Combining SOS1 and MEK Inhibitors in a Murine Model of Plexiform Neurofibroma Results in Tumor Shrinkage.

Individuals with neurofibromatosis type 1 develop rat sarcoma virus (RAS)-mitogen-activated protein kinase-mitogen-activated and extracellular signal-regulated kinase (RAS-MAPK-MEK)-driven nerve tumors called neurofibromas. Although MEK inhibitors transiently reduce volumes of most plexiform neurofibromas in mouse models and in neurofibromatosis type 1 (NF1) patients, therapies that increase the efficacy of MEK inhibitors are needed. BI-3406 is a small molecule that prevents Son of Sevenless (SOS)1 interaction with Kirsten rat sarcoma viral oncoprotein (KRAS)-GDP, interfering with the RAS-MAPK cascade upstream of MEK. Single agent SOS1 inhibition had no significant effect in the DhhCre;Nf1 fl/fl mouse model of plexiform neurofibroma, but pharmacokinetics (PK)-driven combination of selumetinib with BI-3406 significantly improved tumor parameters. Tumor volumes and neurofibroma cell proliferation, reduced by MEK inhibition, were further reduced by the combination. Neurofibromas are rich in ionized calcium binding adaptor molecule 1 (Iba1)+ macrophages; combination treatment resulted in small and round macrophages, with altered cytokine expression indicative of altered activation. The significant effects of MEK inhibitor plus SOS1 inhibition in this preclinical study suggest potential clinical benefit of dual targeting of the RAS-MAPK pathway in neurofibromas. SIGNIFICANCE STATEMENT: Interfering with the RAS-mitogen-activated protein kinase (RAS-MAPK) cascade upstream of mitogen activated protein kinase kinase (MEK), together with MEK inhibition, augment effects of MEK inhibition on neurofibroma volume and tumor macrophages in a preclinical model system. This study emphasizes the critical role of the RAS-MAPK pathway in controlling tumor cell proliferation and the tumor microenvironment in benign neurofibromas.

Abdo-Man: a 3D-printed anthropomorphic phantom for validating quantitative SIRT.

BACKGROUND: The use of selective internal radiation therapy (SIRT) is rapidly increasing, and the need for quantification and dosimetry is becoming more widespread to facilitate treatment planning and verification. The aim of this project was to develop an anthropomorphic phantom that can be used as a validation tool for post-SIRT imaging and its application to dosimetry. METHOD: The phantom design was based on anatomical data obtained from a T1-weighted volume-interpolated breath-hold examination (VIBE) on a Siemens Aera 1.5 T MRI scanner. The liver, lungs and abdominal trunk were segmented using the Hermes image processing workstation. Organ volumes were then uploaded to the Delft Visualization and Image processing Development Environment for smoothing and surface rendering. Triangular meshes defining the iso-surfaces were saved as stereo lithography (STL) files and imported into the Autodesk® Meshmixer software. Organ volumes were subtracted from the abdomen and a removable base designed to allow access to the liver cavity. Connection points for placing lesion inserts and filling holes were also included. The phantom was manufactured using a Stratasys Connex3 PolyJet 3D printer. The printer uses stereolithography technology combined with ink jet printing. Print material is a solid acrylic plastic, with similar properties to polymethylmethacrylate (PMMA). RESULTS: Measured Hounsfield units and calculated attenuation coefficients of the material were shown to also be similar to PMMA. Total print time for the phantom was approximately 5 days. Initial scans of the phantom have been performed with Y-90 bremsstrahlung SPECT/CT, Y-90 PET/CT and Tc-99m SPECT/CT. The CT component of these images compared well with the original anatomical reference, and measurements of volume agreed to within 9 %. Quantitative analysis of the phantom was performed using all three imaging techniques. Lesion and normal liver absorbed doses were calculated from the quantitative images in three dimensions using the local deposition method. CONCLUSIONS: 3D printing is a flexible and cost-efficient technology for manufacture of anthropomorphic phantom. Application of such phantoms will enable quantitative imaging and dosimetry methodologies to be evaluated, which with optimisation could help improve outcome for patients.

