Intermittent treatment of BRAFV600E melanoma cells delays resistance by adaptive resensitization to drug rechallenge.

Patients with melanoma receiving drugs targeting BRAFV600E and mitogen-activated protein (MAP) kinase kinases 1 and 2 (MEK1/2) invariably develop resistance and face continued progression. Based on preclinical studies, intermittent treatment involving alternating periods of drug withdrawal and rechallenge has been proposed as a method to delay the onset of resistance. The beneficial effect of intermittent treatment has been attributed to drug addiction, where drug withdrawal reduces the viability of resistant cells due to MAP kinase pathway hyperactivation. However, the mechanistic basis of the intermittent effect is incompletely understood. We show that intermittent treatment with the BRAFV600E inhibitor, LGX818/encorafenib, suppresses growth compared with continuous treatment in human melanoma cells engineered to express BRAFV600E, p61-BRAFV600E, or MEK2C125 oncogenes. Analysis of the BRAFV600E-overexpressing cells shows that, while drug addiction clearly occurs, it fails to account for the advantageous effect of intermittent treatment. Instead, growth suppression is best explained by resensitization during periods of drug removal, followed by cell death after drug readdition. Continuous treatment leads to transcriptional responses prominently associated with chemoresistance in melanoma. By contrast, cells treated intermittently reveal a subset of transcripts that reverse expression between successive cycles of drug removal and rechallenge and include mediators of cell invasiveness and the epithelial-to-mesenchymal transition. These transcripts change during periods of drug removal by adaptive switching, rather than selection pressure. Resensitization occurs against a background of sustained expression of melanoma resistance genes, producing a transcriptome distinct from that of the initial drug-naive cell state. We conclude that phenotypic plasticity leading to drug resensitization can underlie the beneficial effect of intermittent treatment.

Implementation of the "Healthy Moms, Healthy Kids" Program in Head Start: An Application of the RE-AIM QuEST Framework Centering Equity.

BACKGROUND: Marginalized mothers are disproportionately impacted by depression and face barriers in accessing mental health treatment. Recent efforts have focused on building capacity to address maternal depression in Head Start; however, it is unclear if mental health inequities can be addressed by two-generation programs in Head Start settings. Therefore, this study examined the implementation outcomes and processes of a two-generation program called "Healthy Moms, Healthy Kids" (HMHK) that provided an evidence-based depression treatment to ethnic minority Head Start mothers. METHOD: Quantitative and qualitative data were collected and merged in a convergent mixed method design in accordance with the RE-AIM Qualitative Evaluation for Systematic Translation (RE-AIM QuEST) framework. Qualitative data included interviews with 52 key stakeholders, including intervention participants and staff members, and 176 sets of meeting minutes from the implementation period. Quantitative data included intervention study data and administrative data. RESULTS: It was difficult for HMHK to reach the target population, with only 16.8% of eligible mothers choosing to participate. However, mothers who participated experienced reductions in depressive symptoms and parenting stress and shared a variety of positive impacts in interviews. The program was also more successful in enrolling Latinx mothers who were Spanish-speaking or bilingual rather than English-speaking and Black/African American mothers, limiting its reach. CONCLUSION: Providing IPT therapy groups was effective in reducing maternal depressive symptoms and stress for those who enrolled, but additional work should focus on reducing barriers to participation, considering other delivery models to meet participants' needs, and identifying culturally relevant ways to meet the needs of Black mothers.

Specificity of Phosphorylation Responses to Mitogen Activated Protein (MAP) Kinase Pathway Inhibitors in Melanoma Cells.

