Discovery of vimseltinib (DCC-3014), a highly selective CSF1R switch-control kinase inhibitor, in clinical development for the treatment of Tenosynovial Giant Cell Tumor (TGCT).

Based on knowledge of kinase switch-control inhibition and using a combination of structure-based drug design and standard medicinal chemistry principles, we identified a novel series of dihydropyrimidone-based CSF1R kinase inhibitors displaying exquisite selectivity for CSF1R versus a large panel of kinases and non-kinase protein targets. Starting with lead compound 3, an SAR optimization campaign led to the discovery of vimseltinib (DCC-3014; compound 20) currently undergoing clinical evaluation for the treatment of Tenosynovial Giant Cell Tumor (TGCT), a locally aggressive benign tumor associated with substantial morbidity. 2021 Elsevier ltd. All rights reserved.

Discovery of acyl ureas as highly selective small molecule CSF1R kinase inhibitors.

Based on the structure of an early lead identified in Deciphera's proprietary compound collection of switch control kinase inhibitors and using a combination of medicinal chemistry guided structure activity relationships and structure-based drug design, a novel series of potent acyl urea-based CSF1R inhibitors was identified displaying high selectivity for CSF1R versus the other members of the Type III receptor tyrosine kinase (RTK) family members (KIT, PDGFR-α, PDGFR-ß, and FLT3), VEGFR2 and MET. Based on in vitro biology, in vitro ADME and in vivo PK/PD studies, compound 10 was selected as an advanced lead for Deciphera's CSF1R research program.

Gonadal function protects against organ culture-induced vascular damage. Involvement of prostanoids.

Androgen deprivation induces vascular dysfunction in which altered release and action of prostanoids has been extensively studied. On the other hand, the vascular organ-culture system has been reported as a valid model for phenotypic changes that occur in several cardiovascular pathologies. Since there are no studies analyzing the impact of androgenic loss on vascular vulnerability during induced vascular damage, the objective of this study was to analyze the possible preventive role of male sex hormones on the organ culture-induced vascular damage in rat aorta. The link to possible changes in gross structure was also analyzed. For this purpose, fresh and 20 h-cultured aortic arterial segments from intact and orchidectomized rats were used to analyze: (i) the release and vasomotor effect of the thromboxane A2 (TXA2), prostaglandin (PG) E2, PGF2α and PGI2; (ii) the vasodilator response induced by acetylcholine (ACh) as well as the involvement of prostanoids, in particular TXA2, in the ACh-induced response; (iii) the effect of activation of thromboxane/prostaglandin (TP) receptors on the ACh-induced response; and (iv) the vascular structure. The results showed that organ culture: i) increased production of prostanoids; ii) increased prostanoids-induced vasomotor responses; iii) decreased ACh-induced relaxation after incubation with indomethacin, a blocker of cyclooxygenases; iv) increased the ACh-induced relaxation after incubation with the TXA2 synthase inhibitor, furegrelate, more in arteries from orchidectomized rats than in those of intact rats; v) diminished ACh-induced relaxation after U-46619 incubation only in arteries from orchidectomized rats; and vi) preserved the integrity of the different vascular layers. These results showed the protective role of male sex hormones against the induced vascular damage, since a decreased deleterious effect of prostanoids, in particular that of TXA2, was observed in arteries from rats with intact gonadal function.

Evaluating the national multisite implementation of dialectical behaviour therapy in a community setting: a mixed methods approach.

