Breast cancer is the most frequent malignancy in women worldwide, and triple-negative breast cancer (TNBC) patients have the worst prognosis and highest risk of recurrence. The therapeutic strategies for TNBC are limited. It is urgent to develop new methods to enhance the efficacy of TNBC treatment. Previous studies demonstrated that D-mannose, a hexose, can enhance chemotherapy in cancer and suppress the immunopathology of autoimmune diseases. Here, we show that D-mannose can significantly facilitate TNBC treatment via degradation of PD-L1. Specifically, D-mannose can activate AMP-activated protein kinase (AMPK) to phosphorylate PD-L1 at S195, which leads to abnormal glycosylation and proteasomal degradation of PD-L1. D-mannose–mediated PD-L1 degradation promotes T cell activation and T cell killing of tumor cells. The combination of D-mannose and PD-1 blockade therapy dramatically inhibits TNBC growth and extends the lifespan of tumor-bearing mice. Moreover, D-mannose–induced PD-L1 degradation also results in messenger RNA destabilization of DNA damage repair–related genes, thereby sensitizing breast cancer cells to ionizing radiation (IR) treatment and facilitating radiotherapy of TNBC in mice. Of note, the effective level of D-mannose can be easily achieved by oral administration in mice. Our study unveils a mechanism by which D-mannose targets PD-L1 for degradation and provides methods to facilitate immunotherapy and radiotherapy in TNBC. This function of D-mannose may be useful for clinical treatment of TNBC.
Background Clear cell renal cell carcinoma (ccRCC) is still highly aggressive and lethal even with various therapeutic approaches. As the kidney is an iron metabolism-related organ, exploring and assessing the clinical value of ferroptosis, an iron-dependent regulated cell death, is practical and important. Methods Prognostic ferroptosis-related differentially expressed genes (DEGs) were identified from the KIRC cohort in the cancer genome atlas (TCGA) database, from which a prognostic signature was established using Lasso-penalized Cox regression analysis. Each patient in the KIRC cohort and the E-MTAB-1980 cohort (from the ArrayExpress database) was assigned a calculated signature-correlated risk score and categorized to be either in the high- or low-risk group divided by the median risk score in the KIRC cohort. Then, the independent prognostic value of the signature was further assessed by Kaplan-Meier (K-M) survival, time-dependent receiver operating characteristic (ROC) and Cox regression analyses based on overall survival (OS) in both cohorts. Finally, risk-related DEGs were identified in both cohorts and subjected to enrichment analyses for Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and immune infiltration. Results Among 60 ferroptosis-related genes, 32 prognostic DEGs were identified, from which we constructed a prognostic 12-gene signature with CARS1, HMGCR, CHAC1, GOT1, CD44, STEAP3, AKR1C1, CBS, DPP4, FANCD2, SLC1A5 and NCOA4. Patients in both cohorts were divided into high- and low-risk groups, which were visually distributed in two sets and had positive-risk-related mortality. The K-M survival and the ROC curves validated that the signature has prognostic value with P < 0.05 and area under the curve > 0.7 in both cohorts, respectively. Multivariate Cox regression further confirmed the risk score as an independent prognostic predictor for OS. Commonly enriched terms in GO and KEGG not only showed a high iron correlation but also, interestingly, immune relevance of 3 immune cells (macrophages, mast cells and regulatory T cells) and 1 immune-related function (antigen processing cell co-stimulation). Conclusion We established a novel 12 ferroptosis-related-gene signature that was proven to be an independent prognostic predictor for OS and inferred to be related to tumour immunity in ccRCC; however, the underlying mechanism is still poorly characterized and needs further exploration.