The BRAF-MKK1/2-ERK1/2 pathway is constitutively activated in response to oncogenic mutations of BRAF in many cancer types, including melanoma. Although small molecules that inhibit oncogenic BRAF and MAP kinase kinase (MKK)1/2 have been successful in clinical settings, resistance invariably develops. High affinity inhibitors of ERK1/2 have been shown in preclinical studies to bypass the resistance of melanoma and colon cancer cells to BRAF and MKK1/2 inhibitors, and are thus promising additions to current treatment protocols. But still unknown is how molecular responses to ERK1/2 inhibitors compare with inhibitors currently in clinical use. Here, we employ quantitative phosphoproteomics to evaluate changes in phosphorylation in response to the ERK inhibitors, SCH772984 and GDC0994, and compare these to the clinically used MKK1/2 inhibitor, trametinib. Combined with previous studies measuring phosphoproteomic responses to the MKK1/2 inhibitor, selumetinib, and the BRAF inhibitor, vemurafenib, the outcomes reveal key insights into pathway organization, phosphorylation specificity and off-target effects of these inhibitors. The results demonstrate linearity in signaling from BRAF to MKK1/2 and from MKK1/2 to ERK1/2. They identify likely targets of direct phosphorylation by ERK1/2, as well as inhibitor off-targets, including an off-target regulation of the p38α mitogen activated protein kinase (MAPK) pathway by the MKK1/2 inhibitor, trametinib, at concentrations used in the literature but higher than in vivo drug concentrations. In addition, several known phosphorylation targets of ERK1/2 are insensitive to MKK or ERK inhibitors, revealing variability in canonical pathway responses between different cell systems. By comparing multiple inhibitors targeted to multiple tiers of protein kinases in the MAPK pathway, we gain insight into regulation and new targets of the oncogenic BRAF driver pathway in cancer cells, and a useful approach for evaluating the specificity of drugs and drug candidates.

A New Community-Based Model for Training in Evidence-Based Psychotherapy Practice.

It is critical that evidence-based practices (EBP's) be provided to patients. Efforts to train clinicians in the community in EBP's, however, has been hindered by a lack of resources and rigid and resource intensive models of training. We describe efforts to overcome these barriers in a large scale community-based training program for Interpersonal Psychotherapy implemented with over 1400 clinicians in Los Angeles working within the Los Angeles County Department of Mental Health public system of care. The program, described in detail, is a potential template for training for community-based clinicians in evidence-based psychotherapy practices.

Misleading signs in acute vertigo.

The acute vestibular syndrome is common and usually has a benign cause. Sometimes, however, even experienced neurologists can find it difficult to determine the cause clinically. Furthermore, neuroimaging is known to be insensitive.We describe two cases of acute vestibular syndrome where conflicting clinical findings contributed to a delay in making the correct diagnosis. The first patient with symptomatic vertigo had signs consistent with horizontal benign paroxysmal positional vertigo but also had an abnormal horizontal head impulse test, superficially suggesting acute vestibular neuritis but later accounted for by the finding of a vestibular schwannoma (acoustic neuroma). The second patient also had an abnormal horizontal head impulse test, with skew deviation suggesting stroke as the cause. However, later assessment identified that a long-standing fourth nerve palsy was the true cause for her apparent skew. We discuss potential errors that can arise when assessing such patients and highlight ways to avoid them.

A Phosphoproteomic Comparison of B-RAFV600E and MKK1/2 Inhibitors in Melanoma Cells.

Inhibitors of oncogenic B-RAF(V600E) and MKK1/2 have yielded remarkable responses in B-RAF(V600E)-positive melanoma patients. However, the efficacy of these inhibitors is limited by the inevitable onset of resistance. Despite the fact that these inhibitors target the same pathway, combination treatment with B-RAF(V600E) and MKK1/2 inhibitors has been shown to improve both response rates and progression-free survival in B-RAF(V600E) melanoma patients. To provide insight into the molecular nature of the combinatorial response, we used quantitative mass spectrometry to characterize the inhibitor-dependent phosphoproteome of human melanoma cells treated with the B-RAF(V600E) inhibitor PLX4032 (vemurafenib) or the MKK1/2 inhibitor AZD6244 (selumetinib). In three replicate experiments, we quantified changes at a total of 23,986 phosphosites on 4784 proteins. This included 1317 phosphosites that reproducibly decreased in response to at least one inhibitor. Phosphosites that responded to both inhibitors grouped into networks that included the nuclear pore complex, growth factor signaling, and transcriptional regulators. Although the majority of phosphosites were responsive to both inhibitors, we identified 16 sites that decreased only in response to PLX4032, suggesting rare instances where oncogenic B-RAF signaling occurs in an MKK1/2-independent manner. Only two phosphosites were identified that appeared to be uniquely responsive to AZD6244. When cells were treated with the combination of AZD6244 and PLX4032 at subsaturating concentrations (30 nm), responses at nearly all phosphosites were additive. We conclude that AZD6244 does not substantially widen the range of phosphosites inhibited by PLX4032 and that the benefit of the drug combination is best explained by their additive effects on suppressing ERK1/2 signaling. Comparison of our results to another recent ERK1/2 phosphoproteomics study revealed a surprising degree of variability in the sensitivity of phosphosites to MKK1/2 inhibitors in human cell lines, revealing unexpected cell specificity in the molecular responses to pathway activation.

