5.6% in moderate group and none in the mild group) were increased in more severe groups. Participants with a greater baseline depressive severity reported significantly more psychiatric comorbitities (e..g. [at p < 0.05] increased rates of agoraphobia, bulimia, generalized anxiety, hypocondriasis, panic disorder, post-traumatic stress disorder, social phobia and somatoform disorder, with 23.9 % of participants in the very severe group having reported four or more psychiatric disorders versus 1.2% of the mild group). Combination medication treatments were no more effective in treating severe depressions than was SSRI monotherapy. Remission (61.7% of participants in the mild group achieved remission versus 28.4% in the very severe group) is more difficult to achieve in more severe groups than is response (48.8% of participants in the mild group achieved response versus 58.2% in the very severe group) (p < 0.03) . These data may help us to understand the impact of baseline features on antidepressant medication effectiveness and to inform the personalization of depression treatment across the spectrum of depressive severity.

Objective

To compare response and remission rates in depressed patients with chronic treatment-resistant depression (TRD) treated with vagus nerve stimulation (VNS) Therapy® plus treatment as usual (VNS + TAU) or TAU alone in a meta-analysis using Bayesian hierarchical models.

Data sources and study selection

Six outpatient, multicenter, clinical trials that have evaluated VNS + TAU or TAU in TRD, including two single-arm studies of VNS + TAU (n = 60 and n = 74), a randomized study of VNS + TAU versus TAU (n = 235), a randomized study of VNS + TAU comparing different VNS stimulation intensities (n = 331), a nonrandomized registry of VNS + TAU versus TAU (n = 636), and a single-arm study of TAU (n = 124) to provide longer-term, control data for comparison with VNS-treated patients.

Data extraction

A systematic review of individual patient-level data based on the intent-to-treat principle, including all patients who contributed more than one post-baseline visit. Response was based on the Montgomery–Åsberg Depression Rating Scale (MADRS) and the Clinical Global Impressions scale’s Improvement subscale (CGI-I), as these were the two clinician-rated measures common across all or most studies. Remission was based on the MADRS.

Results

Outcomes were compared from baseline up to 96 weeks of treatment with VNS + TAU (n = 1035) versus TAU (n = 425). The MADRS response rate for VNS + TAU at 12, 24, 48, and 96 weeks were 12%, 18%, 28%, and 32% versus 4%, 7%, 12%, and 14% for TAU. The MADRS remission rate for VNS + TAU at 12, 24, 48, and 96 weeks were 3%, 5%, 10%, and 14% versus 1%, 1%, 2%, and 4%, for TAU. Adjunctive VNS Therapy was associated with a greater likelihood of response (odds ratio [OR] = 3.19, 95% confidence interval [CI]: 2.12, 4.66) and remission (OR = 4.99, CI: 2.93, 7.76), compared with TAU. For patients who had responded to VNS + TAU at 24 weeks, sustained response was more likely at 48 weeks (OR = 1.98, CI: 1.34, 3.01) and at 96 weeks (OR = 3.42, CI: 1.78, 7.31). Similar results were observed for CGI-I response.

Conclusion

For patients with chronic TRD, VNS + TAU has greater response and remission rates that are more likely to persist than TAU.

Background

The co-occurrence of substance use disorder (SUD) and major depressive disorder (MDD) is common and is often thought to impair response to antidepressant therapy. These patients are often excluded from clinical trials, resulting in a significant knowledge gap regarding optimal pharmacotherapy for the treatment of MDD with concurrent SUD.

Methods

In the Combining Medications to Enhance Depression Outcomes study, 665 adult outpatients with chronic and/or recurrent MDD were prospectively treated with either escitalopram monotherapy (escitalopram and placebo) or an antidepressant combination (venalfaxine-XR and mirtazapine or escitalopram and bupropion-SR). Participants with MDD and concurrent SUD (13.1%) were compared to those without SUD (86.9%) on sociodemographic and clinical characteristics at baseline and treatment response at 12-week and 28-week endpoints.

