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Journal For Immunotherapy of Cancer Jun 2024The sustained effectiveness of anti-programmed cell death protein-1/programmed death-ligand 1 treatment is limited to a subgroup of patients with advanced nasopharyngeal...
BACKGROUND
The sustained effectiveness of anti-programmed cell death protein-1/programmed death-ligand 1 treatment is limited to a subgroup of patients with advanced nasopharyngeal carcinoma (NPC), and the specific biomarker determining the response to immunotherapy in NPC remains uncertain.
METHODS
We assessed the associations between pre-immunotherapy and post-immunotherapy serum lipoproteins and survival in a training cohort (N=160) and corroborated these findings in a validation cohort (N=100). Animal studies were performed to explore the underlying mechanisms. Additionally, the relationship between high-density lipoprotein-cholesterol (HDL-C) levels and M1/M2-like macrophages, as well as activated CD8+T cells in tumor tissues from patients with NPC who received immunotherapy, was investigated.
RESULTS
The lipoproteins cholesterol, HDL-C, low-density lipoprotein-cholesterol, triglycerides, apolipoprotein A-1 (ApoA1), and apolipoprotein B, were significantly altered after immunotherapy. Patients with higher baseline HDL-C or ApoA1, or those with increased HDL-C or ApoA1 after immunotherapy had longer progression-free survival, a finding verified in the validation cohort (p<0.05). Multivariate analysis revealed that baseline HDL-C and elevated HDL-C post-immunotherapy were independent predictors of superior PFS (p<0.05). Furthermore, we discovered that L-4F, an ApoA1 mimetic, could inhibit tumor growth in NPC xenografts. This effect was associated with L-4F's ability to polarize M2-like macrophages towards an M1-like phenotype via the activation of mitogen-activated protein kinase (MAPK) p38 and nuclear factor-κB (NF-κB) p65, thereby alleviating immunosuppression in the tumor microenvironment. Importantly, in patients with NPC with high plasma HDL-C levels, the number of M2-like macrophages was significantly decreased, while M1-like macrophages and activated CD8+T cells were notably increased in those with high HDL-C levels.
CONCLUSION
Higher baseline HDL-C levels or an increase in HDL-C post-immunotherapy can enhance immunotherapeutic responses in patients with NPC by reprogramming M2-like macrophages towards the M1 phenotype. This suggests a potential role for prospectively exploring ApoA1 mimetics as adjuvant agents in combination with immunotherapy.
Topics: Humans; Nasopharyngeal Carcinoma; Tumor-Associated Macrophages; Immunotherapy; Animals; Female; Male; Cholesterol, HDL; Mice; Middle Aged; Phenotype; Tumor Microenvironment; Nasopharyngeal Neoplasms; Adult
PubMed: 38871480
DOI: 10.1136/jitc-2023-008146 -
Indian Heart Journal Jun 2024Defining lipid goals solely on low-density lipoprotein- cholesterol (LDL-C) levels in Indian population may cause misclassification due to high prevalence of...
BACKGROUND
Defining lipid goals solely on low-density lipoprotein- cholesterol (LDL-C) levels in Indian population may cause misclassification due to high prevalence of hypertriglyceridemia and small dense LDL-C particles. International guidelines now recommend Apoliporotein-B (Apo-B) and non-high-density lipoprotein-cholesterol (non-HDL-C) levels as alternative targets. In this study, we used a cross-sectional representative population database to determine Apo-B and non-HDL-C cut-offs corresponding to identified LDL-C targets and compared them to international guidelines.
METHODS
A community-based survey carried out in urban Delhi and adjacent rural Ballabhgarh provided lipid values for 3047 individuals. The Spearman correlation coefficient was used to evaluate the degree of relationship between Apo-B and LDL-C and non-HDL-C. Cut-off values for Apo-B and non-HDL-C were established using receiver operator curve analysis correlating with guideline-recommended LDL-C targets.