The comorbidity of Axis I disorders in depressed pregnant women.

Depression during pregnancy is highly prevalent and is associated with increased risk of a variety of negative psychological and medical outcomes in both mothers and offspring. Antenatal depression often co-occurs with significant anxiety, potentially exacerbating morbidities for women and their children. However, screening during the antenatal period is frequently limited to assessment of depression so that other significant comorbid disorders may be missed. Follow-up assessment by clinicians has similarly focused primarily on detection of depressive symptoms. Anxiety, obsessive compulsive disorder, and post-traumatic stress disorder, among others, often go undetected in perinatal care settings, even when depression is identified. Failing to recognize these comorbid diagnoses may lead to inadequate treatment or only partial alleviation of distress. Consequently, screening for and assessment of comorbid disorders is warranted. In this study, 382 pregnant women (M age = 25.8 [SD = 5.3] years, 85.0% Caucasian) receiving care at a university hospital clinic and Maternal Mental Health Care centers in eastern Iowa and who screened positive for depression on the Beck Depression Inventory completed the Structured Clinical Interview for DSM-IV to assess comorbid mental health symptoms and diagnoses. Overall, findings demonstrate high rates of anxiety disorders among women both with and without current major depression, although depressed women reported higher rates of generalized anxiety disorder and post-traumatic stress disorder. Notably, however, incidence-specific symptoms were comparable across groups. Routine screening of both anxiety and depression during pregnancy should be conducted.

Erratum to: Less depressed or less forthcoming? Self-report of depression symptoms in women preparing for in vitro fertilization.

Erratum to: Arch Womens Ment Health (2013) 16:87­92 DOI 10.1007/s00737-012-0317-8. The original version of this article unfortunately missed the Acknowledgment which is stated below: "This work was partially supported by a grant from the NICHD (K12-HD063117)."

Perinatal depression: an update and overview.

Over the last 3 years there have been notable developments in the screening and treatment of perinatal depression. Most importantly, the DSM-V has made only minor changes in the diagnostic criteria for perinatal depression as compared to the DSM-IV; "perinatal," as opposed to "postpartum," is a specifier for depression with a requirement that the depression onset occurs during pregnancy or the first 4 weeks postpartum. Advances in the treatment of perinatal depression have been made over the last 3 years, including both prevention and acute interventions. Additional support has emerged confirming the primary risk factors for perinatal depression: a personal or family history, low SES and poor interpersonal support. There is general agreement that universal screening be conducted for all perinatal women, by both the woman's obstetrician and the baby's pediatrician.

Risk factors for depressive symptoms in adolescent pregnancy in a late-teen subsample.

Depression in adolescent pregnancy is common but underrecognized and can be associated with negative medical outcomes. This brief report examines the relationship between depressive symptoms and various demographic and obstetrical risk factors, as well as the use of antidepressants in pregnant adolescents of late teenage years. Data were derived from a relatively large sample (506 women) recruited from university-based and community mental health centers in Iowa. A cross-sectional analysis did not reveal significant statistical associations between the risk factors and depressive symptoms (Beck Depression Inventory). Antidepressant use was very low (3.7 %), and adolescents with higher depression scores were more likely to take medications. In conclusion, screening for depression in pregnant adolescents should be universal, regardless of demographic and obstetrical risk factors, and promptly addressed.

Less depressed or less forthcoming? Self-report of depression symptoms in women preparing for in vitro fertilization.