Results

The participants with MDD and SUD were more likely to be male and have current suicidal thoughts/plans, and had a greater lifetime severity and number of suicide attempts, and a higher number of concurrent Axis I disorders, particularly concurrent anxiety disorders. There were no significant differences between the MDD with or without SUD groups in terms of dose, time in treatment, response or remission at week 12 and 28. Furthermore, no significant differences in response or remission rates were noted between groups on the basis of the presence or absence of SUD and treatment assignment.

Conclusions

Although significant baseline sociodemographic and clinical differences exist, patients with MDD and concurrent SUD are as likely to respond and remit to a single or combination antidepressant treatment as those presenting without SUD.

Summary

Despite the diverse biological pathways known to be regulated by ubiquitylation, global identification of substrates that are targeted for ubiquitylation has remained a challenge. To globally characterize the ubiquitin-modified proteome (ubiquitinome), we utilized a monoclonal antibody that recognizes diglycine (diGly) containing isopeptides following trypsin digestion. We identify ~19,000 diGly modified lysine residues within ~ 5000 proteins. Using quantitative proteomics we monitored temporal changes in diGly site abundance in response to both proteasomal and translational inhibition indicating both a dependence of on-going translation to observe alterations in site abundance and distinct dynamics of individual modified lysines in response to proteasome inhibition. Further, we demonstrate that quantitative diGly proteomics can be utilized to identify substrates for cullin-RING ubiquitin ligases. Interrogation of the ubiquitinome allows for not only a quantitative assessment of alterations in protein homeostasis fidelity, but also identification of substrates for individual ubiquitin pathway enzymes.

The idea behind the marine cloud-brightening (MCB) geoengineering technique is that seeding marine stratocumulus clouds with copious quantities of roughly monodisperse sub-micrometre sea water particles might significantly enhance the cloud droplet number concentration, and thereby the cloud albedo and possibly longevity. This would produce a cooling, which general circulation model (GCM) computations suggest could—subject to satisfactory resolution of technical and scientific problems identified herein—have the capacity to balance global warming up to the carbon dioxide-doubling point. We describe herein an account of our recent research on a number of critical issues associated with MCB. This involves (i) GCM studies, which are our primary tools for evaluating globally the effectiveness of MCB, and assessing its climate impacts on rainfall amounts and distribution, and also polar sea-ice cover and thickness; (ii) high-resolution modelling of the effects of seeding on marine stratocumulus, which are required to understand the complex array of interacting processes involved in cloud brightening; (iii) microphysical modelling sensitivity studies, examining the influence of seeding amount, seed-particle salt-mass, air-mass characteristics, updraught speed and other parameters on cloud–albedo change; (iv) sea water spray-production techniques; (v) computational fluid dynamics studies of possible large-scale periodicities in Flettner rotors; and (vi) the planning of a three-stage limited-area field research experiment, with the primary objectives of technology testing and determining to what extent, if any, cloud albedo might be enhanced by seeding marine stratocumulus clouds on a spatial scale of around 100×100 km. We stress that there would be no justification for deployment of MCB unless it was clearly established that no significant adverse consequences would result. There would also need to be an international agreement firmly in favour of such action.

Objective

Maternal major depressive disorder is an established risk factor for child psychopathology. The authors previously reported that 1 year after initiation of treatment for maternal depression, children of mothers whose depression remitted had significantly improved functioning and psychiatric symptoms. This study extends these findings by examining changes in psychiatric symptoms, behavioral problems, and functioning among children of depressed mothers during the first year after the mothers' remission from depression.

Method

Children were assessed at baseline and at 3-month intervals with the Schedule for Affective Disorders and Schizophrenia for School-Age Children–Present and Lifetime Version, the Child Behavior Checklist, and the Children's Global Assessment Scale for 1 year after their mothers' remission or for 2 years if the mothers did not remit. The authors compared children of early remitters (0–3 months; N=36), late remitters (3–12 months; N=28), and nonremitters (N=16).