RESULTS
Spearman's rank correlations between Apo-B and LDL-C (0.82) and non-HDL-C and LDL-C (0.93) were significant (p<0.05). Proposed corresponding cut-off values for LDL-C of 55, 70,100,130 and 160 mg/dl for Apo-B and non-HDL-C in our population were 75.3, 75.5, 91.3, 107.6, 119.4 mg/dL and 92.5,96.5, 123.5, 154.5, 179.5 mg/dL respectively. However, in those with triglycerides > 150 mg/dl the corresponding Apo-B and non-HDL-C values were 85.1, 92.7, 103.5, 117.5 and 135 mg/dL and 124.5, 126.5, 147.5, 167.5 and 190.5 mg/L respectively.
CONCLUSION
Based on this study we provide Apo-B and non-HDL cut-offs corresponding to target LDL-C values in Indian patients with and without high triglycerides. It is noted that in individuals with triglycerides>= 150mg/dl, the Apo-B levels are much higher than the values recommended by guidelines.
PubMed: 38871221
DOI: 10.1016/j.ihj.2024.06.003 -
PloS One 2024Utilizing the Mendelian randomization technique, this research clarifies the putative causal relationship between body mass index (BMI) andbone mineral density (BMD),...
SUMMARY
Utilizing the Mendelian randomization technique, this research clarifies the putative causal relationship between body mass index (BMI) andbone mineral density (BMD), and the mediating role of low-density lipoprotein (LDL). The implications of these findings present promising opportunities for enhancing our understanding of complex bone-related characteristics and disorders, offering potential directions for treatment and intervention.
OBJECTIVE
The objective of this study is to examine the correlation between BMI and BMD, while exploring the intermediary role of LDL in mediating the causal impact of BMI on BMD outcomes via Mendelian randomization.
METHODS
In this study, we employed genome-wide association study (GWAS) data on BMI, LDL, and BMD to conduct a comparative analysis using both univariate and multivariate Mendelian randomization.
RESULTS
Our study employed a two-sample Mendelian randomization design. Considering BMI as the exposure and BMD as the outcome, our results suggest that BMI may function as a potential protective factor for BMD (β = 0.05, 95% CI 1.01 to 1.09, P = 0.01). However, when treating LDL as the exposure and BMD as the outcome, our findings indicate LDL as a risk factor for BMD (β = -0.04, 95% CI 0.92 to 0.99, P = 0.04). In our multivariate Mendelian randomization (MVMR) model, the combined influence of BMI and LDL was used as the exposure for BMD outcomes. The analysis pointed towards a substantial protective effect of LDL on BMD (β = 0.08, 95% CI 0.85 to 0.97, P = 0.006). In the analysis of mediation effects, LDL was found to mediate the relationship between BMI and BMD, and the effect was calculated at (β = 0.05, 95% CI 1.052 to 1.048, P = 0.04).
CONCLUSION
Our findings suggest that BMI may be considered a protective factor for BMD, while LDL may act as a risk factor. Moreover, LDL appears to play a mediatory role in the causal influence of BMI on BMD.
Topics: Humans; Bone Density; Body Mass Index; Mendelian Randomization Analysis; Lipoproteins, LDL; Genome-Wide Association Study; Polymorphism, Single Nucleotide; Female
PubMed: 38870109
DOI: 10.1371/journal.pone.0298610 -
International Journal of... 2024Corilagin possesses a diverse range of pharmacologic bioactivities. However, the specific protective effects and mechanisms of action of corilagin in the context of...
INTRODUCTION
Corilagin possesses a diverse range of pharmacologic bioactivities. However, the specific protective effects and mechanisms of action of corilagin in the context of atherosclerosis remain unclear. In this study, we investigated the impact of corilagin on the toll-like receptor (TLR)4 signaling pathway in a mouse vascular smooth muscle cell line (MOVAS) stimulated by oxidized low-density lipoprotein (ox-LDL). Additionally, we examined the effects of corilagin in Sprague-Dawley rats experiencing atherosclerosis.
