Gut microbiota modulate CD8+ T cell immunity in gastric cancer through Butyrate/GPR109A/HOPX.

The gut microbiota and Short-chain fatty acids (SCFAs) can influence the progression of diseases, yet the role of these factors on gastric cancer (GC) remains uncertain. In this work, the analysis of the gut microbiota composition and SCFA content in the blood and feces of both healthy individuals and GC patients indicated that significant reductions in the abundance of intestinal bacteria involved in SCFA production were observed in GC patients compared with the controls. ABX mice transplanted with fecal microbiota from GC patients developed more tumors during the induction of GC and had lower levels of butyric acid. Supplementation of butyrate during the induction of gastric cancer along with H. pylori and N-methyl-N-nitrosourea (MNU) in WT in GPR109A-/-mice resulted in fewer tumors and more IFN-γ+ CD8+ T cells, but this effect was significantly weakened after knockout of GPR109A. Furthermore, In vitro GC cells and co-cultured CD8+ T cells or CAR-Claudin 18.2+ CD8+ T cells, as well as in vivo tumor-bearing studies, have indicated that butyrate enhanced the killing function of CD8+ T cells or CAR-Claudin 18.2+ CD8+ T cells against GC cells through G protein-coupled receptor 109A (GPR109A) and homologous domain protein homologous box (HOPX). Together, these data highlighted that the restoration of gut microbial butyrate enhanced CD8+ T cell cytotoxicity via GPR109A/HOPX, thus inhibiting GC carcinogenesis, which suggests a novel theoretical foundation for GC management against GC.

PITPNC1 Suppress CD8+ T cell immune function and promote radioresistance in rectal cancer by modulating FASN/CD155.

BACKGROUND: Radioresistance is a primary factor contributing to the failure of rectal cancer treatment. Immune suppression plays a significant role in the development of radioresistance. We have investigated the potential role of phosphatidylinositol transfer protein cytoplasmic 1 (PITPNC1) in regulating immune suppression associated with radioresistance. METHODS: To elucidate the mechanisms by which PITPNC1 influences radioresistance, we established HT29, SW480, and MC38 radioresistant cell lines. The relationship between radioresistance and changes in the proportion of immune cells was verified through subcutaneous tumor models and flow cytometry. Changes in the expression levels of PITPNC1, FASN, and CD155 were determined using immunohistochemistry and western blotting techniques. The interplay between these proteins was investigated using immunofluorescence co-localization and immunoprecipitation assays. Additionally, siRNA and lentivirus-mediated gene knockdown or overexpression, as well as co-culture of tumor cells with PBMCs or CD8+ T cells and establishment of stable transgenic cell lines in vivo, were employed to validate the impact of the PITPNC1/FASN/CD155 pathway on CD8+ T cell immune function. RESULTS: Under irradiation, the apoptosis rate and expression of apoptosis-related proteins in radioresistant colorectal cancer cell lines were significantly decreased, while the cell proliferation rate increased. In radioresistant tumor-bearing mice, the proportion of CD8+ T cells and IFN-γ production within immune cells decreased. Immunohistochemical analysis of human and animal tissue specimens resistant to radiotherapy showed a significant increase in the expression levels of PITPNC1, FASN, and CD155. Gene knockdown and rescue experiments demonstrated that PITPNC1 can regulate the expression of CD155 on the surface of tumor cells through FASN. In addition, co-culture experiments and in vivo tumor-bearing experiments have shown that silencing PITPNC1 can inhibit FASN/CD155, enhance CD8+ T cell immune function, promote colorectal cancer cell death, and ultimately reduce radioresistance in tumor-bearing models. CONCLUSIONS: PITPNC1 regulates the expression of CD155 through FASN, inhibits CD8+ T cell immune function, and promotes radioresistance in rectal cancer.

Clinical activity and safety of sintilimab, bevacizumab, and TMZ in patients with recurrent glioblastoma.