While depression has been associated with infertility treatments, it is not routinely assessed in women prior to undergoing in vitro fertilization (IVF) treatment. Findings are mixed regarding the degree to which women report depression prior to IVF. The purpose of this study was to (1) examine response profiles in women preparing for IVF and (2) compare responses to those of postpartum, primary care, and general population groups. Female IVF patients (n = 321; 19-45 years) completed the Patient Health Questionnaire-9 (PHQ-9) at their first visit. Clinical and demographic characteristics and incidence of major depressive disorder (MDD) and other depressive disorders (ODD) were examined. Overall score distributions of the IVF group were compared to those of local postpartum patients and published primary care and general populations. Demographic or clinical characteristics did not account for response differences within the IVF group. The IVF group had lower incidences of MDD and ODD than a PHQ-9 normative group. Women in the IVF group reported no depressive symptoms significantly more than postpartum, primary care, and general population groups. Women preparing to undergo IVF report fewer symptoms of depression than multiple comparison groups. Specific quality of life measures may be needed to assess distress in this population.

Analysis of brief screening tools for the detection of postpartum depression: comparisons of the PRAMS 6-item instrument, PHQ-9, and structured interviews.

Postpartum depression (PPD) is an important mental health issue affecting approximately 10 % of women. Self-report screening measures represent utility for detecting PPD in both clinical and research settings. The current study sought to inspect the accuracy of two screening measures compared to clinical interviews. As part of an ongoing clinical trial, 1,392 women between the ages of 18 and 45 were screened for PPD using the Patient Health Questionnaire-9 (PHQ-9) and a six-item scale developed from CDC Pregnancy Risk Assessment questions (PRAMS-6). Three item subscales of the PRAMS-6 were also inspected-three depression (PRAMS-3D) and three anxiety items (PRAMS-3A). Receiver operating characteristics compared the diagnostic accuracy of the PHQ-9, PRAMS-6, PRAMS-3D, and PRAMS-3A to both the Structured Clinical Interview for the DSM-IV (SCID) and the Hamilton Rating Scale for Depression. The PHQ-9, PRAMS-6, and PRAMS-3D all showed moderate accuracy at diagnosing PPD. Diagnostic cut points are provided. The PRAMS-6 instrument is a brief and effective screening tool for PPD. The time frame of symptom assessment may account for some variability in accuracy between the PHQ-9 and PRAMS screening instruments.

Examination of premenstrual symptoms as a risk factor for depression in postpartum women.

Postpartum depression (PPD) is a significant public health concern with prevalence of major and minor depressions reaching 20 % in the first three postpartum months. Sociodemographic and psychopathology correlates of PPD are well established; however, information on the relationship between premenstrual disorders and the development of PPD is less well established. Thus, the aim of this study was to examine the role of premenstrual syndrome (PMS)/premenstrual dysphoric disorder (PMDD) as a risk factor for PPD. Premenstrual symptoms were assessed retrospectively using the premenstrual symptoms screening tool (PSST) and depression was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) criteria and assessed using the Hamilton Depression Rating Scale (HDRS). A two-stage screening procedure was applied. In the first stage, the Patient Health Questionnaire (PHQ-9) was employed. In the second stage, women endorsing ≥5 symptoms on the PHQ-9 were administered the Structured Clinical Interview for DSM-IV, HDRS, and PSST. Hierarchical linear regression showed that history of depression and PMS/PMDD contributed an additional 2 % of the variance (p < 0.001), beyond that of sociodemographic factor effects. The full model accounted for 13 % of the variance in postpartum depressive symptoms. Using logistic regression, a significant association also emerged between PMS/PMDD and PPD (OR = 1.97). The findings of this study suggest that PMS/PMDD is an important risk factor for PPD. Women endorsing a history of PMS/PMDD should be monitored during the perinatal period.

MomMoodBooster web-based intervention for postpartum depression: feasibility trial results.

