Abstract Dysregulated lipid metabolism, characterized by the accumulation of lipid deposits on Bruch's membrane and in drusen, is considered a key pathogenic event in age‐related macular degeneration (AMD). The imbalance of lipid production, usage, and transport in local tissues, particularly in the retinal pigment epithelium (RPE), is increasingly recognized as crucial in AMD development. However, the molecular mechanisms governing lipid metabolism in the RPE remain elusive. LIPIN1, a multifunctional protein acting as both a modulator of transcription factors and a phosphatidate phosphatase (PAP1), is known to play important regulatory roles in lipid metabolism and related biological functions, such as inflammatory responses. While deficits in LIPIN1 have been linked to multiple diseases, its specific roles in the retina and RPE remain unclear. In this study, we investigated LIPIN1 in RPE integrity and function using a tissue‐specific knockout animal model. The clinical and histological examinations revealed age‐dependent degeneration in the RPE and the retina, along with impaired lipid metabolism. Bulk RNA sequencing indicated a disturbance in lipid metabolic pathways. Moreover, these animals exhibited inflammatory markers reminiscent of human AMD features, including deposition of IgG and C3d on Bruch's membrane. Collectively, our findings indicate that LIPIN1 is a critical component of the complex regulatory network of lipid homeostasis in the RPE. Disruption of LIPIN1‐mediated regulation impaired lipid balance and contributed to AMD‐related pathogenic changes.
A major concern with regard to glioma treatment arises from the fact that high-grade gliomas are insensitive to the majority of anticancer therapies.The aim of the present study was to investigate anti-proliferation potential of the mitotic inhibitor paclitaxel in three glioma cells with different BRAF mutation status.The U-87-MG cells were found to be more resistant to paclitaxel than other two glioma cell lines T98G and DBTRG-05MG, suggesting that the response of glioma cells to paclitaxel is not affected by the BRAF genotype.In addition, despite the induction of both apoptosis and autophagy in all glioma cell lines tested, our study has not specifically addressed the correlation of apoptosis and autophagy induction with growth inhibition.Instead, we found that paclitaxel caused a remarkably significant G 2 /M arrest in response to paclitaxel in T98G and DBTRG-05MG cells, whereas, less significant G 2 /M arrest was detected after paclitaxel treatment in U-87-MG, which exhibited more resistant to paclitaxel than other two cell lines.It is observed that T98G cells with mutant p53 progress through G 0 /G 1 checkpoint and greatly accumulated in the subsequent G 2 /M phase.In case of DBTRG-05MG cells with wild type p53, paclitaxel-induced growth inhibition displayed characteristics of p27 Kip1 -dependent G 2 /M arrest.In this study data suggest that paclitaxel-induced growth inhibition of glioma cells is tightly correlated with the G 2 /M arrest regardless of p53 mutation status.
Abstract Memory/effector T cells efficiently migrate into extralymphoid tissues and sites of infection, providing immunosurveillance and a first line of defense against invading pathogens. Even though it is a potential means to regulate the size, quality, and duration of a tissue infiltrate, T cell egress from infected tissues is poorly understood. Using a mouse model of influenza A virus infection, we found that CD8 effector T cells egressed from the infected lung in a CCR7-dependent manner. In contrast, following antigen-recognition, effector CD8 T cell egress decreased and CCR7 function was reduced in vivo and in vitro, indicating that the exit of CD8 T cells from infected tissues is tightly regulated. Our data suggest that the regulation of T cell egress is a mechanism to retain antigen-specific effectors at the site of infection to promote viral clearance, while decreasing the numbers of bystander T cells and preventing overt inflammation.
Naval Hospital Pensacola Pensacola, FL The opinions and assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the views of the Medical Department of the US Navy or the US Navy Service at large.