BACKGROUND: The implementation of evidence-based interventions for borderline personality disorder in community settings is important given that individuals with this diagnosis are often extensive users of both inpatient and outpatient mental health services. Although work in this area is limited, previous studies have identified facilitators and barriers to successful DBT implementation. This study seeks to expand on previous work by evaluating a coordinated implementation of DBT in community settings at a national level. The Consolidated Framework for Implementation Research (CFIR) (Damschroder et al., Implementation Sci. 4:50, 2009) provided structural guidance for this national level coordinated implementation. METHODS: A mixed methods approach was utilised to explore the national multisite implementation of DBT from the perspective of team leaders and therapists who participated in the coordinated training and subsequent implementation of DBT. Qualitative interviews with DBT team leaders (n = 8) explored their experiences of implementing DBT in their local service and was analysed using content analysis. Quantitative surveys from DBT therapists (n = 74) examined their experience of multiple aspects of the implementation process including orienting the system, and preparations and support for implementation. Frequencies of responses were calculated. Written qualitative feedback was analysed using content analysis. RESULTS: Five themes were identified from the interview data: team formation, implementation preparation, client selection, service level challenges and team leader role. Participants identified team size and support for the team leader as key points for consideration in DBT implementation. Key challenges encountered were the lack of system support to facilitate phone coaching and a lack of allocated time to focus on DBT. Implementation facilitators included having dedicated team members and support from management. CONCLUSIONS: The barriers and facilitators identified in this study are broadly similar to those reported in previous research. Barriers and facilitators were identified across several domains of the CFIR and are consistent with a recently published DBT implementation Framework (Toms et al., Borderline Personal Disord Emot Dysregul. 6: 2, 2019). Future research should pay particular attention to the domain of characteristics of individuals involved in DBT implementation. The results highlight the importance of a mandated service plan for the coordinated implementation of an evidence-based treatment in a public health service. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03180541; Registered June 7th 2017 'retrospectively registered'.

Forensic reconstruction of two military combat related shooting incidents using an anatomically correct synthetic skull with a surrogate skin/soft tissue layer.

Six synthetic head models wearing ballistic protective helmets were used to recreate two military combat-related shooting incidents (three per incident, designated 'Incident 1' and 'Incident 2'). Data on the events including engagement distances, weapon and ammunition types was collated by the Defence Science and Technology Laboratory. The models were shot with 7.62 × 39 mm ammunition downloaded to mean impact velocities of 581 m/s (SD 3.5 m/s) and 418 m/s (SD 8 m/s), respectively, to simulate the engagement distances. The damage to the models was assessed using CT imaging and dissection by a forensic pathologist experienced in reviewing military gunshot wounds. The helmets were examined by an MoD engineer experienced in ballistic incident analysis. Damage to the helmets was consistent with that seen in real incidents. Fracture patterns and CT imaging on two of the models for Incident 1 (a frontal impact) were congruent with the actual incident being modelled. The results for Incident 2 (a temporoparietal impact) produced realistic simulations of tangential gunshot injury but were less representative of the scenario being modelled. Other aspects of the wounds produced also exhibited differences. Further work is ongoing to develop the models for greater ballistic injury fidelity.

Dialectical behaviour therapy for adolescents: a comparison of 16-week and 24-week programmes delivered in a public community setting.

BACKGROUND: Dialectical behaviour therapy for adolescents (DBT-A) is an intervention with a growing evidence base for treating adolescents with emotional and behavioural dysregulation. Previous studies have reported on varying lengths of treatment, however, and optimal treatment duration has not yet been identified. While the treatment developers initially proposed a 16-week programme, they have more recently recommended an extension to 24 weeks. This study compares outcomes for adolescents and parent/guardians who participated in 16- and 24-week DBT-A programmes in a community setting. METHODS: Eighty-four adolescents and 100 parent/guardians participated in 16-week DBT-A, while 68 adolescents and 67 parent/guardians participated in the 24-week programme. Outcome measures for adolescents included the presence and frequency of self-harm, suicidal ideation and depression; and for parents were burden, grief and parental stress. Outcomes were assessed at pre- and postintervention. Linear mixed-effects models were used to estimate the treatment duration effect (24-week vs. 16-week) utilising all available data at pre- and postintervention. RESULTS: Data analyses showed a reduction in the presence and frequency of self-harm at postintervention for adolescents in both programmes. Both adolescent and parent participants in the 16- and 24-week programmes also showed changes indicating significant improvement on all self-report outcome measures (p < .05). A treatment duration effect was identified with adolescents in the 24-week programme reporting greater gains on measures of suicidal ideation and depression (p < .05). However, drop-out rates were higher for the 24-week programme. CONCLUSIONS: The findings of the current study indicate that 24-week DBT-A may have additional benefits in comparison to 16-week DBT-A in terms of further reductions in suicidal ideation and depression. Given the nature of this study, it was not possible to explore a potential time effect, however, so these results should be interpreted with caution. Further research will assist in determining an optimal programme duration of DBT-A.