BACKGROUND: Postpartum depression (PPD)-the most common complication of childbirth-is a significant and prevalent public health problem that severely disrupts family interactions and can result in serious lasting consequences to the health of women and the healthy development of infants. These consequences increase in severity when left untreated; most women with PPD do not obtain help due to a range of logistical and attitudinal barriers. OBJECTIVE: This pilot study was designed to test the feasibility, acceptability, and potential efficacy of an innovative and interactive guided Web-based intervention for postpartum depression, MomMoodBooster (MMB). METHODS: A sample of 53 women who satisfied eligibility criteria (<9 months postpartum, ≥18 years of age, home Internet access and use of personal email, Edinburgh Postnatal Depression Survey score of 12-20 or Patient Health Questionnaire score from 10-19) were invited to use the MMB program. Assessments occurred at screening/pretest, posttest (3 months following enrollment), and at 6 months follow-up. RESULTS: All six sessions of the program were completed by 87% (46/53) of participants. Participants were engaged with the program: visit days (mean 15.2, SD 8.7), number of visits (mean 20.1, SD 12.2), total duration of visits in hours (mean 5.1, SD 1.3), and number of sessions viewed out of six (mean 5.6, SD 1.3) all support high usage. Posttest data were collected from 89% of participants (47/53) and 6-month follow-up data were collected from 87% of participants (46/53). At pretest, 55% (29/53) of participants met PHQ-9 criteria for minor or major depression. At posttest, 90% (26/29) no longer met criteria. CONCLUSIONS: These findings support the expanded use and additional testing of the MMB program, including its implementation in a range of clinical and public health settings.

Collaborative decision making improves interpersonal psychotherapy efficiency: A randomized clinical trial with postpartum women.

Background: Randomized controlled trials of Interpersonal Psychotherapy (IPT) and other psychotherapies for depression have required strict adherence to protocol and do not allow for clinical judgment in deciding frequency of sessions. To determine if such protocols were more effective than allowing therapists to use their clinical judgment, we compared "Clinician-Managed" IPT (CM-IPT), in which clinicians and patients with postpartum depression were allotted 12 sessions and determined collaboratively when to use them, to a once weekly 12 session protocol ("Standard IPT"). We hypothesized that CM-IPT would be more efficient, requiring fewer sessions to reach an equivalent acute outcome, and that CM-IPT would be superior over 12 months because "saved" sessions could be used for maintenance treatment. Method: We conducted a clinical trial including 140 postpartum outpatients with DSM-IV major depression who were randomly assigned to "Standard" IPT (N= 69) or CM-IPT (N= 71). Results: Both CM-IPT and S-IPT were highly efficacious with similar outcomes by 12 weeks but CM-IPT group utilized significantly fewer sessions. Both were superior to a waitlist control. Superiority comparisons at 12 months did not favor the CM-IPT condition. Limitations: Results should be replicated in a more diverse sample to increase generalizability. Conclusions: CM-IPT is more efficient in treating acute depression than mandated weekly IPT. Further, permitting clinicians and patients to use their collaborative judgment is likely to be a more efficient and effective way to conduct future research and to implement evidence-based psychotherapy in the community.

Interpersonal psychotherapy for postpartum depression.

Perinatal depression is prevalent and has a great impact on both mother and infant. There are empirically validated treatments for both postpartum depression and depression during pregnancy. Primary among these is Interpersonal Psychotherapy, which has been shown to be effective for postpartum women across the spectrum from mild to severe depression. At present, Interpersonal Psychotherapy is the best validated treatment for postpartum depression and should be considered first-line treatment, especially for depressed breastfeeding women.

Feasibility and Acceptability of Internet-Based Interpersonal Psychotherapy for Stress, Anxiety, and Depression in Prenatal Women: Thematic Analysis.

