Adherence and forgiveness of two modern ART regimens: lamivudine/dolutegravir and emtricitabine/tenofovir alafenamide/rilpivirine.

Introduction: Few data are available about the forgiveness of two-drug (2DR) or low-barrier three-drug antiretroviral regimens. The aim of this study is to evaluate the real-life forgiveness of lamivudine/dolutegravir (3TC/DTG) and emtricitabine/tenofovir alafenamide/rilpivirine (FTC/TAF/RPV).

Methods: A two center retrospective observational study enrolled all people with HIV (PWH) treated with 3TC/DTG or FTC/TAF/RPV.

Fragment-Based Interrogation of the 14-3-3/TAZ Protein-Protein Interaction.

The identification of chemical starting points for the development of molecular glues is challenging. Here, we employed fragment screening and identified an allosteric stabilizer of the complex between 14-3-3 and a TAZ-derived peptide. The fragment binds preferentially to the 14-3-3/TAZ peptide complex and shows moderate stabilization in differential scanning fluorimetry and microscale thermophoresis.

B/F/TAF forgiveness to non-adherence.

: Background : ART forgiveness is the ability of a regimen to maintain HIV-RNA suppression despite a documented imperfect adherence. We explored forgiveness of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF). : Methods : In this retrospective cohort study pharmacy drug refills were used to calculate the proportion of days covered (PDC) as a proxy of adherence.

Discovery of 14-3-3 PPI Stabilizers by Extension of an Amidine-Substituted Thiophene Fragment.

Protein-protein interaction (PPI) modulation is a promising approach in drug discovery with the potential to expand the 'druggable' proteome and develop new therapeutic strategies. While there have been significant advancements in methodologies for developing PPI inhibitors, there is a relative scarcity of literature describing the 'bottom-up' development of PPI stabilizers (Molecular Glues). The hub protein 14-3-3 and its interactome provide an excellent platform for exploring conceptual approaches to PPI modulation, including evolution of chemical matter for Molecular Glues.

IFNα primes cancer cells for Fusicoccin-induced cell death via 14-3-3 PPI stabilization.

The natural product family of the fusicoccanes (FCs) has been shown to display anti-cancer activity, especially when combined with established therapeutic agents. FCs stabilize 14-3-3 protein-protein interactions (PPIs). Here, we tested combinations of a small library of FCs with interferon α (IFNα) on different cancer cell lines and report a proteomics approach to identify the specific 14-3-3 PPIs that are induced by IFNα and stabilized by FCs in OVCAR-3 cells.

Fusicoccin-A Targets Cancerous Inhibitor of Protein Phosphatase 2A by Stabilizing a C-Terminal Interaction with 14-3-3.

The cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncoprotein found overexpressed in many types of cancer. CIP2A has been shown to stabilize oncoproteins such as cMYC by shielding them from PP2A-mediated dephosphorylation. Here we report that the penultimate residue Ser904 in the C-terminus of CIP2A can be phosphorylated to create a binding site for the regulatory protein 14-3-3.

Fragment-based exploration of the 14-3-3/Amot-p130 interface.

The modulation of protein-protein interactions (PPIs) has developed into a well-established field of drug discovery. Despite the advances achieved in the field, many PPIs are still deemed as ' targets and the design of PPIs stabilizers remains a significant challenge. The application of fragment-based methods for the identification of drug leads and to evaluate the ' of the desired protein target has seen a remarkable development in recent years.

Meta-analysis of Total Effect Decomposition in the Presence of Multiple Mediators: The Example of Schizophrenia Treatment.

Background: Causal mediation analysis addresses mechanistic questions by decomposing and quantifying effects operating through different pathways. Because most individual studies are underpowered to detect mediating effects, we outlined a parametric approach to meta-analyzing causal mediation and interaction analyses with multiple mediators, compared it with a bootstrap-based alternative, and discussed its limitations.

Methods: We employed fixed- and random-effects multivariate meta-analyses to integrate evidence on treatment-mediators and mediators-outcome associations across trials.

Interaction of an IκBα Peptide with 14-3-3.