Results

During the postremission year, children of early-remitting mothers showed significant improvement on all outcomes. Externalizing behavioral problems decreased in children of early- and late-remitting mothers but increased in children of nonremitting mothers. Psychiatric symptoms decreased significantly only in children of mothers who remitted, and functioning improved only in children of early-remitting mothers.

Conclusions

Remission of mothers' depression, regardless of its timing, appears to be related to decreases in problem behaviors and symptoms in their children over the year after remission. The favorable effect of mothers' remission on children's functioning was observed only in children of early-remitting mothers.

Summary

Cullin Ring Ligases (CRLs) represent the largest E3 ubiquitin ligase family in eukaryotes and the identification of their substrates is critical to understanding regulation of the proteome. Using genetic and pharmacologic Cullin inactivation coupled with genetic (GPS) and proteomic (QUAINT) assays, we have identified hundreds of proteins whose stabilities or ubiquitylation status are regulated by CRLs. Together, these approaches yielded many known CRL substrates as well as a multitude of previously unknown putative substrates. One substrate, NUSAP1, we demonstrate is an SCFCyclin F substrate during S and G2 phases of the cell cycle and is also degraded in response to DNA damage. This collection of regulated substrates is highly enriched for nodes in protein interaction networks, representing critical connections between regulatory pathways. This demonstrates the broad role of CRL ubiquitylation in all aspects of cellular biology, and provides a set of proteins likely to be key indicators of cellular physiology.

Objective

Irritability is common during major depressive episodes, but its clinical significance and overlap with symptoms of anxiety or bipolar disorder remains unclear. We examined clinical correlates of irritability in a confirmatory cohort of Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study participants with major depressive disorder (MDD).

Method

Logistic regression was used to identify features associated with presence of irritability on the clinician-rated Inventory of Depressive Symptomatology.

Results

Of 2,307 study participants, 1067(46%) reported irritability at least half the time during the preceding week; they were more likely to be female, to be younger, to experience greater depression severity and anxiety, and to report poorer quality of life, prior suicide attempts, and suicidal ideation. Bipolar spectrum features were not more common among those with irritability.

Conclusion

Irritable depression is not a distinct subtype of MDD, but irritability is associated with greater overall severity, anxiety comorbidity, and suicidality.

Background

Despite the high co-occurrence between depression and asthma, few studies have addressed methods assessing the severity of depressive symptoms among patients with asthma.

Objective

To evaluate the psychometric properties of the Quick Inventory of Depressive Symptomatology–Self-report (QIDS-SR16), a 16-item measure of depressive symptom severity, in patients with asthma.

Methods

The psychometric properties of the QIDS-SR16 were compared at treatment exit with those of the 30-item self-report Inventory of Depressive Symptomatology (IDS-SR30) and the 17-item clinician-rated Hamilton Rating Scale for Depression (HRSD17) in 73 outpatients with asthma who were treated with citalopram or placebo for nonpsychotic major depressive disorder. Correlations between the depression rating scales and the Mini Asthma Quality of Life Questionnaire were calculated.

Results

Internal consistency at exit was strong for the QIDS-SR16 (Cronbach α values are .87 for the QIDS-SR16, .95 for the IDS-SR30, and .87 for the HRSD17). The QIDS-SR16 and HRSD17 total scores were highly correlated (r = 0.85), as were the QIDS-SR16 and IDS-SR30 total scores (r = 0.97). All QIDS-SR16 item total score correlations were significant (P < .001). The QIDS-SR16, IDS-SR30, and HRSD17 showed comparable sensitivity to symptom change, indicating high concurrent validity for all 3 scales. The total QIDS-SR16 baseline to exit change score demonstrated a significant negative correlation (r = −0.49, P < .001) with the Mini Asthma Quality of Life Questionnaire. Thus, greater depressive symptom severity was associated with lower asthma-related quality of life.

Conclusions

The QIDS-SR16 showed good reliability and impressive construct validity. Strong psychometric properties of this brief self-report format and its sensitivity to treatment change suggest that the QIDS-SR16 is a valuable clinical tool.