BACKGROUND: Prenatal mental health is a global health concern. Despite the far-reaching impact of prenatal mental health issues, many women do not receive the psychological care they require. Women in their childbearing years are frequent users of the internet and smartphone apps. Prenatal women are prime candidates for internet-based support for mental health care. OBJECTIVE: This study aimed to examine the feasibility and acceptability of internet-based interpersonal psychotherapy (IPT) for prenatal women. METHODS: Semistructured interviews were conducted with women who had received internet-based IPT modules with guided support as a component of a randomized controlled trial evaluating the scale-up implementation of a digital mental health platform (The Healthy Outcomes of Pregnancy and Postpartum Experiences digital platform) for pregnant women. Qualitative thematic analysis was used to explore and describe women's experiences. Data were analyzed for emerging themes, which were identified and coded. RESULTS: A total of 15 prenatal women were interviewed to examine their experiences and views on the feasibility and acceptability of internet-based IPT modules. Participants found the content informative and appreciated the ways in which the digital mental health platform made the IPT modules accessible to users. Participants voiced some differing requirements regarding the depth and the way information was presented and accessed on the digital mental health platform. The important areas for improvement that were identified were acknowledging greater depth and clarity of content, the need for sociability and relationships, and refinement of the digital mental health platform to a smartphone app. CONCLUSIONS: This study provides useful evidence regarding treatment format and content preferences, which may inform future development. It also provides research data on the feasibility and acceptability of web-based applications for prenatal mental health care. TRIAL REGISTRATION: ClinicalTrials.gov NCT01901796; https://clinicaltrials.gov/ct2/show/NCT01901796.

Implementation of Group Interpersonal Psychotherapy in primary care.

OBJECTIVE: To show the implementation process of IPT-G in primary care, including facilitating and obstructing factors, implementation strategies, and training and supervision of primary care professionals. METHODS: Quantitative (cross-sectional and longitudinal) analysis of pre and post-knowledge tests; qualitative analyses of the training courses; patient recruitment; conduction of IPT-G sessions; supervision of IPT-G therapists; application of a semi-structured questionnaire to assess, investigate, and develop strategies against the identified barriers. RESULTS: About 120 clinicians answered the pre-test; 84 completed the post-test. Pre- and post-test scores of IPT-G knowledge were significantly different. Twenty initially trained clinicians completed additional supervision in IPT-G. Qualitative analysis identified twelve barriers and six facilitators to IPT-G implementation in individual, organizational, and systemic contexts. CONCLUSIONS: Implementation of IPT-G in primary care is a complex process with several steps. In the first step, health professionals were successfully trained in IPT-G. However, subsequent steps were more complex. Therefore, careful planning of IPT-G implementation is essential to maximize the success of this innovation.

Effects of continuity of care and patient dispositional factors on the physician-patient relationship.

BACKGROUND: We developed a questionnaire to examine the influence of physician and patient variables on the quality of the physician-patient relationship. METHODS: More than 300 family medicine patients completed self-report measures of the physician-patient relationship and variables likely to influence it. RESULTS: The quality of relationship was related to continuity of physician care (having a primary physician, duration of that relationship, and frequency of visits) and to patient dispositional variables (neuroticism, positive and negative affectivity) but not to demographic variables. The regression model included having a primary physician, duration of relationship with that physician, and positive affectivity. Relationship quality was, in turn, associated with outcomes (adherence to care, treatment response, satisfaction with care, and commitment to physician). CONCLUSIONS: The quality of physician-patient relationship is influenced by physician continuity and patient dispositional variables. Better understanding of these may contribute to the therapeutic potential of this important relationship.

Risk factors for depressive symptoms during pregnancy.

The present study examined risk factors for depression during pregnancy in a very large population sample. Two research questions have been addressed: first, the association between demographic factors and past negative obstetrical outcomes on depression severity scores, and second, the differences in these factors between women recruited at a university medical center and maternal health centers (MHC). The study included more than 5,000 pregnant women attending regular appointments at the University Obstetrics and Gynecology Clinic or at several MHCs in Eastern Iowa. Participants completed a Beck depression inventory (BDI) and a demographic questionnaire. We performed a statistical analysis on the association between risk factors and depression severity scores. Regression analysis revealed that week of pregnancy, site of recruitment, years of education, income, marital status, employment, and number of miscarriages and stillbirths were significant predictors of total BDI score. Compared to their university counterparts, participants at MHCs had more depressive symptoms, were younger, mostly single, and had lower socioeconomic status and more past negative obstetrical outcomes. Our study can inform providers about some of the risk factors during depression screening in pregnancy to increase diagnostic vigilance and tailor the level of prenatal care accordingly.