METHODS
The cytotoxicity of corilagin was assessed using the CCK8 assay. MOVAS cells, pre-incubated with ox-LDL, underwent treatment with varying concentrations of corilagin. TLR4 expression was modulated by either downregulation through small interfering (si)RNA or upregulation via lentivirus transfection. Molecular expression within the TLR4 signaling pathway was analyzed using real-time polymerase chain reaction (PCR) and Western blotting. The proliferation capacity of MOVAS cells was determined through cell counting. In a rat model, atherosclerosis was induced in femoral arteries using an improved guidewire injury method, and TLR4 expression in plaque areas was assessed using immunofluorescence. Pathological changes were examined through hematoxylin and eosin staining, as well as Oil-Red-O staining.
RESULTS
Corilagin demonstrated inhibitory effects on the TLR4 signaling pathway in MOVAS cells pre-stimulated with ox-LDL, consequently impeding the proliferative impact of ox-LDL. The modulation of TLR4 expression, either through downregulation or upregulation, similarly influenced the expression of downstream molecules. In an in vivo context, corilagin exhibited the ability to suppress TLR4 and MyD88 expression in the plaque lesion areas of rat femoral arteries, thereby alleviating the formation of atherosclerotic plaques.
CONCLUSION
Corilagin can inhibit the TLR4 signaling pathway in VSMCs, possibly by downregulating TLR4 expression and, consequently, relieving atherosclerosis.
Topics: Animals; Toll-Like Receptor 4; Hydrolyzable Tannins; Rats, Sprague-Dawley; Signal Transduction; Atherosclerosis; Muscle, Smooth, Vascular; Lipoproteins, LDL; Male; Glucosides; Mice; Cell Line; Rats; Cell Proliferation; Myocytes, Smooth Muscle; Disease Models, Animal; Myeloid Differentiation Factor 88
PubMed: 38869980
DOI: 10.1177/03946320241254083 -
Heliyon Jun 2024The mechanisms occur in children with obesity after lifestyle intervention remain poorly explained. Here, we investigated the serum proteomes and metabolomes of children...
BACKGROUND AND AIMS
The mechanisms occur in children with obesity after lifestyle intervention remain poorly explained. Here, we investigated the serum proteomes and metabolomes of children with obesity who had undergone 30 days of weight loss intervention.
METHODS AND RESULTS
Serum samples and clinical parameters were collected before and after lifestyle alteration interventions. Proteomic and metabolomic profiling was used to identify the differentially expressed proteins and differentially abundant metabolites in response to weight loss intervention. Lifestyle alteration interventions significantly decreased BMI, waist circumference, hip circumference and body fat, total cholesterol (TC), triglyceride (TG), low-density lipoprotein cholesterol (LDL) and high non-HDL cholesterol, but not TG and high-density lipoprotein cholesterol (HDL), in children with obesity. By comparing the multiomics data, we identified 43 proteins and 165 metabolites that were significantly differentially expressed in children with obesity before and after lifestyle alteration interventions. Using integrated -omics analysis, we obtained 7 KEGG pathways that were organically integrated based on the correlations between differentially expressed proteins (DEPs) and metabolites (DMs). Further interaction analysis identified 7 proteins as candidate DEPs and 9 metabolites as candidate DMs. Interestingly, we found that some of these candidate DEPs and candidate DMs were significantly correlated with clinical parameters.
CONCLUSION
Our results provide valuable proteome and metabolome data resources for better understanding weight loss-associated responses in children with obesity. In addition, we analyzed the number of significantly differentially expressed proteins and metabolites, shed new light on weight loss pathogenesis in children with obesity, and added potential therapeutic agents for obese children.
PubMed: 38867950
DOI: 10.1016/j.heliyon.2024.e31917 -
Heliyon Jun 2024Dysregulation in lipid metabolism contributes to the occurrence and development of various cancers. The connection between changes in lipid metabolism and the...
INTRODUCTION
Dysregulation in lipid metabolism contributes to the occurrence and development of various cancers. The connection between changes in lipid metabolism and the development of intrahepatic cholangiocarcinoma remains uncertain. Our objective was to investigate the significance of blood lipid levels in patients with intrahepatic cholangiocarcinoma who have undergone surgery.