Screening for incontinence in a secure psychiatric service for women.

Incontinence is associated with mental illness and neuroleptic medications but diagnosis and treatment is often poor or non-existent. Problems of incontinence are compounded in secure psychiatric services for women by poor health, obesity, and a sedentary lifestyle. Addressing the physical health of this group necessitates a more accurate picture of the nature, incidence, and management of incontinence. A point-in-time survey of 108 women who agreed to be interviewed (93%) covered presence, frequency, and nature of incontinence, and information on management case note data was used to gather demographic and previous medical history, comparisons were made between patients with and without problems of incontinence. Findings indicate a problem of incontinence in 48% of women with a dominance of problems of stress and urge enuresis. Of modifiable factors that contribute to enuresis, the current study highlighted the contribution of obesity, smoking and clozapine medication. A further finding was the preference for managing rather than treating problems of incontinence. Actions to improve the detection and treatment of this problem are described.

Treatment progress in medium security hospital settings for women: changes in symptoms, personality and service need from admission to discharge.

BACKGROUND: Service evaluations of medium secure hospital facilities for women are underrepresented in the extant literature. HYPOTHESIS: That positive changes in symptoms, personality traits and service need would be evident between admission and discharge among women in a medium security hospital service. METHODS: A pre-test/post-test design was used, with comparisons made between admission and pre-discharge points on a variety of measures of psychiatric symptoms and personality traits. RESULTS: There were significant improvements in mood according to Beck Depression Inventory scores, mood and other symptoms of mental disorder and distress as measured by the Brief Psychiatric Rating Scale and the Modified Post Traumatic Stress Disorder Symptom Scale, personality traits recorded using the Millon Clinical Multiaxial Inventory III and service need as measured by the Camberwell Assessment of Need, Forensic Version. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Significant positive change during treatment, in all clinical areas, is encouraging given poor outcomes for women reported in other research. Findings cannot, however, be unequivocally attributed to the treatments given. Further work is needed to improve early engagement and tailor treatment more specifically to the needs of a heterogeneous population.

Developing an assessment of fire-setting to guide treatment in secure settings: the St Andrew's Fire and Arson Risk Instrument (SAFARI).

BACKGROUND: Arson and fire-setting are highly prevalent among patients in secure psychiatric settings but there is an absence of valid and reliable assessment instruments and no evidence of a significant approach to intervention. AIMS: To develop a semi-structured interview assessment specifically for fire-setting to augment structured assessments of risk and need. METHOD: The extant literature was used to frame interview questions relating to the antecedents, behaviour and consequences necessary to formulate a functional analysis. Questions also covered readiness to change, fire-setting self-efficacy, the probability of future fire-setting, barriers to change, and understanding of fire-setting behaviour. The assessment concludes with indications for assessment and a treatment action plan. The inventory was piloted with a sample of women in secure care and was assessed for comprehensibility, reliability and validity. RESULTS: Staff rated the St Andrews Fire and Risk Instrument (SAFARI) as acceptable to patients and easy to administer. SAFARI was found to be comprehensible by over 95% of the general population, to have good acceptance, high internal reliability, substantial test-retest reliability and validity. CONCLUSIONS: SAFARI helps to provide a clear explanation of fire-setting in terms of the complex interplay of antecedents and consequences and facilitates the design of an individually tailored treatment programme in sympathy with a cognitive-behavioural approach. Further studies are needed to verify the reliability and validity of SAFARI with male populations and across settings.

Engagement in psychosocial treatment: its relationship to outcome and care pathway progress for women in medium-secure settings.