Innovations in Practice: Dialectical behaviour therapy for adolescents: multisite implementation and evaluation of a 16-week programme in a public community mental health setting.

BACKGROUND: Dialectical behaviour therapy for adolescents (DBT-A) is an intervention with a growing evidence base for treating adolescents with emotional and behavioural dysregulation. This study describes the implementation and effectiveness of 16-week DBT-A across multiple sites in publicly funded child/adolescent mental health services (CAMHS) in Ireland. METHOD: The Consolidated Framework for Implementation Research was used to guide this national implementation. Fifty-four clinicians from seven CAMHS teams completed DBT training and delivered the 16-week DBT-A programme. Eighty-four adolescents with emotional and behavioural dysregulation participated in the intervention and outcome measures were administered at preintervention, postintervention and 16-week follow-up. RESULTS: Significant reductions on all outcome measures were observed for DBT-A participants including presence and frequency of self-harm, suicidal ideation and depression. Reductions in the number of acute inpatient admissions, bed days and emergency department visits were also reported. CONCLUSIONS: DBT-A can be successfully implemented in CAMHS settings and yield positive outcomes for adolescents with emotional and behavioural dysregulation.

Dialectical behaviour therapy for treating adults and adolescents with emotional and behavioural dysregulation: study protocol of a coordinated implementation in a publicly funded health service.

BACKGROUND: In the Republic of Ireland, borderline personality disorder (BPD) is a feature of approximately 11-20% of clinical presentations to outpatient clinics within mental health services. These estimates are similar to other countries including the UK and USA. Dialectical behaviour therapy (DBT) is an intervention with a growing body of evidence that demonstrates its efficacy in treating individuals diagnosed with BPD. While a number of randomised controlled trials (RCTs) have demonstrated the efficacy of DBT, there is limited research which evaluates the effectiveness of this model when applied to real world settings. Funding was secured to co-ordinate DBT training in public community-based mental health services across Ireland. As no other study has evaluated a co-ordinated national implementation of DBT, the current study proposes to investigate the effectiveness of DBT in both adult and child/adolescent community mental health services across Ireland, evaluate the coordinated implementation of DBT at a national level, and complete a comprehensive economic evaluation comparing DBT versus treatment-as-usual. METHODS/ DESIGN: This study takes the form of a quasi-experimental design. Individuals attending community mental health services who meet criteria for participation in the DBT programme will be allocated to the intervention group. Individuals who live in areas in Ireland where DBT is not yet available, and individuals who choose not to participate in the intervention, will be invited to participate in a treatment-as-usual comparison group. Self-report clinical measures and health service use questionnaires for DBT participants (and parent/guardians as appropriate) will be administered at pre-, mid- and post-intervention, as well as follow-up for participants who complete the intervention. Survey and interview data for DBT therapists will be gathered at three time points: prior to DBT training, 6 months after teams begin delivery of the intervention, and 2 years following training completion. DISCUSSION: It is anticipated that the results of this study will provide evidence for the effectiveness of DBT for patients, and report on recommendations regarding best practice guidelines for implementation of DBT and its economic merit in a publicly funded service. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03180541 ; Registered June 7th 2017 'retrospectively registered'.

Correction to: Dialectical behaviour therapy for treating adults and adolescents with emotional and behavioural dysregulation: study protocol of a coordinated implementation in a publicly funded health service.

Upon publication of the original article (1) it was highlighted by the authors that there was just one error in the manuscript in the 'Sample size' subsection of the Methods/Design.

Innovations in Practice: Dialectical behaviour therapy - skills training for emotional problem solving for adolescents (DBT STEPS-A): evaluation of a pilot implementation in Irish post-primary schools.

