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Abstract Regulatory T-cells (Tregs) play a major role in suppressing anti-tumor immune responses. Mogamulizumab, an anti-CC chemokine receptor type 4 (CCR4) monoclonal antibody, depletes effector Tregs (eTregs). However, the clinical efficacy of mogamulizumab was limited in phase Ia/Ib studies for solid tumors (NCT01929486); the finding suggests that mogamulizumab may also deplete beneficial CCR4+CD8+ T-cells in patients. Therefore, we focused on CTLs and aimed to identify a way to protect CCR4+ CTLs. Here, we evaluated the association of CCR4 expression in cytotoxic T-lymphocytes (CTLs) with antigen and cytokine stimulations and kinase inhibition using cytomegalovirus antigen instead of tumor antigen. CCR4 expression in CTLs was induced by antigen stimulation (mean 3.14–29.0%), enhanced by transforming growth factor-β1 (TGF-β1) (mean 29.0–51.2%), and downregulated by trametinib with (mean 51.2–11.4%) or without TGF-β1 treatment (mean 29.0–6.98%). Phosphorylation of ERK in CD8+ T-cells was suppressed by trametinib. Regarding the effect on immunological function of CTL, trametinib reduced cytokine production but not affected cytotoxicity. Importantly, trametinib alleviated CTL reduction by anti-CCR4 antibody without affecting eTreg depletion because CCR4 expression in eTregs was not downregulated. In conclusion, combination therapy with trametinib may improve the clinical efficacy of mogamulizumab.

This study aimed to investigate the effect of a rehabilitation program combined with pain management targeting pain perception and activity avoidance on multifaceted outcomes in older patients with acute vertebral compression fractures (VCFs). We randomised 65 older adults with acute VCFs to either an intervention group (n = 32), involving usual rehabilitation combined with pain management that targeted pain perception and activity avoidance, or a control group (n = 33), involving only usual rehabilitation. The usual rehabilitation was initiated immediately after admission. All patients were treated conservatively. Pain management aimed to improve the patients’ daily behaviour by increasing their daily activities despite pain, rather than by focusing on eliminating the pain. Pain intensity and psychological statuses such as depression, pain catastrophising, and physical activity levels were assessed on admission. Two weeks postadmission and at discharge, physical performance measures were assessed along with the above-given measurements. A significant main effect of the group was observed for the intensity of lower back pain, favouring the intervention group (F = 5.135, p=0.027). At discharge, it was significantly better in the intervention group than in the control group (p=0.011). A time-by-group interaction emerged for magnification of the pain catastrophising scale (p=0.012), physical activity levels (p

ObjectiveTo investigate the effectiveness of exercise and/or educational intervention on physical activity and pain in patients with hip/knee osteoarthritis (OA) using systematic review and meta-analysis.MethodsWe searched randomized controlled trials that investigated physical activity and pain and compared exercise and/or educational intervention with usual care in patients with hip/knee OA in MEDLINE (PubMed), ProQuest, Scopus, and the Physiotherapy Evidence Database (PEDro), including all those published by April 30, 2022 and written in English. Studies that newly applied analgesics after onset of the intervention were excluded. The revised Cochrane risk-of-bias tool for randomized trials was used to assess the methodological qualities. The random-effects model was used for meta-analysis with standard mean differences using RevMan version 5.4. The body of evidence for each study was synthesized using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach.ResultsTwenty studies including 2,350 patients were included (7 exercise studies, 8 educational intervention studies and 5 combination studies). The meta-analysis demonstrated that there is very low evidence that combination therapy of exercise and educational intervention improve the physical activity level at the endpoint (4 articles; SMD 0.33, 95% CI 0.04 to 0.51, P = 0.03). Low evidence was observed for combination therapy reducing pain (4 articles; SMD -0.15, 95% CI -0.29 to -0.02, P = 0.03).DiscussionThe current evidence indicated that combination therapy of exercise and educational intervention leads to improved physical activity and pain reduction in hip/knee OA patients, but the risk of bias in each study, especially in allocation concealment, downgraded the evidence level. These findings support the use of a combination therapy of exercise and educational intervention to promote physical activity levels in patients with hip/knee OA.Trail registrationThere was no financial support for this research. The protocol was registered at the International Prospective Register of Systematic Reviews (registration code: CRD42020205804).

Pendant-type (P)-helicene oligomers with p-phenylene ethynylene main chains up to a tetramer were synthesized by a building block method. The (P)-tetramer reversibly formed a ladderlike bimolecular aggregate upon cooling and disaggregated upon heating in (trifluoromethyl)benzene. Two bis(tetramer)s, in which two (P)-tetramers were connected by hexadecamethylene linkers, were also synthesized. The head-to-tail bis(tetramer) formed an intramolecular aggregate, and the head-to-head bis(tetramer) formed an intermolecular aggregate in toluene. The results suggest the antiparallel aggregation structure of the pendant-type (P)-tetramers. The structure of the linker was proven to be effective in controlling intramolecular and intermolecular aggregations. [ABSTRACT FROM AUTHOR]