METHODS
Ninety-seven ICC patients who underwent surgery were retrospectively enrolled. After 92.2 months of follow-up, the Kaplan-Meier analysis and Cox proportional hazard model were used to calculate overall survival and recurrence-free survival.
RESULTS
The median age of this cohort was 56 years, and 79 (81.4 %) of them were male. Eighty-eight (90.7 %) patients presented with tumor recurrence and 73 (75.3 %) died. In multivariate analyses, high-density lipoprotein cholesterol level (<0.91 ≥ 0.91 mmol/L, hazard ratio [HR] = 2.55; 95 % CI: 1.38-4.71), lymph node metastasis (Yes No, HR = 2.58; 95 % CI: 1.28-5.19), etiology factor (chronic HBV infection others, HR = 0.5; 95 % CI: 0.28-0.88) and multiple tumor lesions (Yes No, HR = 1.85; 95 % CI: 1.01-3.39) were independent predictors of overall survival. However, only high-density lipoprotein cholesterol level (HR = 1.86; 95 % CI: 1.19-2.92) emerged as the independent factor for recurrence-free survival. High-density lipoprotein cholesterol level (HR = 2.07; 95 % CI: 1.26-3.41), etiology factor (HR = 0.49; 95 % CI: 0.29-0.84), and multiple tumor lesions (HR = 2.00; 95 % CI: 1.14-3.51) were independent predictors of early recurrence. For patients who did not experience the spread of cancer to the lymph nodes, there was a significant correlation between the level of high-density lipoprotein cholesterol and their overall survival, recurrence-free survival, and early recurrence. For patients with low pre-operation high-density lipoprotein cholesterol levels, high post-operation high-density lipoprotein cholesterol levels were associated with better prognosis.
CONCLUSIONS
Low serum high-density lipoprotein cholesterol level might serve as a sign of poor clinical outcomes (overall survival and recurrence-free survival) and early recurrence among intrahepatic cholangiocarcinoma patients. Strengthening the monitoring and intervention of intrahepatic cholangiocarcinoma patients with poor prognosis might be critical for improving the prognosis.
PubMed: 38867946
DOI: 10.1016/j.heliyon.2024.e32113 -
Lipids in Health and Disease Jun 2024Familial hypercholesterolemia (FH) is a common inherited metabolic disease that causes premature atherosclerosis, cardiovascular disease, and even death at a young age....
BACKGROUND
Familial hypercholesterolemia (FH) is a common inherited metabolic disease that causes premature atherosclerosis, cardiovascular disease, and even death at a young age. Approximately 95% of FH-causing genetic variants that have been identified are in the LDLR gene. However, only 10% of the FH population worldwide has been diagnosed and adequately treated, due to the existence of numerous unidentified variants, uncertainties in the pathogenicity scoring of many variants, and a substantial number of individuals lacking access to genetic testing.
OBJECTIVE
The aim of this study was to identify a novel variant in the LDLR gene that causes FH in a Chinese family, thereby expanding the spectrum of FH-causing variants.
METHODS
Patients were recruited from Beijing Anzhen Hospital, Capital Medical University. FH diagnosis was made according to the Dutch Lipid Clinical Network (DLCN) criteria. Whole-exome sequencing (WES) was conducted to identify the FH-causing variant in the proband, and amplicon sequencing was used to verify the variant in his family members.
RESULTS
A three-generation Chinese family was recruited, and two FH patients were clinically diagnosed, both without known FH-causing variants. These two FH patients and another possible patient carried a novel variant, NC_000019.9(NM_000527.5):c.89_92dup (NP_000518.1:p.Phe32Argfs*21), in the ligand-binding domain of the low-density lipoprotein (LDL) receptor that led to a frameshift. The FH adults in the family showed severe clinical symptoms and statin therapy resistance.
CONCLUSION
This study identified a novel pathogenic LDLR variant, c.89_92dup, associated with severe FH clinical manifestations and statin therapy resistance.
