Genotoxicity and Epigenotoxicity of Carbazole-Derived Molecules on MCF-7 Breast Cancer Cells.

The carbazole compounds (1-(9-ethyl-7-(furan-2-yl)-9H-carbazol-3-yl)-N-methylmethanamine) and (1-(9-ethyl-7-(thiazol-4-yl)-9H-carbazol-3-yl)-N-methylmethanamine), second-generation analogues of (1-(9-ethyl-9H-carbazol-3-yl)-N-methylmethanamine), restore p53 signaling in Y220C p53-mutated cancer cells by binding to a mutation-induced surface crevice and acting as molecular chaperones. In the present paper, these three molecules have been tested for mutant p53-independent genotoxic and epigenomic effects on wild-type p53 MCF-7 breast adenocarcinoma cells, employing a combination of Western blot for phospho-γH2AX histone, Comet assay and methylation-sensitive arbitrarily primed PCR to analyze their intrinsic DNA damage-inducing and DNA methylation-changing abilities. We demonstrate that small modifications in the substitution patterns of carbazoles can have profound effects on their intrinsic genotoxic and epigenetic properties, with and being eligible candidates as "anticancer compounds" and "anticancer epi-compounds" and a "damage-corrective" compound on human breast adenocarcinoma cells.

Fast acting allosteric phosphofructokinase inhibitors block trypanosome glycolysis and cure acute African trypanosomiasis in mice.

The parasitic protist Trypanosoma brucei is the causative agent of Human African Trypanosomiasis, also known as sleeping sickness. The parasite enters the blood via the bite of the tsetse fly where it is wholly reliant on glycolysis for the production of ATP. Glycolytic enzymes have been regarded as challenging drug targets because of their highly conserved active sites and phosphorylated substrates.

Synthesis and Study of Multifunctional Cyclodextrin-Deferasirox Hybrids.

Metal dyshomeostasis is central to a number of disorders that result from, inter alia, oxidative stress, protein misfolding, and cholesterol dyshomeostasis. In this respect, metal deficiencies are usually readily corrected by treatment with supplements, whereas metal overload can be overcome by the use of metal-selective chelation therapy. Deferasirox, 4-[(3Z,5E)-3,5-bis(6-oxo-1-cyclohexa-2,4-dienylidene)-1,2,4-triazolidin-1-yl]benzoic acid, Exjade, or ICL670, is used clinically to treat hemosiderosis (iron overload), which often results from multiple blood transfusions.

Discovery of a Potent and Orally Bioavailable Cyclophilin Inhibitor Derived from the Sanglifehrin Macrocycle.

Cyclophilins are a family of peptidyl-prolyl isomerases that are implicated in a wide range of diseases including hepatitis C. Our aim was to discover through total synthesis an orally bioavailable, non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. An initial lead 2 derived from the sanglifehrin A macrocycle was optimized using structure based design to produce a potent and orally bioavailable inhibitor 3.

Discovery of Potent Cyclophilin Inhibitors Based on the Structural Simplification of Sanglifehrin A.

Cyclophilin inhibition has been a target for the treatment of hepatitis C and other diseases, but the generation of potent, drug-like molecules through chemical synthesis has been challenging. In this study, a set of macrocyclic cyclophilin inhibitors was synthesized based on the core structure of the natural product sanglifehrin A. Initial compound optimization identified the valine-m-tyrosine-piperazic acid tripeptide (Val-m-Tyr-Pip) in the sanglifehrin core, stereocenters at C14 and C15, and the hydroxyl group of the m-tyrosine (m-Tyr) residue as key contributors to compound potency.

Fragment screening using capillary electrophoresis (CEfrag) for hit identification of heat shock protein 90 ATPase inhibitors.

CEfrag is a new fragment screening technology based on affinity capillary electrophoresis (ACE). Here we report on the development of a mobility shift competition assay using full-length human heat shock protein 90α (Hsp90α), radicicol as the competitor probe ligand, and successful screening of the Selcia fragment library. The CEfrag assay was able to detect weaker affinity (IC(50) >500 µM) fragments than were detected by a fluorescence polarization competition assay using FITC-labeled geldanamycin.