Inflammatory responses mediated by the transcription factor nuclear factor kappa-light-chain enhancer of activated B cells (NF-κB) play key roles in immunity, autoimmune diseases, and cancer. NF-κB is directly regulated through protein-protein interactions, including those with IκB and 14-3-3 proteins. These two important regulatory proteins have been reported to interact with each other, although little is known about this interaction.

The role of weight gain in explaining the effects of antipsychotic drugs on positive and negative symptoms: An analysis of the CATIE schizophrenia trial.

Second-generation antipsychotics are associated with moderate benefits in terms of improved schizophrenia symptoms, but also with higher rates of side-effects such as excessive weight gain (WG); a consensus on their efficacy has not been reached. To date, no study has evaluated the interplay of treatments and side-effects in a single framework, which is a critical step to clarify the role of side-effects in explaining the efficacy of these antipsychotics. We used recent methods for mediation and interaction to clarify the role of WG in explaining the effects of second-generation drugs on schizophrenia symptoms.

Protein X-ray crystallography of the 14-3-3ζ/SOS1 complex.

Activation of Ras-MAPK signaling regulates essential cellular functions; its aberration leads to irregular cell proliferation and differentiation (i.e. pancreatic cancer).

The role of PANSS symptoms and adverse events in explaining the effects of paliperidone on social functioning: a causal mediation analysis approach.

To date, no study has evaluated the joint role of symptoms and adverse events as mediators of the effect of second-generation antipsychotics on patients' social functioning. We used recently developed methods for mediation analysis with multiple mediators to clarify the interplay of adverse events and symptoms in explaining the effects of paliperidone (R code for implementing the mediation analysis for multiple mediators is provided). We used data from 490 participants in a 6-week randomized dose-response trial that assigned three fixed dosages of ER OROS paliperidone (3, 9, and 15 mg/day).

14-3-3: A Case Study in PPI Modulation.

In recent years, targeting the complex network of protein⁻protein interactions (PPIs) has been identified as a promising drug-discovery approach to develop new therapeutic strategies. 14-3-3 is a family of eukaryotic conserved regulatory proteins which are of high interest as potential targets for pharmacological intervention in human diseases, such as cancer and neurodegenerative and metabolic disorders. This viewpoint is built on the “hub” nature of the 14-3-3 proteins, binding to several hundred identified partners, consequently implicating them in a multitude of different cellular mechanisms.

Biophysical and structural insight into the USP8/14-3-3 interaction.

The ubiquitin-specific protease 8 (USP8)/14-3-3 protein-protein interaction has recently been shown to exert a significant role in the pathogenesis of Cushing's disease (CD). USP8 is a deubiquitinase that prevents epidermal growth factor receptor (EGFR) degradation. Impairment of 14-3-3 binding leads to a higher deubiquitination of EGFR and results in a higher EGFR signaling and an increased production of adrenocorticotropic hormone.

Structural characterization of 14-3-3ζ in complex with the human Son of sevenless homolog 1 (SOS1).

The deviant Ras activation machinery is found in approximately 30% of all human cancers. SOS1 is an important protagonist of this pathway that plays a key-role in aberrant cell proliferation and differentiation. Interaction of SOS1 with 14-3-3 proteins modulates SOS1 activity in Ras-MAPK signaling.

Factors associated with length of psychiatric hospitalization.

Objective: Criteria for psychiatric hospitalization have undergone marked changes. Efforts to limit length-of-hospitalization risk greater morbidity at discharge and increased needs for appropriate aftercare. Accordingly, we evaluated factors associated with length of psychiatric hospitalization and aftercare-types.

Metabolic syndrome in psychiatrically hospitalized patients treated with antipsychotics and other psychotropics.

Objective: We evaluated prevalence and risk factors for metabolic syndrome in inpatients treated with antipsychotics, with or without other psychotropic drugs. Although the literature on metabolic syndrome in psychiatry has expanded in recent years, we seek to elucidate some of the remaining gaps by examining a severely and chronically ill population heavily treated with pharmacological agents.