PURPOSE: There are limited and no standard therapies for recurrent glioblastoma. We herein report the antitumour activity and safety of sintilimab, bevacizumab and temozolomide (TMZ) in recurrent glioblastoma. METHODS: We retrospectively analysed eight patients with recurrent glioblastoma treated with sintilimab (200 mg) every three weeks + bevacizumab (10 mg/kg) every three weeks + TMZ (200 mg/m²orally) (5 days orally every 28 days for a total of four weeks). The primary objective was investigator-assessed median progression-free survival(mPFS). Secondary objectives were to assess the 6-month PFS, objective response rate (ORR) and duration of response (DOR) accroding to RANO criteria. RESULTS: The mPFS time for 8 patients was 3.340 months (95% CI: 2.217-4.463), The longest PFS was close to 9 months. Five patients were assessed to have achieved partial response (PR), with an overall remission rate of 62.5%, Four patients experienced a change in tumour volume at the best response time of greater than 60% shrinkage from baseline, and one patient remained progression free upon review, with a DOR of more than 6.57 months. The 6-month PFS was 25% (95% CI: 5.0-55.0%). Three patients had a treatment-related adverse events, though no grade 4 or 5 adverse events occurred. CONCLUSION: In this small retrospective study, the combination regimen of sintilimab, bevacizumab and TMZ showed promising antitumour activity in treatment of recurrent glioblastoma, with a good objective remission rate.

Development of a Clinical Risk Score Prediction Tool for 5-, 9-, and 13-Year Risk of Dementia.

Importance: Although researchers have devoted substantial efforts, money, and time to studying the causes of dementia and the means to prevent it, no effective treatment exists yet. Identifying preclinical risk factors of dementia could help prevent or delay its progression. Objective: To develop a point risk score prediction model of dementia. Design, Setting, and Participants: This study used a large UK population-based prospective cohort study conducted between March 13, 2006, and October 1, 2010. Data analysis was performed from June 7 to September 15, 2021. Individual analyses of time end points were concluded at the first dementia diagnosis during the follow-up period. The data were split into training and testing data sets to separately establish and validate a prediction model. Main Outcomes and Measures: Outcomes of interest included 5-, 9-, and 13-year dementia risk. Least absolute shrinkage and selection operator and multivariate Cox proportional hazards regression models were used to identify available and practical dementia predictors. A point risk score model was developed for the individual prediction of 5-, 9-, and 13-year dementia risk. Results: A total of 502 505 participants were selected; the population after exclusions for missing data and dementia diagnosis at baseline was 444 695 (205 187 men; mean [SD] age, 56.74 [8.18] years; 239 508 women; mean [SD] age, 56.20 [8.01] years). Dementia occurrence during the 13 years of follow-up was 0.7% for men and 0.5% for women. The C statistic of the final multivariate Cox proportional hazards regression model was 0.86 for men and 0.85 for women in the training data set, and 0.85 for men and 0.87 for women in the testing data set. Men and women shared some modifiable risk and protective factors, but they also presented independent risk factors that accounted for 31.7% of men developing dementia and 53.35% of women developing dementia according to the weighted population-attributable fraction. The total point score of the risk score model ranged from -18 to 30 in men and -17 to 30 in women. The risk score model yielded nearly 100% prediction accuracy of 13-year dementia risk both in men and women. Conclusions and Relevance: In this diagnostic study, a practical risk score tool was developed for individual prediction of dementia risk, which may help individuals identify their potential risk profile and provide guidance on precise and timely actions to promote dementia delay or prevention.

Allogeneic Platelet-Rich Plasma Therapy as an Effective and Safe Adjuvant Method for Chronic Wounds.

BACKGROUND: Platelet-rich plasma (PRP) improves the healing of refractory wounds, and its application is receiving more attention in the field of wound repair. However, when a patient's condition is very poor, it may be difficult to provide whole blood to harvest autologous PRP. METHODS: We evaluated the efficacy and safety of allogeneic PRP in the field of chronic refractory wound repair. Sixty patients (39 males and 21 females, 57 ± 10 y old) with chronic wounds were enrolled in this prospective, randomized, single-center study during January 2014 to January 2018. Their wounds were treated by standard care. The patients with chronic refractory wounds were divided into allogeneic PRP treatment and control groups on the basis of the presence or absence of allogeneic PRP in wounds after debridement, respectively. Allogeneic PRP was prepared by collecting whole blood from healthy individuals and two-step centrifugation. Clinical effects were evaluated by visually observing wound conditions and objectively assessing wound surfaces. RESULTS: After 30 d of treatment, the allogeneic PRP-treated group showed bright red granulation that bled easily with reduced inflammatory exudation. No rejection reactions were observed. The rate of chronic wound healing was much faster in the allogeneic PRP-treated group than that in the control group. CONCLUSIONS: The present study shows that combined treatment of chronic wounds by standard care and allogeneic PRP significantly shortens healing time, suggesting that allogeneic PRP is an effective, safe adjuvant treatment for chronic wounds.

