Prexasertib (LY2606368) reduces clonogenic survival by inducing apoptosis in primary patient-derived osteosarcoma cells and synergizes with cisplatin and talazoparib

Progress in the systemic control of osteosarcoma has been limited over the past decades thus indicating the urgent clinical need for the development of novel treatment strategies. Therefore, we have recently developed new preclinical models to study promising novel agents for the treatment of pediatric osteosarcoma. The checkpoint kinase (chk) inhibitor prexasertib (LY2606368) and its salt form (LSN2940930) have recently been shown to be active in adult and pediatric malignancies, including sarcoma. We have now tested the potency of prexasertib in clonogenic survival assays in two new lines of primary patient-derived osteosarcoma cells and in two established osteosarcoma cell lines as a single agent and in combination with cisplatin and the poly ADP-ribose polymerase (PARP) inhibitor talazoparib. Prexasertib alone results in strongly reduced clonogenic survival at low nanomolar concentrations and acts by affecting cell cycle progression, induction of apoptosis and induction of double-stranded DNA breakage at concentrations that are well below clinically tolerable and safe plasma concentrations. In combination with cisplatin and talazoparib, prexasertib acts in a synergistic fashion. Chk1 inhibition by prexasertib and its combination with the DNA damaging agent cisplatin and the PARP-inhibitor talazoparib thus emerges as a potential new treatment option for pediatric osteosarcoma which will now have to be tested in preclinical primary patient derived in vivo models and clinical studies.     

Depression in type 1 diabetes and risk of dementia

Objective: Depression afflicts 14% of individuals with type 1 diabetes (T1D). Depression is a robust risk factor for dementia but it is unknown if this holds true for individuals with T1D, who recently started living to an age conferring dementia risk. We examined if depression is a dementia risk factor among elderly individuals with T1D.

Methods: 3,742 individuals with T1D age ≥50 were followed for dementia from 1/1/96-9/30/2015. Depression, dementia, and comorbidities were abstracted from electronic medical records. Cox proportional hazard models estimated the association between depression and dementia adjusting for demographics, glycosylated hemoglobin, severe dysglycemic epidsodes, stroke, heart disease, nephropathy, and end stage renal disease. The cumulative incidence of dementia by depression was estimated conditional on survival dementia-free to age 55.

Results: Five percent (N = 182) were diagnosed with dementia and 20% had baseline depression. Depression was associated with a 72% increase in dementia (fully adjusted HR = 1.72; 95% CI:1.12-2.65). The 25-year cumulative incidence of dementia was more than double for those with versus without depression (27% vs. 12%).

Conclusions: For people with T1D, depression significantly increases dementia risk. Given the pervasiveness of depression in T1D, this has major implications for successful aging in this population recently living to old age.     

Complications in Intermediate Uveitis: Prevalence,Time of Onset,and Effects on Vision in Short-Term and Long-Term Follow-Up

Purpose: To study the prevalence and time of onset of ocular complications in intermediate uveitis (IU) and to assess their effects on visual outcome in short-term and long-term follow-up.

Methods: A retrospective cohort study of patients with IU who had a minimal follow-up of one year.

Results: 96 patients (174 eyes, 70% females) were included with a mean age at presentation of 30 years. Children constituted 38% of all patients. Mean follow- up was 64.9 months. Pars planitis was the most common form followed by sarcoidosis and multiple sclerosis. Cystoid macular edema (CME), cataract, epiretinal membrane and posterior synechiae were the most prevalent complications. Posterior synechiae, band keratopathy, cataract and papillitis at presentation were associated with worse presenting visual acuity (VA). Of the late-onset complications, glaucoma/ocular hypertension (OHT) was the most significantly associated with worse long-term VA. Most sight-threatening complications (namely CME and glaucoma) were diagnosed at presentation while late complications predominantly affected the posterior segment and included among others peripheral retinal elevations, vasoproliferative tumors, and vitreous hemorrhage. Median LogMAR VA improved at short-term and long-term follow-up, from 0.2 to 0.1 (p<0.001). Subgroup analysis revealed significant VA improvement for eyes with all the different complications except for eyes with glaucoma/OHT.

Conclusion: IU is a chronic low-grade uveitis that may be associated with protean early and late complications of the anterior or posterior segments or both. Optimal treatment regimens are imperative for the strict control of inflammation and proper management of complications thus allowing a favorable long-term prognosis.     

The Effect of Residential Aged Care Size,Ownership Model,and Multichain Affiliation on Resident Comfort and Symptom Management at the End of Life

Context

In most resource-rich countries, a large and growing proportion of older adults with complex needs will die while in a residential aged care (RAC) facility.

Comment on “Intraocular fluid biomarkers (liquid biopsy) in human diabetic retinopathy” Graefes Arch Clin Exp Ophthalmol. 2021 Jul 3. doi: 10.1007/s00417-021-05285-y

Graefe's Archive for Clinical and Experimental Ophthalmology -     

The Art Therapy Working Alliance Inventory: the development of a measure

Two studies present the development and validation of the Art Therapy Working Alliance Inventory measure, based on Bordin’s [1979. The generalizability of the psychoanalytic concept of the working alliance. Psychotherapy: Theory, Research & Practice, 16, 252–260] conceptualisation of the therapeutic working alliance. The measure captures unique aspects of the art therapy working alliance that take into account the client’s relation to the art medium in the presence of the art therapist. The measure’s reliability and validity were examined. In Study 1, 40 art therapy students, who participated in art therapeutic simulations as clients during their training programme, rated the measure in its development phase; in Study 2, 104 art therapy students completed the final questionnaire and the Working Alliance Inventory in regard to therapeutic simulations. Exploratory factor analysis revealed three main factors: perceiving the art medium as an effective therapeutic tool (Art Task); the affective and explorative experience during art-making (Art Experience); and, acceptance of the art therapist’s interventions in the art medium (Art Therapist Acceptance). Associations were found between Art Task and Art Therapist Acceptance with each of the working alliance components, as well as between Art Experience with the Bond component. Implications for practice and research are discussed.

Plain-language summary

• In verbal psychotherapy, a strong therapeutic alliance between client and therapist is necessary to achieve therapeutic goals. In art therapy, this alliance includes a third object: the art medium, comprised of art materials, artmaking and artworks.

• In this study, we developed and tested a new questionnaire for art therapy service users which measures the client-art medium alliance formed in art therapy. The new questionnaire is based on the Working Alliance Inventory, a well-known measure used in psychotherapy (Horvath & Greenberg, 1989) and is called the Art Therapy-Working Alliance Inventory.

• In order to measure the alliance between the client and the art medium, the Art Therapy-Working Alliance Inventory asks about three main areas: the client’s perception of the art medium as a therapeutic tool (Art-Task), the client’s affective experience of his/her artwork (Art Experience), and the client’s acceptance/rejection of the art-therapist’s interventions in the art medium (Art Therapist Acceptance).

• We asked 104 art therapy students to assume the role of clients in simulated art therapy sessions and then fill out the questionnaire at the end. We found a strong association between the two alliance scores; in other words, the stronger the alliance between the client and the art therapist, the stronger the alliance between the client and the art medium.

• Thus, we concluded that the Art Therapy-Working Alliance Inventory can serve as a useful tool in the research of art therapy practice.