Dynamic reorganization of signaling systems frequently accompany pathway perturbations, yet quantitative studies of network remodeling by pathway stimuli are lacking. Here, we report the development of a quantitative proteomics platform centered on multiplex Absolute Quantification (AQUA) technology to elucidate the architecture of the cullin-RING ubiquitin ligase (CRL) network and to evaluate current models of dynamic CRL remodeling. Current models suggest that CRL complexes are controlled by cycles of CRL deneddylation and CAND1 binding. Contrary to expectations, acute CRL inhibition with MLN4924, an inhibitor of the NEDD8-activating enzyme, does not result in a global reorganization of the CRL network. Examination of CRL complex stoichiometry reveals that, independent of cullin neddylation, a large fraction of cullins are assembled with adaptor modules while only a small fraction are associated with CAND1. These studies suggest an alternative model of CRL dynamicity where the abundance of adaptor modules, rather than cycles of neddylation and CAND1 binding, drives CRL network organization.

Objective

The clinician-rated (QIDS-C16) and self-report (QIDS-SR16) versions of the 16-item Quick Inventory of Depressive Symptomatology have been extensively examined in adult populations. This study evaluated both versions of the QIDS and the 17-item Children’s Depressive Rating Scale-Revised (CDRS-R) in an adolescent outpatient sample.

Method

Both the QIDS-C16 and QIDS-SR16 were completed for the adolescents. Three different methods were used to complete the QIDS-C16: (a) adolescents’ responses to clinician interviews; (b) parents’ responses to clinician interview; and (c) a composite score using the most pathological response from the two interviews. Both classical and item response theory methods were used. Factor analyses evaluated the dimensionality of each scale.

Results

The sample included 140 adolescent outpatients. All versions of the QIDS, save the parent interview, and the CDRS-R were very reliable (α ≥ 0.8). All four versions of the QIDS are reasonably effective and unidimensional. The CDRS-R was clearly at least two-dimensional. The CDRS-R was the most discriminating among low and extremely high levels of depression. The QIDS-SR16 was the most discriminating at moderate levels of depression. There was no relation between the QIDS scores and concurrent Axis III comorbidities.

Conclusion

The QIDS-C16 and the QIDS-SR16 are suitable for use in adolescents.

Background

Depressive symptoms as assessed by self-report scales are present at a striking rate of 45% in Chronic Kidney Disease (CKD) patients at dialysis initiation. These scales may emphasize somatic symptoms of anorexia, sleep disturbance, and fatigue, which may co-exist with chronic disease symptoms and lead to an over-estimation of depression diagnosis. No studies have validated these scales in CKD patients prior to dialysis initiation.

Study Design

We conducted a diagnostic test study in CKD participants to investigate the screening characteristics of two depression self-report scales against a gold standard structured psychiatric interview.

Setting and Participants

272 consecutively recruited outpatients with Stages 2-5 CKD not treated by dialysis were studied.

Index Tests

The Beck Depression Inventory (BDI) and the 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16) depression screening scales were administered to all participants.

Reference Test

A structured Diagnostic and Statistical Manual of Mental Disorders IV-based interview, the Mini International Neuropsychiatric Interview, was administered by trained persons blinded to self-report scale scores.

Results

Fifty-seven (21%) of 272 had major depression by the reference test. The best cutoff scores by receiver/responder operating characteristic curves to identify a major depressive episode were 11 for BDI and 10 for QIDS-SR16. Sensitivities were 89%, 95% CI (78%, 96%) (BDI) and 91% (80%, 97%) (QIDS-SR16), while specificities were 88% (83%, 92%) (BDI) and 88% (83%, 92%) (QIDS-SR16). The positive and negative likelihood ratios for these cutoffs were 7.6 and 0.1 (BDI) and 7.5 and 0.1 (QIDS-SR16).

Limitations

Single-center study and a sample not representative of US demographics.