Antiaging Properties of Exosomes from Adipose-Derived Mesenchymal Stem Cells in Photoaged Rat Skin.

Adipose-derived stem cells (ADSCs) have been documented as possible candidates for skin rejuvenation. However, the effects of ADSC-derived exosomes on photoaged skin remain to be fully elucidated. This study was aimed at determining the antiaging effects of ADSC-derived exosomes on photoaged skin. Human ADSCs were isolated from the adipose tissue of healthy women and cultured in vitro. Then, exosomes were extracted from the cultured ADSCs, purified by ultracentrifugation, and verified by examination of cell morphology using transmission electron microscopy and the identification of specific biomarkers. Meanwhile, the optimal exosome concentration and treatment time were selected. The photoaged skin model was created by subjecting Sprague-Dawley rats to ultraviolet B radiation. Exosomes were injected into the photoaged skin in a single therapeutic dose. The thickness of the epidermis and dermis was observed by HE staining. The relative mRNA expression of type I collagen, type III collagen, and matrix metalloproteinases (MMP-1 and MMP-3) was determined by real-time PCR. In the rat model of photoaged skin, the injected exosomes markedly decreased the epidermal thickness and increased the dermal thickness of the photoaged skin 7 days after treatment. Moreover, the proportion of the stratum corneum of the epidermis was decreased. Furthermore, real-time RT-PCR showed that the mRNA expression of type I collagen was increased and that of type III collagen, MMP-1, and MMP-3 was decreased. Our results demonstrate that ADSC-derived exosome treatment could significantly improve skin photodamage and that ADSC-derived exosomes may be a potential agent for photoaged skin treatment.

A novel role of angiotensin II in epidermal cell lineage determination: Angiotensin II promotes the differentiation of mesenchymal stem cells into keratinocytes through the p38 MAPK, JNK and JAK2 signalling pathways.

BACKGROUND: Recent evidence suggests that angiotensin II (Ang II) plays a role in cutaneous wound healing. Mesenchymal stem cells (MSCs) are known as a rich source of cells that re-establish healed skin. However, the potential impact of Ang II on MSC differentiation into keratinocytes is still unknown. OBJECTIVE: The present study was conducted to explore the effect of Ang II on the differentiation of bone marrow-derived MSCs (BM-MSCs) into keratinocytes. METHODS: Bone marrow-derived MSCs were isolated from rat bone marrow and cultured. The expression of Ang II type 1 (AT1 ) and type 2 (AT2 ) receptors was examined by immunofluorescence staining. The differentiation of BM-MSCs into keratinocytes was investigated by flow cytometry or/and histological observation. RESULTS: The BM-MSCs constitutively expressed both AT1 and AT2 receptors. The differentiation of BM-MSCs into keratinocytes was successfully induced. Interestingly, incubation of BM-MSCs with Ang II further promoted the differentiation of BM-MSCs into keratinocyte, which was abolished by pretreament with losartan, an AT1 receptor antagonist, but not by PD123319, an AT2 receptor antagonist. Moreover, the p38 mitogen-activated protein kinase (MAPK) inhibitor SB203580, the c-Jun N-terminal kinase (JNK) inhibitor SP600125 and the Janus-activated kinase (JAK)2 inhibitor AG490 suppressed Ang II-induced differentiation of BM-MSCs into keratinocytes. The phosphoinositide-3 kinase (PI3K) inhibitor wortmannin and MEK1/2 inhibitor U0126 had no effect on BM-MSC differentiation into keratinocytes. CONCLUSIONS: Our data demonstrated for the first time that Ang II plays a promotive role in the differentiation of BM-MSC into keratinocytes through the AT1 receptor, and that the p38 MAPK, JNK and JAK2 signalling pathways are involved in this process.