This study aimed to identify the correlation between influencing factors of activities of daily living (ADLs), mental health, and health-related quality of life (HRQoL) among post-stroke patients who ...enrolled in a transitional care service in a public hospital. This cross-sectional study involved 67 stroke patients who were enrolled in a transitional care service and visited the outpatient clinic at a public hospital in Seoul between March and December 2022. Their general characteristics, ADLs, mental health, and HRQoL were assessed. The data were analyzed using independent samples t-tests, analysis of variance, and Pearson correlation analysis, and the influencing factors were analyzed using regression analysis. HRQoL showed a statistically significant difference between patients living in different types of arrangements (t = 2.50, p = 0.015), and patients scores on the modified Rankin Scale (t = 7.08, p < 0.001). HRQoL was also significantly correlated with ADLs and mental health in stroke patients (r = -0.59, p < 0.001; r = -0.41, p < 0.001, respectively). Meanwhile, stroke severity (β = -0.30, p = 0.002), living arrangements (β = -0.30, p = 0.009) and ADLs (β = -0.45, p < 0.001) were found to influence HRQoL (F = 6.87, p < 0.001, R
= 0.47). Reduced dependence for ADLs, improvements in symptoms consequent to stroke, and support related to living arrangements contributed to improved HRQoL and interventions for post-stroke patients in the transitional care service of a public hospital.
BackgroundChimeric antigen receptor (CAR) -T cell therapies have proven to be effective against various liquid tumors. However, the development of CAR-T against solid tumors has been challenging due ...to insufficient efficacy and potential on-target off-tumor toxicities caused by low expression of tumor antigens on normal tissues. Testing various affinities of CARs has demonstrated that lower affinity CARs maintain its anti-tumor effect while minimizing safety concerns (1). In order to develop a CAR-T against solid tumors expressing Mucin1, we have screened for Mucin1 binding antibodies and tested their anti-tumor effect in vitro and in vivo. The potential of on-target off-tumor toxicity was also measured in vitro.MethodsAnti-Mucin1 human single chain variable fragments (scFv) were obtained via screening against a scFv display library. Anti-Mucin1 scFvs were incorporated into CARs and in vitro, in vivo functions against various tumor cells expressing Mucin1 were tested. For in vivo studies, tumor bearing NOG mice (HCC1954 cells) received anti-Mucin1 CAR-T cells. Therapeutic efficacy was evaluated by measuring tumor volumes. Potential on-target off-tumor toxicity against Mucin1 on normal cells was tested by investigating the killing effect of anti-Mucin1 CAR-T against cancer cell line (HCC70) and non-tumorigenic breast epithelial cell line (MCF-10A) in co-culture systemsResultsIn vitro activity of anti-Mucin1 CAR-T cells that displayed a range of affinities for Mucin1 (27nM to 320nM) showed similar cytokine secretion levels and cytotoxicity against Mucin-1 expressing tumor cell lines (HCC70 and T47D). Robust anti-tumor activity was also demonstrated in vivo against large tumors (400~500 mm3) with relatively small numbers of CAR-T cells (0.5 x 106 CAR-T cells per mouse). In vivo expansion of CAR-T cells were observed in all scFv-CAR-T cases and accompanied by close to complete regression of tumors within 25 days post CAR-T cell injection. Of the 4 scFv CAR-Ts, 2H08 (with a Kd of 94nM) was tested for activity against normal breast epithelial cells. When 2H08-CAR-T was cocultured with a mixture of HCC70 and MCF-10A cells, they preferentially killed only the Mucin1 overexpressing HCC70 cells leaving MCF-10 cells intact.ConclusionsOur study demonstrates anti-tumor activity of a novel scFv-derived CAR-T recognizing Mucin1 and its effectiveness in large pre-established tumors in vivo. We also demonstrate that 2H08-CAR-T can distinguish between target overexpressing cancer cells and normal epithelial cells, which suggests that by toning down the affinity of CAR against antigen one can improve the safety profile of solid tumor antigen targeting CAR-T cell therapies.ReferenceCastellarin M, Sands C, Da T, Scholler J, Graham K, Buza E, Fraietta J, Zhao Y, June C. A rational mouse model to detect on-target, off-tumor CAR T cell toxicity. JCI Insight 2020; 5:e136012Ethics ApprovalAll experiments were done under protocols approved by the Institutional Animal Care and Use Committee (IACUC) (Study#LGME21-011).ConsentWritten informed consent was obtained from the patient for publication of this abstract and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.