Conclusions

We found that a Beck Depression Inventory score of ≥11 was a sensitive and specific cutoff for identifying a major depressive episode in CKD patients not on dialysis. Both the Beck Depression Inventory and the Quick Inventory of Depressive Symptomatology-Self Report are effective screening tools.

Background

Depression is prevalent in long-term dialysis patients and is associated with death and hospitalization. Whether depression is present through all chronic kidney disease (CKD) stages or appears after dialysis therapy initiation is not clear. We determined the prevalence of a major depressive episode and other psychiatric illnesses by using a structured gold-standard clinical interview and demographic and clinical variables associated with major depressive episode in patients with CKD.

Study Design

Observational cross-sectional study using a Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition)-based structured interview administered by trained persons to 272 consecutive participants. Multivariable logistic regression was used to determine demographic and clinical variables associated with major depressive episode.

Setting & Participants

Patients with stages 2 to 5 CKD not treated by using dialysis were consecutively approached and enrolled from a Veterans Affairs CKD clinic.

Predictors

Demographic and clinical variables.

Outcome

Major depressive episode diagnosed by using a structured Diagnostic and Statistical Manual of Mental Disorders (Fourth Edition)-based interview, the Mini International Neuropsychiatric Interview.

Results

The cohort had a mean age of 64.5 ± 12.0 years. Thirty-eight percent were African American, and 55% had diabetes mellitus. Percentages of patients with stages 2, 3, 4, and 5 CKD were 6%, 38%, 41%, and 14%, respectively. Mean hemoglobin level was 12.5 ± 2.0 g/dL. The prevalence of a major depressive episode was 21% and did not vary significantly among different CKD stages. Variables associated with a major depressive episode were diabetes mellitus, comorbid psychiatric illness, and history of drug or alcohol abuse.

Limitations

Single-center study composed of primarily male veterans.

Conclusions

One in 5 patients with CKD had a major depressive episode. Patients with CKD should be screened routinely for depression given this high prevalence and the independent association of depression with poor outcomes in patients with end-stage renal disease receiving maintenance dialysis.

Receptor tyrosine kinases (RTKs) activate pathways mediated by serine/threonine (Ser/Thr) kinases such as the PI3K (phosphatidylinositol 3-kinase)-Akt pathway, the Ras-MAPK (mitogen-activated protein kinase)-RSK pathway, and the mTOR (mammalian target of rapamycin)-p70 S6 pathway that control important aspects of cell growth, proliferation, and survival. The Akt, RSK, and p70 S6 family of protein kinases transmit signals by phosphorylating substrates on a RxRxxS/T motif. Here, we developed a large-scale proteomic approach to identify over 200 substrates of this kinase family in cancer cell lines driven by the c-Met, epidermal growth factor receptor (EGFR), or platelet-derived growth factor receptor a (PDGFRα) RTKs. We identified a subset of proteins with RxRxxS/T sites for which phosphorylation was decreased by RTKIs as well as by inhibitors of the PI3K, mTOR, and MAPK pathways and determined the effects of siRNA directed against these substrates on cell viability. We found that phosphorylation of the protein chaperone SGTA (small glutamine-rich tetratricopeptide repeat-containing protein alpha) at Ser305 is essential for PDGFRα stabilization and cell survival in PDGFRα-dependent cancer cells. Our approach provides a new view of RTK and Akt-RSK-S6 kinase signaling, revealing many previously unidentified Akt-RSK-S6 kinase substrates that merit further consideration as targets for combination therapy with RTKIs.

Constitutive activation of one or more kinase signaling pathways is a hallmark of many cancers. Here we extend the previously described mass spectrometry–based KAYAK approach by monitoring kinase activities from multiple signaling pathways simultaneously. This improved single-reaction strategy, which quantifies the phosphorylation of 90 synthetic peptides in a single mass spectrometry run, is compatible with nanogram to microgram amounts of cell lysate. Furthermore, the approach enhances kinase monospecificity through substrate competition effects, faithfully reporting the signatures of many signaling pathways after mitogen stimulation or of basal pathway activation differences across a panel of well-studied cancer cell lines. Hierarchical clustering of activities from related experiments groups peptides phosphorylated by similar kinases together and, when combined with pathway alteration using pharmacological inhibitors, distinguishes underlying differences in potency, off-target effects and genetic backgrounds. Finally, we introduce a strategy to identify the kinase, and even associated protein complex members, responsible for phosphorylation events of interest.