Background Dietary and lifestyle factors may play an important role in the increasing prevalence of nephrolithiasis. We aimed to review and quantify the associations between lifestyle factors and incident nephrolithiasis and suggest lifestyle changes for the primary prevention of nephrolithiasis. Methods PubMed, EMBASE, and Cochrane Library were searched up to May 2019, for observational studies and randomized controlled trials (RCTs) that assessed modifiable lifestyle factors and risk of nephrolithiasis in adults. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were computed using a random effects model. The I 2 statistic was employed to evaluate heterogeneity. Subgroup analysis, sensitivity analysis and meta-regression were also conducted whenever possible. Results Fifty relevant articles with 1,322,133 participants and 21,030 cases in total were identified. Prominent risk factors for incident stones were body mass index (1.39,1.27–1.52), dietary sodium (1.38, 1.21–1.56), fructose, meat, animal protein, and soda. In contrast, protective factors included fluid intake (0.55, 0.51–0.60), a Dietary Approaches to Stop Hypertension (DASH) style diet (0.69, 0.64–0.75), alcohol (0.69, 0.56–0.85), water, coffee, tea, vegetables, fruits, dietary fiber, dietary calcium (0.83, 0.76–0.90), and potassium. Vitamin D (1.22, 1.01–1.49) and calcium (1.16, 1.00–1.35) supplementation alone increased the risk of stones in meta-analyses of observational studies, but not in RCTs, where the cosupplementation conferred significant risk. Conclusions Several modifiable factors, notably fluid intake, dietary patterns, and obesity, were significantly associated with nephrolithiasis. Long-term RCTs are required to investigate the cost-effectiveness of dietary patterns for stone prevention. The independent and combined effects of vitamin D and calcium supplementation on nephrolithiasis need further elucidation.
Abbreviations & Acronyms BC = bladder capacity BP = base pressure BPS = bladder pain syndrome CMG = cystometrogram ELISA = enzyme-linked immunosorbent assay GAG = glycosaminoglycan GAPDH = glyceraldehydes-3-phosphate dehydrogenase HA = hyaluronic acid IC = interstitial cystitis ICI = intercontraction intervals IL-6 = interleukin-6 mRNA = messenger ribonucleic acid NS = normal saline PP = peak pressure PS = protamine sulfate RNA = ribonucleic acid RT-PCR = reverse transcription polymerase chain reaction RV = residual volume Objectives: To measure interleukin-6 levels in a protamine sulfate-induced chronic cystitis rat model treated with hyaluronic acid, and to study the correlation among interleukin-6, bladder inflammatory degree and voiding frequency. Methods: A chronic cystitis model was created in female rats by using long-term intermittent intravesical protamine sulfate (0.5 mL, 30 mg/mL). Then, hyaluronic acid (0.5 mL, 0.8 mg/mL) was also instilled intravesically in the rats. Interleukin-6 levels were analyzed with immunohistochemistry, real-time reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay. Hematoxylin-eosin staining was carried out to examine bladder inflammatory degree based on a four-point scoring system (from 0 -none to 3 -severe). Voiding patterns were investigated by cystometrography. Results: According to cystometrography, protamine sulfate-induced rats had significantly shorter intercontraction intervals and less bladder capacity (P < 0.001). The bladder tissue of the rats showed severe chronic inflammation. Immunohistochemistry, reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay showed significantly higher expression of interleukin-6 (P < 0.001). After intravesical administration of hyaluronic acid, both intercontraction intervals and bladder capacity increased significantly (P < 0.001), whereas both bladder inflammatory degree and interleukin-6 levels decreased significantly (P < 0.001). Furthermore, there was a strong correlation between interleukin-6 levels and inflammatory degree (r = 0.727, P < 0.001), and also between interleukin-6 levels and voiding frequency (r = -0.761, P < 0.001). Conclusions: Intravesical administration of hyaluronic acid decreases interleukin-6 levels, as well as the severity of bladder inflammation and voiding frequency in a rat model of chronic cystitis. Interleukin-6 levels closely correlate with the inflammatory degree and voiding frequency. Thus, they can be regarded as an assessment measure of therapeutic impact.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.