Biomimetic Smart Nanoplatform for Dual Imaging-Guided Synergistic Cancer Therapy

Developing an integrated multimodal diagnosis and therapeutics nanoplatform is of great importance to enhance the cancer therapy outcome. Herein, we report a highly efficient and biocompatible nanoplatform based on the...

Curcumin as an Epigenetic Therapeutic Agent in Myelodysplastic Syndromes (MDS)

Growth Factor Independence 1 (GFI1) is a transcription factor with an important role in the regulation of development of myeloid and lymphoid cell lineages and was implicated in the development of myelodysplastic syndrome (MDS) and acute myeloid leukaemia (AML). Reduced expression of GFI1 or presence of the GFI1-36N (serine replaced with asparagine) variant leads to epigenetic changes in human and murine AML blasts and accelerated the development of leukaemia in a murine model of human MDS and AML. We and other groups previously showed that the GFI1-36N allele or reduced expression of GFI1 in human AML blasts is associated with an inferior prognosis. Using GFI1-36S, -36N -KD, NUP98-HOXD13-tg mice and curcumin (a natural histone acetyltransferase inhibitor (HATi)), we now demonstrate that expansion of GFI1-36N or –KD, NUP98-HODXD13 leukaemic cells can be delayed. Curcumin treatment significantly reduced AML progression in GFI1-36N or -KD mice and prolonged AML-free survival. Of note, curcumin treatment had no effect in GFI1-36S, NUP98-HODXD13 expressing mice. On a molecular level, curcumin treatment negatively affected open chromatin structure in the GFI1-36N or -KD haematopoietic cells but not GFI1-36S cells. Taken together, our study thus identified a therapeutic role for curcumin treatment in the treatment of AML patients (homo or heterozygous for GFI1-36N or reduced GFI1 expression) and possibly improved therapy outcome.

Effects of acute stress on exposure therapy outcome and generalization in woman: considering the modulatory role of hormonal contraceptive use

The administration of glucocorticoids (GC) as an adjunct to exposure might represent a promising strategy to improve exposure therapy outcome in anxiety disorders (AD). The beneficial effects, however, might be sex-dependent and/or further modulated by hormonal factors (e.g., contraceptive usage in women). In the present study, we investigated whether acute stress before exposure therapy affects its efficacy in women using oral contraceptives (OC) relative to free-cycling (FC) women. In addition, possible effects of stress on generalization of therapy effects towards untreated stimuli were examined. Women with fears of spiders and cockroaches were randomly assigned to a stress (n=24) or no-stress (n=24) group prior to a standardized one-session exposure. Acute stress did not influence exposure-induced reduction in fear and avoidance of the treated stimuli (spiders). However, stress led to a less pronounced beneficial exposure outcome for treated stimuli in OC women relative to FC women. This effect occurred on the level of subjective fear and self-report questionnaires at post-treatment (24 hours after exposure) and follow-up (4 weeks after exposure). No effects of stress on generalization of therapy effects towards untreated stimuli (cockroaches) were found. Our findings suggest that OC usage diminishes the beneficial effects of stress on exposure therapy outcome seen in FC women. We present first clinical findings regarding the interaction of stress (and possibly GCs) and OC in exposure therapy of AD. OC intake in women constitutes a crucial factor to be considered in augmentation studies using stress and GCs.

Regulatory B Cells Involvement in Autoimmune Phenomena Occurring in Pediatric Graves’ Disease Patients

Graves’s disease is the most common type of autoimmune hyperthyroidism. Numerous studies indicate different factors contributing to the onset of the disease. Despite years of research, the exact pathomechanism of Graves’ disease still remains unresolved, especially in the context of immune response. B cells can play a dual role in autoimmune reactions, on the one hand, as a source of autoantibody mainly targeted in the thyroid hormone receptor (TSHR) and, on the other, by suppressing the activity of proinflammatory cells (as regulatory B cells). To date, data on the contribution of Bregs in Graves’ pathomechanism, especially in children, are scarce. Here, we investigated the frequencies of Bregs before and during a methimazole therapy approach. We reported higher Foxp3+ and IL-10+ Breg levels with CD38- phenotype and reduced numbers of CD38 + Foxp3 + IL-10+ in pediatric Graves’ patients. In addition, selected Breg subsets were found to correlate with TSH and TRAb levels significantly. Noteworthy, certain subpopulations of Bregs were demonstrated as prognostic factors for methimazole therapy outcome. Our data demonstrate the crucial role of Bregs and their potential use as a biomarker in Graves’ disease management.