Objective:

The purpose of this study was to determine whether there are differences in depression characteristics among premenopausal, perimenopausal, and postmenopausal women with major depressive disorder. This study also evaluated these differences between postmenopausal women with major depressive disorder who are taking and not taking hormone therapy.

Methods:

Analyses conducted with data from the Sequenced Treatment Alternatives to Relieve Depression study focused on female outpatients with non-psychotic major depressive disorder seeking treatment in 41 primary or psychiatric care settings across the United States. Baseline demographic and clinical characteristics were compared among women not taking hormone therapy who were premenopausal (N=950), perimenopausal (N=380), or postmenopausal (N=562). These comparisons were also made between postmenopausal women (n=768) taking (N=171) or not taking (N=562) hormone therapy.

Results:

After adjusting for sociodemographic and clinical baseline differences, premenopausal women were more likely to present with irritability than either peri- or postmenopausal women, and were more likely to have decreased appetite and less likely to have early morning insomnia than perimenopausal women. Postmenopausal women were more likely to have suicidal ideation and poorer physical functioning than either of the other groups, and were more likely to have sympathetic arousal and gastrointestinal symptoms than premenopausal women. After adjusting for baseline differences, postmenopausal women taking hormone therapy had better physical functioning, fewer melancholic features, less sympathetic arousal, and more lack of involvement in activities than women not taking hormone therapy.

Conclusions:

Menopausal status and postmenopausal use of hormone therapy may influence the clinical presentation of major depressive episodes in women.

Adverse events during selective serotonin reuptake inhibitor (SSRI) treatment are frequent and may lead to premature treatment discontinuation. If attrition is associated with early worsening of side effects or the frequency, intensity, or burden of side effects, interventions to maximize retention could be focused on patients with these events. Outpatient participants (n=265) with nonpsychotic major depressive disorder entered an 8-week trial with an SSRI. At baseline and week 2, specific side effects were evaluated with the Systematic Assessment for Treatment Emergent Events – Systematic Inquiry, and at week 2 the Frequency, Intensity, and Burden of Side Effects Rating globally assessed side effects. Attrition was defined by those participants who left treatment after week 2 but before week 8. No specific week 2 side effect, either treatment emergent or with worsening intensity, was independently associated with attrition. Global ratings of side effect frequency, intensity, or burden at week 2 were also not associated with subsequent attrition. Neither global ratings nor specific side effects at week 2 were related to patient attrition during SSRI treatment. Other factors appear to contribute to patient decisions about continuing with treatment.

Objective

Presymptomatic individuals with the Huntingtin (HTT) CAG expansion mutation that causes Huntington’s disease may have higher levels of depressive symptoms than healthy comparison populations. However, the prevalence of HTT CAG repeat expansions among individuals diagnosed with major depressive disorder has not been established.

Method

This was a case-control genetic association study of HTT CAG allele size in two discovery cohorts of individuals with major depressive disorder and comparison subjects without major depression as well as a replication cohort of individuals with major depression and comparison subjects without major depression.

Results

CAG repeat lengths of 36 or greater were observed in six of 3,054 chromosomes from individuals with major depression, compared with none of 4,155 chromosomes from comparison subjects. In a third cohort, one expanded allele was observed among 1,202 chromosomes in the major depression group, compared with none of 2,678 chromosomes in comparison subjects. No clear pattern of clinical features was shared among individuals with the expanded repeats.

Conclusions

In clinical populations of individuals diagnosed with major depression, approximately 3 in 1,000 carried expanded HTT CAG alleles.