Discovery and characterization of novel, potent, non-peptide parathyroid hormone-1 receptor antagonists.

A 1,3,4-benzotriazepine was identified as a suitable lead in our effort toward obtaining a non-peptide parathyroid hormone-1 receptor (PTH1R) antagonist. A process of optimization afforded derivatives displaying nanomolar PTH1R affinity, a representative example of which behaved as a PTH1R antagonist in cell-based cyclic adenosine monophosphate (cAMP) assays, with selectivity over PTH2 receptors.

Linking case management and community development.

Case management, in various forms, is now institutionalized as a core part of policy and programs designed to deliver home- and community-based services to older adults. The case management role, in theory, requires attention to both client and system goals, although in practice the system goals that have received most attention have been gatekeeping and resource allocation. While case managers have been admonished to find and develop resources in the community, this has primarily taken the form of including informal services in individual client care plans.

Efficacy of sertraline in posttraumatic stress disorder secondary to interpersonal trauma or childhood abuse.

Background: In posttraumatic stress disorder (PTSD), the nature of the trauma and the age of occurrence may have substantial effects on psychobiological sequelae and treatment response. Interpersonal trauma (physical/sexual assault) and childhood abuse are both prevalent and associated with later PTSD. This analysis was conducted to specifically assess the efficacy of sertraline in the treatment of PTSD secondary to interpersonal trauma or childhood abuse.

Novel, achiral 1,3,4-benzotriazepine analogues of 1,4-benzodiazepine-based CCK(2) antagonists that display high selectivity over CCK(1) receptors.

A series of 1,3,4-benzotriazepine-based CCK(2) antagonists have been devised by consideration of the structural features that govern CCK receptor affinity and the receptor subtype selectivity of 1,4-benzodiazepine-based CCK(2) antagonists. In contrast to the latter compounds, these novel 1,3,4-benzotriazepines are achiral, yet they display similar affinity for CCK(2) receptors to the earlier molecules and are highly selective over CCK(1) receptors.

High-dose sertraline strategy for nonresponders to acute treatment for obsessive-compulsive disorder: a multicenter double-blind trial.

Objective: To evaluate the efficacy and safety of high-dose sertraline for patients with obsessive-compulsive disorder (OCD) who failed to respond to standard sertraline acute treatment.

Method: Sixty-six nonresponders to 16 weeks of sertraline treatment who met DSM-III-R criteria for current OCD were randomly assigned, in a double-blind continuation phase of a multicenter trial, either to continue on 200 mg/day of sertraline or to increase their dose to between 250 and 400 mg/day for 12 additional weeks. Efficacy measures included the Yale-Brown Obsessive Compulsive Scale (YBOCS), the National Institute of Mental Health Global Obsessive Compulsive Scale (NIMH Global OC Scale), and the Clinical Global Impressions-Severity of Illness and -Improvement (CGI-I) scales.

Clinical correlates of poor sleep quality in posttraumatic stress disorder.

Sleep disturbances (SD) are a core clinical feature of PTSD. The goal of the study was to determine the influence of patient-related characteristics, disorder-related characteristics, and psychiatric comorbidity on the severity of SD in PTSD outpatients (n = 367) who were not recruited for a sleep study. Increased severity of SD paralleled increasing overall PTSD severity.

Gender differences in clinical presentation and response to sertraline treatment of generalized anxiety disorder.

Objective: To evaluate gender differences in the clinical presentation of generalized anxiety disorder (GAD) and response to sertraline treatment.

Methods: Adult outpatients who met DSM-IV criteria for GAD with a minimum Hamilton rating scale for anxiety (HAM-A) total score>or=18 were randomized to 12 weeks of double-blind treatment with flexible doses (50-150 mg) of sertraline (n=182; female, 59%) or placebo (n=188; female, 51%).

Results: Clinical presentation of GAD was very similar in men and women in terms of the severity of the HAM-A psychic factor, severity of concomitant depression symptoms, duration of GAD, quality of life and impairment in physical health.