BACKGROUND: Whole school approaches to mental health are recommended where schools and community partners work together to support positive mental health for young people. Universal interventions which adopt this approach are limited however. This study evaluates the pilot implementation of DBT STEPS-A, a social-emotional learning programme for adolescents, in Ireland. METHOD: Data were collected at the beginning and end of the academic year from students who participated in DBT STEPS-A and a control group. A matched comparison was conducted where a subset of the data was analysed consisting of 72 adolescents aged 15-16 years from two schools in the south of Ireland. Outcomes included emotion symptoms, dysfunctional coping and DBT skill use. Linear mixed-effects models were used to estimate the treatment effect (intervention vs. control). RESULTS: A statistically significant treatment effect was observed on two of four outcome measures (emotion symptom index: p = 0.011; internalising problems: p = 0.012). The effect sizes were large (Cohen's F squared = 0.65 and 0.83 respectively). CONCLUSIONS: Significant reductions on measures which assess constructs including depression, anxiety and social stress were found for the intervention group. The results suggest that DBT STEPS-A may yield positive effects for adolescents who complete the intervention. Feedback from adolescents and teachers suggests that refinement of content, structure and implementation may make the programme more accessible to an adolescent population.

Phase 1 dose-finding study of rebastinib (DCC-2036) in patients with relapsed chronic myeloid leukemia and acute myeloid leukemia.

A vailable tyrosine kinase inhibitors for chronic myeloid leukemia bind in an adenosine 5'-triphosphate-binding pocket and are affected by evolving mutations that confer resistance. Rebastinib was identified as a switch control inhibitor of BCR-ABL1 and FLT3 and may be active against resistant mutations. A Phase 1, first-in-human, single-agent study investigated rebastinib in relapsed or refractory chronic or acute myeloid leukemia. The primary objectives were to investigate the safety of rebastinib and establish the maximum tolerated dose and recommended Phase 2 dose. Fifty-seven patients received treatment with rebastinib. Sixteen patients were treated using powder-in-capsule preparations at doses from 57 mg to 1200 mg daily, and 41 received tablet preparations at doses of 100 mg to 400 mg daily. Dose-limiting toxicities were dysarthria, muscle weakness, and peripheral neuropathy. The maximum tolerated dose was 150 mg tablets administered twice daily. Rebastinib was rapidly absorbed. Bioavailability was 3- to 4-fold greater with formulated tablets compared to unformulated capsules. Eight complete hematologic responses were achieved in 40 evaluable chronic myeloid leukemia patients, 4 of which had a T315I mutation. None of the 5 patients with acute myeloid leukemia responded. Pharmacodynamic analysis showed inhibition of phosphorylation of substrates of BCR-ABL1 or FLT3 by rebastinib. Although clinical activity was observed, clinical benefit was insufficient to justify continued development in chronic or acute myeloid leukemia. Pharmacodynamic analyses suggest that other kinases inhibited by rebastinib, such as TIE2, may be more relevant targets for the clinical development of rebastinib (clinicaltrials.gov Identifier:00827138).

Taxane-induced hedgehog signaling is linked to expansion of breast cancer stem-like populations after chemotherapy.

Recurrence of breast cancer after chemotherapy is thought to arise from resistant breast cancer stem cells which are eventually able to repopulate the tumor. The Hedgehog (HH) signaling pathway has been shown to regulate the proliferation and survival of breast cancer stem cells, and has been shown to promote resistance to chemotherapy through the activation of multi-drug resistance and pro survival pathways. Here we report that exposure of heterogenous breast cancer cell lines to docetaxel (DOC) resulted in release of Sonic Hedgehog ligand (SHH) and activation of the HH pathway as evidenced by increased expression and nuclear translocation of the downstream effector Gli-1 at 4-24 h after DOC treatment. This activation had little effect on the bulk of the tumor cell population as inhibition of HH signaling failed to increase apoptosis in response to DOC. However, HH pathway activation was required for clonogenic growth of cell lines after DOC. Increases in stemness markers as well as mammosphere formation were observed after treatment with DOC suggesting an increase in the breast cancer stem cell populations. These increases were similar to that of cell lines cultured in the presence of recombinant SHH and could be eliminated by co-treatment with HH inhibitors. These results suggest that HH pathway activation induced by DOC treatment does not have a chemosensitizing effect on the heterogeneous tumor population, but may be required for survival and expansion of breast cancer stem cells after chemotherapy.

Pulse-shaping based two-photon FRET stoichiometry.