BACKGROUND: Engaging patients in treatment in secure settings is a major challenge. Engagement is associated with a shorter length of stay, whereas treatment non-completion is associated with an increased risk of recidivism. AIMS: The aims of this study were to assess differences between high and low treatment attendees in a women's medium secure unit and to compare progress over the course of their stay. METHODS: Sixty consecutive admissions to a women's medium secure unit were classified into high and low treatment attendee groups. The two groups were compared in terms of risk behaviours and psychometric measures of symptomatology, impulsivity and personality. RESULTS: High treatment attendees had a shortened length of stay, showed less disturbed behaviour and made more progress in terms of a reduction in symptoms overall and traumatic stress symptoms specifically. Low treatment attendees were more likely to have a diagnosis of schizophrenia/schizotypal illness than personality disorder, less likely to be impulsive and more likely to have scores indicative of severe disorder on the personality subscales of the Millon Clinical Multiaxial Inventory-III. CONCLUSION: Attendance at groups in this medium security unit had clear advantages for patients and potential cost savings for services and the community, but we found a subgroup of women who found it difficult to attend. Given the small sample size, we advocate replication, but our findings suggest the following: Implications for practice development of motivational interventions to help patients make a therapeutic alliance more accurate assessment of treatment readiness, to avoid mistimed interventions that are counterproductive more effective deployment of milieu therapeutic approaches to stabilise behaviour at an early stage of hospitalisation abandonment of a 'one size fits all' approach to groups for mixed patient populations. More 'customised' approaches would allow more appropriate 'pacing' of treatment and adaptations of interventions according to need during the treatment course.

Treatment of chronic anorexia nervosa: a 4-year follow-up of adult patients treated in an acute inpatient setting.

Despite evidence from a number of long-term follow-up studies of anorexia nervosa that nearly 50% of patients eventually make a full recovery, controlled trials of psychotherapy for anorexia nervosa are lacking. Those with severe and enduring problems represent a considerable therapeutic challenge. Thirty-four consecutive adult referrals to the inpatient treatment unit who fulfilled Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnostic criteria for anorexia nervosa were examined pre-admission, post-discharge and 4 years after admission. Characteristics of remitted and non-remitted patients were examined. Secondary analyses considered the differences between patients with anorexia nervosa, restricting type and anorexia nervosa binging/purging type. The findings highlight a number of differences between patients with anorexia nervosa (restricting type) versus anorexia nervosa (binging/purging type) as well as remitted versus non-remitted patients. The use of a comprehensive battery of assessments found that resolution of eating disorder symptomatology was paralleled by improvements in emotional and psychological distress and improvement in body image perception and coping skills. Better results were obtained for those who had continuity of care on an outpatient basis. This pattern is particularly significant given the more 'chronic' nature of the sample that were older, with a higher incidence of binge-eating and purging than previous samples. Results provide some encouragement for the treatment of those adults with anorexia nervosa who typically have less favourable outcomes.

Therapeutic dosing of an orally active, selective cathepsin S inhibitor suppresses disease in models of autoimmunity.

The purpose of the study was to examine the potential of inhibition of cathepsin S as a treatment for autoimmune diseases. A highly selective cathepsin S inhibitor, CSI-75, was shown to upregulate levels of the cathepsin S substrate, invariant chain Lip10, in vitro as well as in vivo in C57Bl/6 mice after oral administration. Functional activity of the compound was shown by a reduction in the OVA-specific response of OVA-sensitized splenocytes from C57Bl/6 mice as well as from OVA-TCR transgenic mice (DO11.10). Since these studies revealed a selective suppression of the Th1 and Th17 cytokines causing a shift to Th2, CSI-75 was tested in the murine HC-gp39-immunization model. Indeed, CSI-75 specifically reduced the circulating HC-gp39-specific IgG2a in these mice indicating selective inhibition of the Th1 type of response in vivo. The importance of especially the Th1 and Th17 cell subsets in the pathology of autoimmune diseases, renders CatS inhibition a highly interesting potential therapeutic treatment of autoimmune diseases. Therefore, CSI-75 was tested in a murine model of multiple sclerosis (i.e. experimental autoimmune encephalomyelitis (EAE)) in a semi-therapeutic setting (ie. oral treatment after initial sensitization to antigen). Finally, in a murine model with features resembling rheumatoid arthritis (the collagen-induced arthritis (CIA) model), CSI-75 was tested in a therapeutic manner (after disease development). CSI-75 caused a significant reduction in disease score in both disease models, indicating a promising role for CatS inhibitors in the area of therapeutic treatments for autoimmune diseases.