RASSF2 belongs to the Ras‐association domain family (RASSF) of proteins, which may be involved in the Hippo signalling pathway. However, the role of RASSF2 in vivo is unknown. Here, we show that ...Rassf2 knockout mice manifest a multisystemic phenotype including haematopoietic anomalies and defects in bone remodelling. Bone marrow (BM) transplantation showed that Rassf2−/− BM cells had a normal haematopoietic reconstitution activity, indicating no intrinsic haematopoietic defects. Notably, in vitro differentiation studies revealed that ablation of Rassf2 suppressed osteoblastogenesis but promoted osteoclastogenesis. Co‐culture experiments showed that an intrinsic defect in osteoblast differentiation from Rassf2−/− osteoblast precursors likely leads to both haematopoiesis and osteoclast defects in Rassf2−/− mice. Moreover, Rassf2 deficiency resulted in hyperactivation of nuclear factor (NF)‐κB during both osteoclast and osteoblast differentiation. RASSF2 associated with IκB kinase (IKK) α and β forms, and suppressed IKK activity. Introduction of either RASSF2 or a dominant‐negative form of IKK into Rassf2−/− osteoclast or osteoblast precursors inhibited NF‐κB hyperactivation and normalized osteoclast and osteoblast differentiation. These observations indicate that RASSF2 regulates osteoblast and osteoclast differentiation by inhibiting NF‐κB signalling.
The Ras‐binding protein RASSF2 has poorly defined functions in cell‐cycle control and apoptosis, and has been linked to Hippo signalling. Loss of Rassf2 in vivo disrupts osteoblast differentiation via NF‐κB pathway deregulation, with consequent effects on bone formation and haematopoietic development.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Alopecia is traditionally viewed as androgen-dependent, but emerging evidence has implicated oxidative stress in the pathogenesis of hair loss. Current treatments for alopecia have limited efficacy, ...leading to the need for new therapies. Human dermal papilla cells (hDPCs) play a pivotal role in hair follicle (HF) development and hair growth regulation. In this study, we investigated the potential of (S)-3-((S)-2-(6-(2,3-dihydrobenzob1,4dioxin-6-yl)-1-oxoisoindolin-2-yl)butanamido)-4-oxo-5-(2,3,5,6 tetrafluorophenoxy) pentanoic acid (THPA), a pan-caspase inhibitor, to reduce ROS-induced cellular damage and apoptosis in hDPCs. Our study revealed that THPA effectively suppressed hydrogen peroxide-induced apoptosis while also attenuating activated caspase signaling. Additionally, THPA restored the down-regulated expression of β-catenin, a key mediator of the Wnt/β-catenin pathway, in hDPCs exposed to hydrogen peroxide. Furthermore, significant alterations in Akt/mTOR/p70S6K signaling were observed following THPA treatment. Notably, THPA treatment led to a reduction in the expression of Dickkopf-1 (DKK-1), an inhibitor of the Wnt/β-catenin pathway implicated in hair follicle regression. Moreover, THPA treatment decreased the expression of the cell senescence markers p21 and p16, suggesting a potential role in preserving hDPC function and delaying hair follicle regression. Collectively, our findings highlight the therapeutic potential of THPA in preventing hair loss by protecting hDPCs against oxidative stress damage.
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