Förster Resonance Energy Transfer (FRET) based measurements that calculate the stoichiometry of intermolecular interactions in living cells have recently been demonstrated, where the technique utilizes selective one-photon excitation of donor and acceptor fluorophores to isolate the pure FRET signal. Here, we present work towards extending this FRET stoichiometry method to employ two-photon excitation using a pulse-shaping methodology. In pulse-shaping, frequency-dependent phases are applied to a broadband femtosecond laser pulse to tailor the two-photon excitation conditions to preferentially excite donor and acceptor fluorophores. We have also generalized the existing stoichiometry theory to account for additional cross-talk terms that are non-vanishing under two-photon excitation conditions. Using the generalized theory we demonstrate two-photon FRET stoichiometry in live COS-7 cells expressing fluorescent proteins mAmetrine as the donor and tdTomato as the acceptor.

Lead identification and structure-activity relationships of heteroarylpyrazole arylsulfonamides as allosteric CC-chemokine receptor 4 (CCR4) antagonists.

A knowledge-based library of aryl 2,3-dichlorophenylsulfonamides was synthesised and screened as human CCR4 antagonists, in order to identify a suitable hit for the start of a lead-optimisation programme. X-ray diffraction studies were used to identify the pyrazole ring as a moiety that could bring about intramolecular hydrogen bonding with the sulfonamide NH and provide a clip or orthogonal conformation that was believed to be the preferred active conformation. Replacement of the core phenyl ring with a pyridine, and replacement of the 2,3-dichlorobenzenesulfonamide with 5-chlorothiophenesulfonamide provided compound 33 which has excellent physicochemical properties and represents a good starting point for a lead optimisation programme. Electronic structure calculations indicated that the preference for the clip or orthogonal conformation found in the small molecule crystal structures of 7 and 14 was in agreement with the order of potency in the biological assay.

Lead identification of benzimidazolone and azabenzimidazolone arylsulfonamides as CC-chemokine receptor 4 (CCR4) antagonists.

A knowledge-based library of 2,3-dichlorophenylsulfonyl derivatives of commercially available aryl amines was synthesised and screened as human CCR4 antagonists, in order to identify a suitable hit for the start of a lead-optimisation programme. Hits were required to be more potent than an existing indazole series, have better physicochemical properties (clogP <3.5, chrom logD7.4 <5.3 and CLND solubility >116 µg/mL), and be stable to acid and light. The benzimidazol-2-one core was identified as a hit suitable for further investigation. Substitution at N1 with small alkyl groups was tolerated; however, these analogues were inactive in the whole blood assay (pA2 <5). Azabenzimidazolone analogues were all found to be active, with compound 38 exhibiting whole blood activity of 6.1, low molecular weight (389) and chrom logD7.4 (2.4), high LE (0.43), and solubility (152 µg/mL). In addition, 38 had human serum albumin binding of around 93% and met all the criteria for progression to lead optimisation.

Inhibition of ULK1/2 and KRAS G12C controls tumor growth in preclinical models of lung cancer.

Mutational activation of KRAS occurs commonly in lung carcinogenesis and, with the recent FDA approval of covalent inhibitors of KRAS G12C such as sotorasib or adagrasib, KRAS oncoproteins are important pharmacological targets in non-small cell lung cancer (NSCLC). However, not all KRAS G12C -driven NSCLCs respond to these inhibitors, and the emergence of drug resistance in those patients that do respond can be rapid and pleiotropic. Hence, based on a backbone of covalent inhibition of KRAS G12C , efforts are underway to develop effective combination therapies. Here we report that inhibition of KRAS G12C signaling increases autophagy in KRAS G12C expressing lung cancer cells. Moreover, the combination of DCC-3116, a selective ULK1/2 inhibitor, plus sotorasib displays cooperative/synergistic suppression of human KRAS G12C -driven lung cancer cell proliferation in vitro and superior tumor control in vivo . Additionally, in genetically engineered mouse models of KRAS G12C -driven NSCLC, inhibition of either KRAS G12C or ULK1/2 decreases tumor burden and increases mouse survival. Consequently, these data suggest that ULK1/2-mediated autophagy is a pharmacologically actionable cytoprotective stress response to inhibition of KRAS G12C in lung cancer.

Combining VPS34 inhibitors with STING agonists enhances type I interferon signaling and anti-tumor efficacy.