Efficacy of sertraline in a 12-week trial for generalized anxiety disorder.

Objective: Sertraline's efficacy and tolerability in treating generalized anxiety disorder were evaluated.

Method: Adult outpatients with DSM-IV generalized anxiety disorder and a total score of 18 or higher on the Hamilton Anxiety Rating Scale were eligible. After a 1-week single-blind placebo lead-in, patients were randomly assigned to 12 weeks of double-blind treatment with placebo (N=188, mean baseline anxiety score=25) or flexible doses (50-150 mg/day) of sertraline (N=182, mean anxiety score=25).

Case management: who needs it? Does it work?

Even after 30 years of experience, two questions persist about case management practice. Who needs it and does it work? Answers to these questions are neither direct nor simple. This article examines the significance of various contexts (policy, system, community, and organization) to efforts attempting to provide responses to these basic questions.

Sertraline versus imipramine treatment of comorbid panic disorder and major depressive disorder.

Objective: To evaluate the efficacy and tolerability of sertraline and imipramine in patients with comorbid panic disorder and major depressive disorder.

Method: Outpatients meeting a DSM-IV diagnosis of panic disorder and concurrent major depressive disorder were randomized in a 2:1 ratio to 26 weeks of double-blind treatment with either sertraline, in daily doses of 50 to 100 mg, or imipramine, in daily doses of 100 to 200 mg. Primary outcome measures were panic attack frequency (derived from patient diaries) and the Montgomery-Asberg Depression Rating Scale (MADRS).

Audit tools for palliative care services: identification of neglected aspects of care.

The purpose of this study was to investigate the extent to which audit of palliative care service occurs nationally in Britain and Ireland. The following items were measured: (1) audit tools employed, (2) aspects of services undergoing audit, (3) changes in practice as a result of audit, and (4) obstacles to conducting some aspects of the audit. Audit practices were surveyed by means of a postal questionnaire distributed to managers of all hospice and palliative care services in the United Kingdom and Republic of Ireland.

Site-specific cross-linking reveals a differential direct interaction of class 1, 2, and 3 ADP-ribosylation factors with adaptor protein complexes 1 and 3.

We have used a site-specific photo-cross-linking approach to identify direct interactions between clathrin adaptor protein (AP)1 complexes and small GTPases of the ADP-ribosylation factor (ARF) family and to explore the specificity of this interaction on immature secretory granule (ISG) membranes. ISG membranes are a well-characterized, highly enriched preparation of membranes that has previously been shown to have the membrane-associated factors for ARF1 recruitment that are not present on artificial liposomes. All three classes of ARF proteins could be recruited to ISG membranes, displaying differential requirements for GTPgammaS.

Double-blind placebo-controlled pilot study of sertraline in military veterans with posttraumatic stress disorder.

The efficacy of sertraline in the treatment of civilian posttraumatic stress disorder (PTSD) has been established by two large placebo-controlled trials. The purpose of the current pilot study was to obtain preliminary evidence of the efficacy of sertraline in military veterans suffering from PTSD. Outpatient Israeli military veterans with a DSM-III-R diagnosis of PTSD were randomized to 10 weeks of double-blind treatment with sertraline (50-200 mg/day; N = 23, 83% male, mean age = 41 years) or placebo (N = 19, 95% male, mean age = 38 years).

Sertraline and fluoxetine treatment of obsessive-compulsive disorder: results of a double-blind, 6-month treatment study.

The purpose of this study was to evaluate the comparative efficacy and tolerability of sertraline and fluoxetine in the treatment of obsessive-compulsive disorder (OCD). Outpatients meeting DSM-IV criteria for OCD, with a Yale-Brown Obsessive-Compulsive (Y-BOCS) total score >or= 17, an NIMH Global Obsessive-Compulsive (NIMH-OC) scale score >or= 7, and a CGI-Severity score >or= 4 were randomized to 24 weeks of double-blind treatment with sertraline (N = 77) or fluoxetine (N = 73). Primary efficacy measures consisted of the Y-BOCS, the NIMH-OC scale, and the CGI-Severity (CGI-S) and Improvement (CGI-I) scales.