Senescent Tumor Cells Build a Cytokine Shield in Colorectal Cancer.

Cellular senescence can either support or inhibit cancer progression. Here, it is shown that intratumoral infiltration of CD8+ T cells is negatively associated with the proportion of senescent tumor cells in colorectal cancer (CRC). Gene expression analysis reveals increased expression of C-X-C motif chemokine ligand 12 (CXCL12) and colony stimulating factor 1 (CSF1) in senescent tumor cells. Senescent tumor cells inhibit CD8+ T cell infiltration by secreting a high concentration of CXCL12, which induces a loss of CXCR4 in T cells that result in impaired directional migration. CSF1 from senescent tumor cells enhance monocyte differentiation into M2 macrophages, which inhibit CD8+ T cell activation. Neutralization of CXCL12/CSF1 increases the effect of anti-PD1 antibody in allograft tumors. Furthermore, inhibition of CXCL12 from senescent tumor cells enhances T cell infiltration and results in reducing the number and size of tumors in azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced CRC. These findings suggest senescent tumor cells generate a cytokine barrier protecting nonsenescent tumor cells from immune attack and provide a new target for overcoming the immunotherapy resistance of CRC.

Abrogation of B-RafV600E induced senescence by FoxM1 expression.

B-RafV600E oncogene mutation occurs in various cancers and is associated with tumor initiation. However, genetic modification of B-RafV600E in cells induces MAPK activation and results in oncogene-induced senescence. Overcoming the oncogene-induced senescence by B-RafV600E requires activation of another oncogene pathway, such as AKT signaling. In the present study, we explored the factors involved in overcoming the senescence program in cells activated by B-RafV600E and AKT signaling. B-RafV600E activation caused a feedback inhibition of AKT phosphorylation and resulted in downregulation of FoxM1, one of the AKT downstream components. AKT activation by PTEN downregulation induced FoxM1 expression, and co-expression of B-RafV600E and FoxM1 overcame the cellular senescence. These observations suggested that FoxM1 is critical downstream gene of AKT and functions to overcome B-RafV600E-induced senescence.

Senescent fibroblasts drive ageing pigmentation: ​A potential therapeutic target for senile lentigo.

Cutaneous ageing is an important extrinsic process that modifies the pigmentary system. Because cellular senescence is a fundamental ageing mechanism, we examined the role of senescent cells in ageing pigmentation. Methods: Biopsies obtained from senile lentigo and perilesional normal skin were assayed for a marker of cellular senescence, p16INK4A. To determine the secretory phenotypes of senescent fibroblasts, we performed microarray, RNA sequencing and methylation array analyses in senile lentigo and senescent fibroblasts. To further investigate the impact of senescent cells on ageing-related pigmentation, an intervention that targeted senescent cells using radiofrequency was performed. Results:In vivo, senescent fibroblasts accumulated at the sites of age-related pigmentation. Phenotype switching of the cells resulted in the repression of stromal-derived factor 1 (SDF1) by promoter methylation. SDF1 induced melanocyte differentiation via stromal-epithelial interactions, ultimately driving skin pigmentation. Furthermore, the elimination of senescent fibroblasts from pigmented skin using radiofrequency was accompanied by skin lightening, rendering it a potential target for treatment. Conclusion: Aged pigmented skin contains an increasing proportion of senescent fibroblasts. Cells with phenotype switching exhibited a loss of SDF1, which stimulates the melanogenic process and thereby contributes to aging pigmentation. These data may promote the development of new therapeutic paradigms, such as a stroma-targeting therapy for pigmentary disorders.

The effects of cognitive activity combined with active extremity exercise on balance, walking activity, memory level and quality of life of an older adult sample with dementia.

[Purpose] The purpose of this study was to compare the effectiveness of cognitive activity combined with active physical exercise for a sample of older adults with dementia. [Subjects] A convenience sample of 30 patients with dementia (Mini-Mental State Examination score between 16 and 23) was used. Participants were randomly allocated to one of two groups: cognitive activity combined with physical exercise CAE, n=11), and only cognitive activity CA, n=9). [Methods] Both groups participated in a therapeutic exercise program for 30 minutes, three days a week for 12 weeks. The CAE group performed an additional exercise for 30 minutes a day, three days a week for 12 weeks. A Wii Balance Board (WBB, Nintendo, Japan) was used to evaluate postural sway as an assessment of balance. The Berg Balance Scale (BBS) and Modified Falls Efficacy Scale (MFES) were used to assess dynamic balance abilities. The Timed Up-and-Go test (TUG) was used to assess gait, and the Digit Span Test (DST) and 7 Minute Screening Test (7MST) were used to measure memory performance. The Mini-Mental Status Exam-Korean version (MMSE-K), Kenny Self-Care Evaluation (KSCE), and Short Geriatric Depression Scale (GDS) were used to assess quality of life (QOL). [Results] There were significant beneficial effects of the therapeutic program on balance (velocity in EOWB, path length in ECNB, BBS, and MMFE), QOL (MMSE-KC, GDS, KSCE), and memory performance (DSB) in the CAE group compared to CA group, and between pre-test and post-test. [Conclusion] A 12-week CAE program resulted in improvements in balance, memory and QOL. Therefore, some older adults with dementia have the ability to acquire effective skills relevant to daily living.