Importance Disparity in overall survival (OS) and differences in the frequency of driver gene variants by race and ethnicity have been separately observed in patients with colorectal cancer; however, how these differences contribute to survival disparity is unknown. Objective To quantify the association of molecular, socioeconomic, and clinical covariates with racial and ethnic disparities in overall survival among patients with colorectal cancer. Design, Setting, and Participants This single-center cohort study was conducted at a tertiary-level cancer center using relevant data on all patients diagnosed with colorectal cancer from January 1, 1973, to March 1, 2023. The relative contribution of variables to the disparity was determined using mediation analysis with sequential multivariate Cox regression models. Main Outcome OS, from diagnosis date and from start of first-line chemotherapy. Results The study population of 47 178 patients (median [IQR] age, 57.0 [49-66] years; 20 465 [43.4%] females and 26 713 [56.6%] males; 3.0% Asian, 8.7% Black, 8.8% Hispanic, and 79.4% White individuals) had a median (IQR) follow-up from initial diagnosis of 124 (174) months and OS of 55 (145) months. Compared with White patients, Black patients had worse OS (hazard ratio [HR], 1.16; 95% CI, 1.09-1.24; P <.001), whereas Asian and Hispanic patients had better OS (HR, 0.66; 95% CI, 0.59-0.74; P <.001; and 0.86; 95% CI, 0.81-0.92; P <.001, respectively). When restricted to patients with metastatic disease, the greatest disparity was between Black patients compared with White patients (HR, 1.2; 95% CI, 1.06-1.37; P <.001). Evaluating changes in OS disparity over 20 years showed disparity decreasing among Asian, Hispanic, and White patients, but increasing between Black patients and White patients (HRs, 1.18; 95% CI, 1.07-1.31 for 2008-2012; 1.24, 95% CI, 1.08-1.42 for 2013-2017; and 1.50; 95% CI, 1.20-1.87 for 2018-2023). Survival outcomes for first-line chemotherapy were worse for Black patients compared with White patients (median OS, 18 vs 26 months; HR, 1.30; 95% CI, 1.01-1.70). Among 7628 patients who had clinical molecular testing, APC , KRAS, and PIK3CA showed higher variant frequency in Black patients (false discovery rate [FDR], 0.01; < 0.001; and 0.01, respectively), whereas BRAF and KIT were higher among White patients (FDR, 0.001 and 0.01). Mediation analysis identified neighborhood socioeconomic status as the greatest contributor to OS disparity (29%), followed by molecular characteristics (microsatellite instability status, KRAS variation and BRAF variation, 10%), and tumor sidedness (9%). Conclusions This single-center cohort study identified substantial OS disparity and differing frequencies of driver gene variations by race and ethnicity. Socioeconomic status had the largest contribution but accounted for less than one-third of the disparity, with substantial contribution from tumor molecular features. Further study of the associations of genetic ancestry and the molecular pathogenesis of colorectal cancer with chemotherapy response is needed.
Background: The co-inhibitory receptor PD-1 is expressed in many tumours including head and neck squamous cell carcinoma (HNSCC) and is an important immunotherapy target. However, the role of PD-1 ligands, PD-L1 and particularly PD-L2, in the tumour-stromal cell interactions that cause a tumour-permissive environment in HNSCC is not completely understood and is the focus of our study. Methods: Expression of PD-L1 and PD-L2 was analysed by immunohistochemistry in situ in HNSCC tumour tissue. Co-cultures were established between stromal cells (fibroblasts and macrophages) and human papilloma virus (HPV)-positive and HPV-negative HNSCC cell lines (HNSCCs) and PD-1 ligands expression was analysed using flow cytometry. Results: PD-L1 and PD-L2 were expressed both in tumour cells and stroma in HNSCC tissue in situ. In vitro, basal expression of PD-L1 and PD-L2 was low in HNSCCs and high on fibroblasts and macrophages. Interestingly, HPV-positive but not HPV-negative HNSCCs increased the expression of both PD-1 ligands on fibroblasts upon co-culture. This effect was not observed with macrophages. Conversely, both fibroblasts and macrophages increased PD-1 ligands on HPV-positive HNSCCs, whilst this was not observed in HPV-negative HNSCCs. Crucially, we demonstrate that up-regulation of PD-L1 and PD-L2 on fibroblasts by HPV-positive HNSCCs is mediated via TLR9. Conclusions: This work demonstrates in an in vitro model that HPV-positive HNSCCs regulate PD-L1/2 expression on fibroblasts via TLR9. This may open novel avenues to modulate immune checkpoint regulator PD-1 and its ligands by targeting TLR9.
Poster: ECR 2018 / C-2656 / CT colonography: a bibliometric analysis of the 100 most cited articles in the field by: D. J. Bowden , M. J. Lee, M. M. Morrin; Dublin/IE
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