Impact of occupational therapy in an integrated adult social care service: Audit of Therapy Outcome Measure Findings

PurposeHealth and social care services should demonstrate the quality of their interventions for commissioners, patients and carers, plus it is a requirement for occupational therapists to measure and record outcomes. Use of the “Therapy Outcome Measure” (TOMs) standardised tool was implemented by an occupational therapy adult social care service to demonstrate outcomes from April 2020, following integration to a community NHS Trust.Design/methodology/approachThe aim was to demonstrate occupational therapy outcomes in adult social care through a local audit of the TOMs. The objective was to determine if clients improved following occupational therapy intervention in the four domains of impairment, activity, participation and wellbeing/carer wellbeing. 70 cases were purposively sampled over a 2-month timeframe, extracting data from the local electronic recording system.FindingsOccupational therapy in adult social care clearly makes an impact with their client group and carers. Evidence from the dataset demonstrates clinically significant change, as 93% of clients seen by adult social care occupational therapy staff showed an improvement in at least one TOMs domain during their whole episode of care. 79% of activity scores, 20% of participation scores and 50% of wellbeing scores improved following intervention. 79% of carer wellbeing scores improved following occupational therapy.Research limitations/implicationsThe audit did not collect data on uptake from the separate teams (equipment, housing, STAR and adult social care work) in occupational therapy adult social care. Potential sampling bias occurred as cases with completed scores only were purposively sampled. Sampling was not random which prevented data gathering on uptake of TOMs across the separate teams. Additionally, the audit results can only be applied to the setting from which the data was collected, so has limited external validity.Originality/valueThese novel findings illustrate the valuable and unique impact of occupational therapy in this adult social care setting. The integration of adult social care into an NHS Community Trust has supported the service to measure outcomes, by utilising the same standardised tool in use by allied health professions across the Trust.

Digital Quantification of Tumor PD-L1 Predicts Outcome of PD-1-Based Immune Checkpoint Therapy in Metastatic Melanoma

BackgroundPD-1-based immune checkpoint blockade (ICB) is a highly effective therapy in metastatic melanoma. However, 40-60% of patients are primarily resistant, with valid predictive biomarkers currently missing. This study investigated the digitally quantified tumor PD-L1 expression for ICB therapy outcome prediction.Patients and MethodsTumor tissues taken prior to PD-1-based ICB for unresectable metastatic disease were collected within the prospective multicenter Tissue Registry in Melanoma (TRIM). PD-L1 expression (clone 28-8; cut-off=5%) was determined by digital and physician quantification, and correlated with therapy outcome (best overall response, BOR; progression-free survival, PFS; overall survival, OS).ResultsTissue samples from 156 patients were analyzed (anti-PD-1, n=115; anti-CTLA-4+anti-PD-1, n=41). Patients with PD-L1-positive tumors showed an improved response compared to patients with PD-L1-negative tumors, by digital (BOR 50.5% versus 32.2%; p=0.026) and physician (BOR 54.2% versus 36.6%; p=0.032) quantification. Tumor PD-L1 positivity was associated with a prolonged PFS and OS by either digital (PFS, 9.9 versus 4.6 months, p=0.021; OS, not reached versus 13.0 months, p=0.001) or physician (PFS, 10.6 versus 5.6 months, p=0.051; OS, not reached versus 15.6 months, p=0.011) quantification. Multivariable Cox regression revealed digital (PFS, HR=0.57, p=0.007; OS, HR=0.44, p=0.001) and physician (OS, HR=0.54, p=0.016) PD-L1 quantification as independent predictors of survival upon PD-1-based ICB. The combination of both methods identified a patient subgroup with particularly favorable therapy outcome (PFS, HR=0.53, p=0.011; OS, HR=0.47, p=0.008).ConclusionPre-treatment tumor PD-L1 positivity predicted a favorable outcome of PD-1-based ICB in melanoma. Herein, digital quantification was not inferior to physician quantification, and should be further validated for clinical use.