Methods: With data from medical records of 589 adults hospitalized at McLean Hospital in 2010 and 2011, we used standard statistical analyses to characterize risks and covariates of metabolic syndrome.

Marijuana impacts mood in bipolar disorder: a pilot study.

Patients with bipolar disorder (BP) often report subjective mood improvements after smoking marijuana (MJ); however, empirical studies supporting this claim have not been conducted. We conducted this study to determine if marijuana has an impact on mood in bipolar patients who smoke marijuana (MJBP), hypothesizing MJBP participants would experience improved mood after smoking MJ. All participants completed electronic mood ratings three times daily and recorded episodes of MJ use using Palm Pilot devices in their own environments in order to examine the impact of MJ use on mood in MJ-smoking bipolar patients ( = 12) and pure MJ smokers (MJ; = 20).

Pilot randomized, controlled trial of pramipexole to augment antipsychotic treatment.

The preferential dopamine D(3)-agonist pramipexole (4.25±0.38 mg/day) or placebo were added for up to 12 weeks to ongoing antipsychotic treatment for 24 adult patients with DSM-IV schizophrenia or schizoaffective disorder.

Use of mood stabilizers for hospitalized psychotic and bipolar disorder patients.

Treatments given to patients with primary psychotic disorders include mood stabilizers (MSs) combined with other psychotropics, despite the limited evidence of efficacy, safety, and lack of regulatory approval. We analyzed records of 636 inpatients at the McLean Hospital (2002-2009), who were diagnosed with bipolar disorder (n=318), a schizoaffective disorder (n=210), or schizophrenia (n=108), to evaluate MS-usage, drug-selections, combinations and doses, improvement, adverse-effect risks, associated factors, and secular trends. Between 2002 and 2009, the use of MSs increased from 53 to 94% of patients, MSs per patient increased by 74%, and the total final doses (lithium-equivalents in milligrams/day) increased by 35%.

Characteristics and clinical changes during hospitalization in bipolar and psychotic disorder patients with versus without substance-use disorders.

Background: Co-morbid substance-use disorders (SUDs) are prevalent among patients with severe psychiatric disorders, but the characteristics of such patients remain incompletely defined, and their current treatments and responses, poorly documented.

Methods: We evaluated the records of 481 consecutive inpatients diagnosed with DSM-IV bipolar or schizoaffective disorders, or schizophrenia, admitted to McLean Hospital in 2004 or 2009. Demographic and clinical characteristics, and treatments, were extracted from hospital and pharmacy records for bivariate and multivariate analyses.

International consensus study of antipsychotic dosing.

Objective: Potency equivalents for anti-psychotic drugs are required to guide clinical dosing and for designing and interpreting research studies. Available dosing guidelines are limited by the methods and data from which they were generated.

Method: With a two-step Delphi method, the authors surveyed a diverse group of international clinical and research experts, seeking consensus regarding antipsychotic dosing.

Changes in medication practices for hospitalized psychiatric patients: 2009 versus 2004.

Background: We tested the hypothesis that combinations and total daily doses of psychotropics for hospitalized patients diagnosed with major psychiatric disorders are rising.

Methods: We evaluated McLean Hospital records of 481 consecutive inpatients with DSM-IV schizophrenia, schizoaffective, or bipolar disorders in 2004 (n = 278) or 2009 (n = 203) to compare characteristics and treatments.

Results: In 2009, Clinical Global Impression (CGI)-severity scores were 6% lower at intake and improved 1.

Health and economic burden of metabolic comorbidity among individuals with bipolar disorder.

Objectives: To compare the prevalence and health care costs of metabolic conditions in patients with bipolar disorder to age- and sex-matched control patients using a large insurance claims database.

Methods: A retrospective analysis of medical service and prescription claims from the Thomson Reuters (Healthcare) MarketScan Commercial Database (which includes claims information on >12 million employees with employer-based insurance and their dependents in the United States) was conducted. Claims data for 28,531 patients with bipolar disorder were compared for 1 year with data for 85,593 age- and sex-matched control patients with no mental health disorders and no psychotropic medication use.