Intramolecular transfer of phosphate during collision-induced dissociation (CID) in ion trap mass spectrometers has recently been described. Because phosphorylation events are assigned to discrete serine, threonine, and tyrosine residues based on the presence of site-determining ions in MS/MS spectra, phosphate transfer may invalidate or confound site localization in published large-scale phosphorylation data sets. Here, we present evidence for the occurrence of this phenomenon using synthetic phosphopeptide libraries, specifically for doubly-charged species. We found, however, that the extent of the transfer reaction was insufficient to cause localization of phosphorylation sites to incorrect residues. We further compared CID to electron-transfer dissociation (ETD) for site localization using synthetic libraries and a large-scale yeast phosphoproteome experiment. The agreement in site localization was >99.5 and 93%, respectively, suggesting that ETD-based site localization is no more reliable than CID. We conclude that intramolecular phosphate transfer does not affect the reliability of current or past phosphorylation data sets.

Activating mutations of FMS-like tyrosine kinase-3 (FLT3) are found in approximately 30% of patients with acute myeloid leukemia (AML). FLT3 is therefore an attractive drug target. However, the molecular mechanisms by which FLT3 mutations lead to cell transformation in AML remain unclear. To develop a better understanding of FLT3 signaling as well as its downstream effectors, we performed detailed phosphoproteomic analysis of FLT3 signaling in human leukemia cells. We identified over 1000 tyrosine phosphorylation sites from about 750 proteins in both AML (wild type and mutant FLT3) and B cell acute lymphoblastic leukemia (normal and amplification of FLT3) cell lines. Furthermore, using stable isotope labeling by amino acids in cell culture (SILAC), we were able to quantified over 400 phosphorylation sites (pTyr, pSer, and pThr) that were responsive to FLT3 inhibition in FLT3 driven human leukemia cell lines. We also extended this phosphoproteomic analysis on bone marrow from primary AML patient samples, and identify over 200 tyrosine and 800 serine/threonine phosphorylation sites in vivo. This study showed that oncogenic FLT3 regulates proteins involving diverse cellular processes and affects multiple signaling pathways in human leukemia that we previously appreciated, such as Fc epsilon RI-mediated signaling, BCR, and CD40 signaling pathways. It provides a valuable resource for investigation of oncogenic FLT3 signaling in human leukemia.

Background

Alcohol dependence is extremely common in patients with bipolar disorder and is associated with unfavorable outcomes including treatment non-adherence, violence, increased hospitalization and decreased quality of life. While naltrexone is a standard treatment for alcohol dependence, no controlled trials have examined its use in patients with co-morbid bipolar disorder and alcohol dependence. In this pilot study, the efficacy of naltrexone in reducing alcohol use and on mood symptoms was assessed in bipolar disorder and alcohol dependence.

Methods

Fifty adult outpatients with bipolar I or II disorders and current alcohol dependence with active alcohol use were randomized to 12 weeks of naltrexone (50 mg/day) add-on therapy or placebo. Both groups received manual-driven cognitive behavioral therapy designed for patients with bipolar disorder and substance-use disorders. Drinking days and heavy drinking days, alcohol craving, liver enzymes, and manic and depressed mood symptoms were assessed.

Results

The two groups were similar in baseline and demographic characteristics. Naltrexone showed trends (p < .10) toward a greater decrease in drinking days (binary outcome), alcohol craving, and some liver enzyme levels than placebo. Side effects were similar in the two groups. Response to naltrexone was significantly related to medication adherence.

Conclusions

Results suggest the potential value and acceptable tolerability of naltrexone for alcohol dependence in bipolar disorder patients. A larger trial is needed to establish efficacy.