Topics: Humans; Hyperlipoproteinemia Type II; Receptors, LDL; Male; Frameshift Mutation; Female; Pedigree; Adult; Middle Aged; Exome Sequencing
PubMed: 38867270
DOI: 10.1186/s12944-024-02173-2 -
Cell Communication and Signaling : CCS Jun 2024KRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short...
BACKGROUND
KRAS-mutant non-small cell lung cancer (NSCLC) shows a relatively low response rate to chemotherapy, immunotherapy and KRAS-G12C selective inhibitors, leading to short median progression-free survival, and overall survival. The MET receptor tyrosine kinase (c-MET), the cognate receptor of hepatocyte growth factor (HGF), was reported to be overexpressed in KRAS-mutant lung cancer cells leading to tumor-growth in anchorage-independent conditions.
METHODS
Cell viability assay and synergy analysis were carried out in native, sotorasib and trametinib-resistant KRAS-mutant NSCLC cell lines. Colony formation assays and Western blot analysis were also performed. RNA isolation from tumors of KRAS-mutant NSCLC patients was performed and KRAS and MET mRNA expression was determined by real-time RT-qPCR. In vivo studies were conducted in NSCLC (NCI-H358) cell-derived tumor xenograft model.
RESULTS
Our research has shown promising activity of omeprazole, a V-ATPase-driven proton pump inhibitor with potential anti-cancer properties, in combination with the MET inhibitor tepotinib in KRAS-mutant G12C and non-G12C NSCLC cell lines, as well as in G12C inhibitor (AMG510, sotorasib) and MEK inhibitor (trametinib)-resistant cell lines. Moreover, in a xenograft mouse model, combination of omeprazole plus tepotinib caused tumor growth regression. We observed that the combination of these two drugs downregulates phosphorylation of the glycolytic enzyme enolase 1 (ENO1) and the low-density lipoprotein receptor-related protein (LRP) 5/6 in the H358 KRAS G12C cell line, but not in the H358 sotorasib resistant, indicating that the effect of the combination could be independent of ENO1. In addition, we examined the probability of recurrence-free survival and overall survival in 40 early lung adenocarcinoma patients with KRAS G12C mutation stratified by KRAS and MET mRNA levels. Significant differences were observed in recurrence-free survival according to high levels of KRAS mRNA expression. Hazard ratio (HR) of recurrence-free survival was 7.291 (p = 0.014) for high levels of KRAS mRNA expression and 3.742 (p = 0.052) for high MET mRNA expression.
CONCLUSIONS
We posit that the combination of the V-ATPase inhibitor omeprazole plus tepotinib warrants further assessment in KRAS-mutant G12C and non G12C cell lines, including those resistant to the covalent KRAS G12C inhibitors.
Topics: Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms; Proto-Oncogene Proteins p21(ras); Cell Line, Tumor; Animals; Proto-Oncogene Proteins c-met; Mutation; Omeprazole; Mice; Pyridines; Pyrimidines; Xenograft Model Antitumor Assays; Mice, Nude; Pyrimidinones; Female; Triazines; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Piperazines; Piperidines; Pyridazines; Pyridones
PubMed: 38867255
DOI: 10.1186/s12964-024-01667-x -
The Journal of Headache and Pain Jun 2024Currently, the treatment and prevention of migraine remain highly challenging. Mendelian randomization (MR) has been widely used to explore novel therapeutic targets....
BACKGROUND
Currently, the treatment and prevention of migraine remain highly challenging. Mendelian randomization (MR) has been widely used to explore novel therapeutic targets. Therefore, we performed a systematic druggable genome-wide MR to explore the potential therapeutic targets for migraine.
METHODS
We obtained data on druggable genes and screened for genes within brain expression quantitative trait locis (eQTLs) and blood eQTLs, which were then subjected to two-sample MR analysis and colocalization analysis with migraine genome-wide association studies data to identify genes highly associated with migraine. In addition, phenome-wide research, enrichment analysis, protein network construction, drug prediction, and molecular docking were performed to provide valuable guidance for the development of more effective and targeted therapeutic drugs.