1H-imidazo[4,5-c]pyridine-4-carbonitrile as cathepsin S inhibitors: separation of desired cellular activity from undesired tissue accumulation through optimization of basic nitrogen pka.

Based on the theoretical understanding of the in vivo lysosomotropism, by adjusting the pk(a) of basic nitrogen containing cathepsin S inhibitors, a set of compounds with pk(a) 6-8 were identified to have excellent cell based Lip10 activity, yet avoiding undesired sequestration in spleen.

Dealing with Feelings: the effectiveness of cognitive behavioural group treatment for women in secure settings.

BACKGROUND: Women in secure psychiatric settings have gender specific treatment needs. The current study examined the feasibility of a Dealing with Feelings Skills Group training for dual diagnosis women admitted to a medium secure setting. METHOD: A pre-test--post-test design was used to evaluate a group programme adapted from dialectical behaviour therapy skills training. RESULTS: Most patients had a primary diagnosis of personality disorder. Treatment completers (n = 29) were compared with non-completers (n = 15). Clinically significant changes in treatment completers were apparent on coping response measures of positive reappraisal, problem solving and alternative rewards; on measures of anxiety and suicidality; on self-reported ability to engage in activities to reduce negative mood and to recognize mood changes. Self-harming and aggressive behaviours also reduced in the 3 months following group treatment. CONCLUSION: An adapted coping skills component of DBT benefit many dual diagnosis patients: issues related to treatment drop-out and failure to benefit are discussed.

Trifluoromethylphenyl as P2 for ketoamide-based cathepsin S inhibitors.

The trifluoromethylphenyl P2 motif from previously reported heteroarylnitrile series has been successfully applied for the design and synthesis of highly potent novel ketoamide-based cathepsin S inhibitors. The key in this process is the change of the torsion angle between the P2 phenyl ring and the attached secondary amide by adding a small Cl, F, or Me group at the 2-position.

Optimisation of 2-cyano-pyrimidine inhibitors of cathepsin K: improving selectivity over hERG.

Several structure-guided optimisation strategies were explored in order to improve the hERG selectivity profile of cathepsin K inhibitor 1, whilst maintaining its otherwise excellent in vitro and in vivo profile. Ultimately, attenuation of clogP and pK(a) properties proved a successful approach and led to the discovery of a potent analogue 23, which, in addition to the desired selectivity over hERG (>1000-fold), displayed a highly attractive overall profile.

6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile as cathepsin S inhibitors.

6-Phenyl-1H-imidazo[4,5-c]pyridine-4-carbonitrile analogues were identified as potent and selective cathepsin S inhibitor against both purified enzyme and in human JY cell based cellular assays. This core has a very stable thio-trapping nitrile war-head in comparison with the well reported pyrimidine-2-carbonitrile cysteine cathepsin inhibitors. Compound 47 is also very potent in in vivo mouse spleenic Lip10 accumulation assays.

4-(3-Trifluoromethylphenyl)-pyrimidine-2-carbonitrile as cathepsin S inhibitors: N3, not N1 is critically important.

Using computer aided modelling studies, a new extended P2/S2 interaction was identified. This extended region can accommodate a variety of functional groups, such as aryls and basic amines. It was discovered that the N3 nitrogen of the pyrimidine-2-carbonitrile is critical for its cathepsin cysteine protease inhibition. N1 nitrogen also contributes to the inhibitory activity, but to a very limited degree. An 'in situ double activation' mechanism was proposed to explain these results.

Design and optimization of a series of novel 2-cyano-pyrimidines as cathepsin K inhibitors.