An immunosuppressive tumor microenvironment promotes tumor growth and is one of the main factors limiting the response to cancer immunotherapy. We have previously reported that inhibition of vacuolar protein sorting 34 (VPS34), a crucial lipid kinase in the autophagy/endosomal trafficking pathway, decreases tumor growth in several cancer models, increases infiltration of immune cells and sensitizes tumors to anti-programmed cell death protein 1/programmed cell death 1 ligand 1 therapy by upregulation of C-C motif chemokine 5 (CCL5) and C-X-C motif chemokine 10 (CXCL10) chemokines. The purpose of this study was to investigate the signaling mechanism leading to the VPS34-dependent chemokine increase. NanoString gene expression analysis was applied to tumors from mice treated with the VPS34 inhibitor SB02024 to identify key pathways involved in the anti-tumor response. We showed that VPS34 inhibitors increased the secretion of T-cell-recruitment chemokines in a cyclic GMP-AMP synthase (cGAS)/stimulator of interferon genes protein (STING)-dependent manner in cancer cells. Both pharmacological and small interfering RNA (siRNA)-mediated VPS34 inhibition increased cGAS/STING-mediated expression and secretion of CCL5 and CXCL10. The combination of VPS34 inhibitor and STING agonist further induced cytokine release in both human and murine cancer cells as well as monocytic or dendritic innate immune cells. Finally, the VPS34 inhibitor SB02024 sensitized B16-F10 tumor-bearing mice to STING agonist treatment and significantly improved mice survival. These results show that VPS34 inhibition augments the cGAS/STING pathway, leading to greater tumor control through immune-mediated mechanisms. We propose that pharmacological VPS34 inhibition may synergize with emerging therapies targeting the cGAS/STING pathway.

Enabling 3D CT-scanning of cultural heritage objects using only in-house 2D X-ray equipment in museums.

Visualizing the internal structure of museum objects is a crucial step in acquiring knowledge about the origin, state, and composition of cultural heritage artifacts. Among the most powerful techniques for exposing the interior of museum objects is computed tomography (CT), a technique that computationally forms a 3D image using hundreds of radiographs acquired in a full circular range. However, the lack of affordable and versatile CT equipment in museums, combined with the challenge of transporting precious collection objects, currently keeps this technique out of reach for most cultural heritage applications. We propose an approach for creating accurate CT reconstructions using only standard 2D radiography equipment already available in most larger museums. Specifically, we demonstrate that a combination of basic X-ray imaging equipment, a tailored marker-based image acquisition protocol, and sophisticated data-processing algorithms, can achieve 3D imaging of collection objects without the need for a costly CT imaging system. We implemented this approach in the British Museum (London), the J. Paul Getty Museum (Los Angeles), and the Rijksmuseum (Amsterdam). Our work paves the way for broad facilitation and adoption of CT technology across museums worldwide.

An evaluation of the skills group component of DBT-A for parent/guardians: a mixed methods study.

OBJECTIVES: Previous research indicates that dialectical behaviour therapy for adolescents (DBT-A) is effective in treating emotionally dysregulated adolescents with self-harm and/or suicidal ideation. As part of the DBT-A programme, parents attend the weekly skills group with their child. However, few studies have evaluated parental outcomes in DBT-A. This multi-site study aims to explore the outcomes and experiences of parents who participated in a 16-week DBT-A programme in Ireland. METHODS: This study was conducted in community-based child and adolescent mental health services (CAMHS) in the national public health system in Ireland. Participants were parent/guardians of adolescents attending a DBT-A programme in their local CAMHS. Participants attended the group skills component of the DBT-A programme. This study utilised a mixed methods approach where both quantitative and qualitative data were collected from participants. Self-report measures of burden, grief and parental stress were completed at pre-intervention, post-intervention and 16-week follow-up. Qualitative written feedback was obtained at post-intervention. The data were analysed using multi-level linear mixed-effects models and content analysis. RESULTS: One hundred participants (76% female) took part in this study. Significant decreases were reported for objective burden, subjective burden, grief and parental stress from pre- to post-intervention (p < 0.01). Participants reported that the skills component of DBT-A was useful in meeting their own needs and the needs of their child. DISCUSSION: DBT-A shows promise for parents as well as their adolescent child. Future studies should evaluate changes to family relationships following completion of the programme and also include controlled comparison groups.