Irritability is a diagnostic symptom of child-adolescent but not adult major depressive disorder (MDD) in both the DSM-IV and ICD-10 systems. We explore the importance of irritability for sub-typing adult DSM-IV MDD in the National Comorbidity Survey Replication (NCS-R), a national US adult household survey. The WHO Composite International Diagnostic Interview (CIDI) was used to assess prevalence of many DSM-IV disorders in the lifetime and in the year before interview (12-month prevalence). MDD was assessed conventionally (i.e., requiring either persistent sadness or loss of interest), but with irritability included as one of the Criterion A symptoms. We also considered the possibility that irritability might be a diagnostic symptom of adult MDD (i.e., detect cases who had neither sad mood nor loss of interest). Twelve-month MDD symptom severity was assessed with the Quick Inventory of Depressive Symptomatology and role impairment with the Sheehan Disability Scale. After excluding bipolar spectrum disorders, irritability during depressive episodes was reported by roughly half of respondents with lifetime DSM-IV MDD. Irritability in the absence of either sad mood or loss of interest, in comparison, was rare. Irritability in MDD was associated with early age-of-onset, lifetime persistence, comorbidity with anxiety and impulse-control disorders, fatigue and self-reproach during episodes, and disability. Irritability was especially common in MDD among respondents in the age range 18–44 and students. Further investigation is warranted of distinct family aggregation, risk factors, and treatment response. Consideration should also be given to including irritability as a non-diagnostic symptom of adult MDD in DSM-V and ICD-11.

Cholangiocarcinoma, also known as bile duct cancer, is the second most common primary hepatic carcinoma with a median survival of less than 2 years. The molecular mechanisms underlying the development of this disease are not clear. To survey activated tyrosine kinases signaling in cholangiocarcinoma, we employed immunoaffinity profiling coupled to mass spectrometry and identified DDR1, EPHA2, EGFR, and ROS tyrosine kinases, along with over 1,000 tyrosine phosphorylation sites from about 750 different proteins in primary cholangiocarcinoma patients. Furthermore, we confirmed the presence of ROS kinase fusions in 8.7% (2 out of 23) of cholangiocarcinoma patients. Expression of the ROS fusions in 3T3 cells confers transforming ability both in vitro and in vivo, and is responsive to its kinase inhibitor. Our data demonstrate that ROS kinase is a promising candidate for a therapeutic target and for a diagnostic molecular marker in cholangiocarcinoma. The identification of ROS tyrosine kinase fusions in cholangiocarcinoma, along with the presence of other ROS kinase fusions in lung cancer and glioblastoma, suggests that a more broadly based screen for activated ROS kinase in cancer is warranted.

Background

Clinically useful treatment moderators of Major Depressive Disorder (MDD) have not yet been identified, though some baseline predictors of treatment outcome have been proposed. The aim of iSPOT-D is to identify pretreatment measures that predict or moderate MDD treatment response or remission to escitalopram, sertraline or venlafaxine; and develop a model that incorporates multiple predictors and moderators.

Methods/Design

The International Study to Predict Optimized Treatment - in Depression (iSPOT-D) is a multi-centre, international, randomized, prospective, open-label trial. It is enrolling 2016 MDD outpatients (ages 18-65) from primary or specialty care practices (672 per treatment arm; 672 age-, sex- and education-matched healthy controls). Study-eligible patients are antidepressant medication (ADM) naïve or willing to undergo a one-week wash-out of any non-protocol ADM, and cannot have had an inadequate response to protocol ADM. Baseline assessments include symptoms; distress; daily function; cognitive performance; electroencephalogram and event-related potentials; heart rate and genetic measures. A subset of these baseline assessments are repeated after eight weeks of treatment. Outcomes include the 17-item Hamilton Rating Scale for Depression (primary) and self-reported depressive symptoms, social functioning, quality of life, emotional regulation, and side-effect burden (secondary). Participants may then enter a naturalistic telephone follow-up at weeks 12, 16, 24 and 52. The first half of the sample will be used to identify potential predictors and moderators, and the second half to replicate and confirm.

Discussion

First enrolment was in December 2008, and is ongoing. iSPOT-D evaluates clinical and biological predictors of treatment response in the largest known sample of MDD collected worldwide.

Trial registration

International Study to Predict Optimised Treatment - in Depression (iSPOT-D) ClinicalTrials.gov Identifier: NCT00693849

URL: http://clinicaltrials.gov/ct2/show/NCT00693849?term=International+Study+to+Predict+Optimized+Treatment+for+Depression&rank=1