Morphing structural features of HTS-derived chemotypes led to the discovery of novel 2-cyano-pyrimidine inhibitors of cathepsin K with good pharmacokinetic profiles, for example, compound 20 showed high catK potency (IC(50)=4nM), >580-fold selectivity over catL and catB, and oral bioavailability in the rat of 52%.

Dioxo-triazines as a novel series of cathepsin K inhibitors.

A novel dioxo-triazine series of cathepsin K inhibitors was identified from HTS. A rapid exploratory programme led to the discovery of potent and selective cathepsin K inhibitors, typified by compound 24 which displayed IC(50) values of 17nM against catK and >10,000nM in catL, catB and catS assays.

Assessing comorbid substance use in detained psychiatric patients: issues and instruments for evaluating treatment outcome.

This review assesses the issues involved in the selection and treatment of patients comorbid for mental illness and substance misuse being treated in secure psychiatric facilities. It includes those individuals who have a history of offending and whose placement is the result of severe behavioral disturbance. The relevant issues in the assessment and treatment of these patients are reviewed and a battery of tests is suggested on the basis of their usefulness with this population in terms of their brevity, ease of administration, and for their value in planning treatment, providing motivational feedback, and monitoring change. The paucity of assessment tools developed specifically for this patient population is highlighted.

Improved methods for testing antiresorptive compounds in human osteoclast cultures.

We cultured human bone marrow-derived stem cells on bovine bone slices in 96-well plates in the presence of M-CSF and RANKL, allowing them to differentiate into osteoclasts. Secreted TRACP 5b was a useful endpoint measurement to demonstrate effects of inhibitors of osteoclast differentiation in the culture system, reflecting accurately the number of formed osteoclasts. Inhibitors of osteoclast activity were added into the cultures after the differentiation period, and the cultures were continued to allow the formed osteoclasts to resorb bone. CTX values obtained after the resorption period were normalized with TRACP 5b values obtained after the differentiation period, before adding the inhibitors. This normalization prevents false results that could be obtained from the presence of different amounts of osteoclasts in different wells before adding the inhibitors. These results demonstrate that the use of TRACP 5b and CTX allows rapid and reliable testing of antiresorptive compounds in human osteoclast cultures.

The development of a 'best practice' service for women in a medium-secure psychiatric setting: treatment components and evaluation.

The inadequacy of inpatient facilities for women with severe psychiatric and co-morbid difficulties has been repeatedly documented. The establishment of effective therapeutic programmes for women in medium psychiatric facilities is also in their infancy, and little research has been undertaken. This article describes the development of a 'best practice' psychological treatment programme for women with a dual diagnosis. Emphasis is placed on the need to develop further intensive gender-specific services using an established model for effective therapeutic service development. In addition to a detailed description of the group therapy programme, staff training initiatives, methods for ensuring treatment integrity and a methodology for service evaluation is given.

Usefulness of the CANFOR-S for measuring needs among mentally disordered offenders resident in medium or low secure hospital services in the UK: a pilot evaluation.

BACKGROUND: The short form of the forensic version of the Camberwell Assessment of Needs (CANFOR-S) (Thomas et al., 2003) is of potential value in all clinical forensic settings, but so far reported mainly with high security hospital patients. AIMS: To conduct a pilot study of the feasibility of using the CANFOR-S in medium and low security hospital units and to report preliminary findings there. METHODS: Thirty-six of 38 patients on one medium secure ward for women, one low secure ward for women and one low secure ward for men, all in the same hospital, agreed to participate in the study. Staff and patients completed the CANFOR-S as part of a larger formal assessment package. RESULTS: All the women and 18 of the 20 men completed the CANFOR-S. It was found to be easy and quick (25 minutes) to use, and acceptable. Staff and patient ratings were similar on all but one item: needs with regard to safety to others, with staff consistently rating more. Men and women were similar in number of needs, but had different needs profiles. Those in medium security were generally more needy than those in low security. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: The CANFOR-S is feasible for clinical practice, with results perceived as useful in treatment planning by patients and staff. More widespread use could improve service planning.