RESULTS
We identified 21 druggable genes significantly associated with migraine (BRPF3, CBFB, CDK4, CHD4, DDIT4, EP300, EPHA5, FGFRL1, FXN, HMGCR, HVCN1, KCNK5, MRGPRE, NLGN2, NR1D1, PLXNB1, TGFB1, TGFB3, THRA, TLN1 and TP53), two of which were significant in both blood and brain (HMGCR and TGFB3). The results of phenome-wide research showed that HMGCR was highly correlated with low-density lipoprotein, and TGFB3 was primarily associated with insulin-like growth factor 1 levels.
CONCLUSIONS
This study utilized MR and colocalization analysis to identify 21 potential drug targets for migraine, two of which were significant in both blood and brain. These findings provide promising leads for more effective migraine treatments, potentially reducing drug development costs.
Topics: Humans; Migraine Disorders; Mendelian Randomization Analysis; Genome-Wide Association Study; Quantitative Trait Loci; Genetic Predisposition to Disease; Brain
PubMed: 38867170
DOI: 10.1186/s10194-024-01805-3 -
BMJ Open Jun 2024The main objective of the study is to investigate the short-term efficacy of Acceptance and Commitment Therapy (ACT) on the simultaneous modification of biological... (Randomized Controlled Trial)
Randomized Controlled Trial
Effects of a brief intervention based on Acceptance and Commitment Therapy versus usual care for cardiac rehabilitation patients with coronary heart disease (ACTonHEART): a randomised controlled trial.
OBJECTIVES
The main objective of the study is to investigate the short-term efficacy of Acceptance and Commitment Therapy (ACT) on the simultaneous modification of biological indicators of risk and psychological well-being in patients with coronary heart disease attending cardiac rehabilitation (CR).
DESIGN
This was a two-arm randomised controlled trial comparing a brief, manualised, ACT-based intervention with usual care (UC).
SETTING
The study was conducted in an outpatient CR unit in Italy. Data collection took place from January 2016 to July 2017.
PARTICIPANTS
Ninety-two patients were enrolled and randomised, following an unbalanced randomisation ratio of 2:1 to the ACT group (n=59) and the control group (n=33). Eighty-five patients completed the ACT (n=54) and the UC (n=31) interventions and were analysed.
INTERVENTIONS
The control group received UC, a 6 weeks multidisciplinary outpatient CR programme, encompassing exercise training, educational counselling and medical examinations. The experimental group, in addition to UC, participated in the Acceptance and Commitment Therapy on HEART disease (ACTonHEART) intervention encompassing three group sessions based on ACT.
OUTCOMES
The primary outcomes were Low Density Lipoproteins (LDL)cholesterol, resting systolic blood pressure, body mass index (BMI) and psychological well-being measured by the Psychological General Well-Being Index (PGWBI). Outcome measures were assessed at baseline and at the end of CR.
RESULTS
Based on linear mixed models, no significant group × time interaction was observed for either the primary outcomes (β, 95% CI: PGWBI =-1.13, -6.40 to -4.14; LDL cholesterol =-2.13, -11.02 to -6.76; systolic blood pressure =-0.50, -10.76 to -9.76; diastolic blood pressure =-2.73, -10.12 to -4.65; BMI =-0.16, -1.83 to -1.51, all p values >0.05) or the secondary outcomes (all p values >0.05). A significant time effect was found for the PGWBI total (beta=4.72; p=0.03).
CONCLUSIONS
Although analyses revealed null findings, the results can inform the design of future ACT-based CR interventions and can help researchers to strike a balance between the idealised implementation of an ACT intervention and the structural limitations of existing CR programmes.
TRIAL REGISTRATION NUMBER
NCT01909102.
Topics: Humans; Male; Female; Acceptance and Commitment Therapy; Middle Aged; Coronary Disease; Cardiac Rehabilitation; Aged; Italy; Treatment Outcome; Cholesterol, LDL
PubMed: 38866567
DOI: 10.1136/bmjopen-2024-084070