Integrated single-cell and Mendelian randomization analyses: dissecting underlying causes of varied efficacy in immune neoadjuvant therapy for esophageal carcinoma

BackgroundHepatocellular carcinoma (HCC) represents one of the most prevalent malignant neoplasms worldwide, characterized by poor prognosis and low 5-year survival rates. Despite extensive research, its pathogenesis remains largely unclear. Within the tumor microenvironment (TME), monocytes play a dual role: they participate in tumor cell recognition and elimination while regulating immune responses through cytokine secretion. This study aims to investigate the association between differentially expressed genes in monocytes and HCC development.MethodsThis investigation employed single-cell transcriptomic analysis of human hepatic innate lymphoid cells (ILCs) to identify monocyte subpopulations and their cellular markers. Subsequently, two-sample Mendelian randomization (MR) analysis was conducted to examine the causal relationships between these cells, their associated genes, and HCC development.ResultsThrough comprehensive analysis of the monocyte cluster, we identified 2338 differentially expressed genes (DEGs). MR analysis revealed 13 genes significantly associated with HCC risk:ConclusionThis study represents the first integration of single-cell sequencing technology with MR analysis to investigate the relationship between monocytes and HCC. Through this innovative methodological approach, we have revealed potential associations between monocyte gene expression and HCC development, providing new directions for further research on HCC prevention and treatment, as well as identifying potential therapeutic targets.

Paeonol enhances a recombinant EGFR-targeted fusion protein-drug conjugate induced antitumor efficacy in esophageal cancer.

4109 Background: Survival in patients (pts) with cancer has been linked to pt-reported clinically deficient quality of life (cdQOL). We examined patient-reported QOL and overall survival (OS) in pts with esophageal cancer (EC) or Barrett esophagus (BE) previously enrolled in the Mayo Clinic Esophageal Adenocarcinoma and Barrett's Esophagus Registry (EABE). Methods: Pts enrolled in the EABE between 09/01 and 01/09 returned a baseline questionnaire including a validated numerical analogue measure of overall QOL. Pts were categorized as having cdQOL at enrollment as defined by a score of ≤ 5 on a 0-10 scale. Kaplan-Meier methodology and Cox models explored OS in relation to cdQOL in pts with EC and BE. Results: 1,498 pts were included for analysis, 831 had BE (max follow-up of 7.5 years) and 667 had EC (max follow-up of 7.7 years). CdQOL was less likely in BE pts than EC pts (11% vs 28%). Five-year OS rate was significantly less in BE and EC for the cdQOL group (differences of 11% and 24%). Pts, where staging is available, having early stage (T1-2N0M0) EC (158 pts) or locally advanced stage EC (370 pts) had lower 5-year survival rate if they reported cdQOL (27% vs. 73%, HR=0.24, p<0.0001) and (13% vs. 25%, HR=0.58, p<0.0001). None of the pts with metastatic (TxNxM1b) disease (n=62) who had cdQOL survived to 5 years compared to 3% for those with non-cdQOL (p=0.56). Median survival was also significantly less in cdQOL early stage and locally advanced, but not metastatic, EC groups. Conclusions: A deficit in QOL is strongly associated with OS in patients with BE and nonmetastatic EC. CdQOL is a significant predictor of OS in patients with EC and should be considered as a stratification factor in the design of clinical trials. Predictor N (events) 5-year survival rate Cox proportional hazard p value HR (95% CI) BE (N = 831, 77 events) QOL ≤ 5 (cdQOL)QOL > 5 91 (18) 740 (59) 77% (66%–89%)88% (85%–91%) <0.0001 0.30 (0.18–0.51) EC (N = 667, 350 events) QOL ≤ 5 (cdQOL)QOL>5 191 (130)476 (220) 14% (9%–23%)38% (33%–45%) <0.0001 0.46 (0.37–0.58) No significant financial relationships to disclose.

ObjectiveThe causal associations of circulating lipids with Barrett’s Esophagus (BE) and Esophageal Cancer (EC) has been a topic of debate. This study sought to elucidate the causality between circulating lipids and the risk of BE and EC.MethodsWe conducted two-sample Mendelian randomization (MR) analyses using single nucleotide polymorphisms (SNPs) of circulating lipids (n = 94,595 − 431,167 individuals), BE (218,792 individuals), and EC (190,190 individuals) obtained from the publicly available IEU OpenGWAS database. The robustness and reliability of the results were ensured by employing inverse-variance weighted (IVW), weighted median, MR-Egger, and MR-PRESSO methods. The presence of horizontal pleiotropy, heterogeneities, and stability of instrumental variables were assessed through MR-Egger intercept test, Cochran’s Q test, and leave-one-out sensitivity analysis. Additionally, bidirectional MR and multivariable MR (MVMR) were performed to explore reverse causality and adjust for known confounders, respectively.ResultsNone of the testing methods revealed statistically significant horizontal pleiotropy, directional pleiotropy, or heterogeneity. Univariate MR analyses using IVW indicated a robust causal relationship between increased triglycerides and BE (odds ratio [OR] = 1.79, p-value = 0.009), while no significant association with EC was observed. Inverse MR analysis indicated no evidence of reverse causality in the aforementioned outcomes. In MVMR analyses, elevated triglycerides (TRG) were significantly and positively associated with BE risk (OR = 1.79, p-value = 0.041).ConclusionThis MR study suggested that genetically increased triglycerides were closely related to an elevated risk of BE, potentially serving as a biomarker for the diagnosis of BE in the future.

Comparison of Site-Reported and Core Laboratory-Reported Creatine Kinase-MB Values in Non–ST-Segment Elevation Acute Coronary Syndrome (from the International Trial SYNERGY)

Background and aims: Esophageal cancer (EC) is a deadly disease with a very low 5-year survival rate. The incidence of EC shows great geographical variations with high prevalence in Northern China. Although epidemiological studies suggest that environmental factors may be etiologic factors of EC, strong evidence supporting a causative role of genetic factors in familial EC comes from i) familial aggregation of EC in Yangcheng County, ii) the distinct high EC incidence in Chaoshan migrants to Nanao, and iii) molecular genetic studies such as BRCA2 germline mutations. Recent technological advances allow the identification of long regions of homozygosity (known as IBD segments) in genomic DNAs, which represent the sharing of a common ancestor in those regions, using the high density SNP arrays. Previous studies suggest that a high rate of consanguinity, which produces germline genomic homozygosity, is associated with cancers. We aim to use the IBD approach for mapping the susceptibility locus with low-penetrance SNPs in hereditary ESCC patients in Henan, one of the highest ESCC risk regions in the world. Screening programs based on knowledge of founder mutations may reduce cancer mortality by prevention. Thus, our second aim is to assess if a founder effect exists and predisposes individuals to ESCC in Henan. Methods: Genomic DNAs were extracted from blood samples of Henan family history positive (FH+) ESCC patients and healthy normal individuals. The germline homozygosity in 30 Henan FH+ ESCC patients was explored by using Affymetrix GeneChip Human mapping SNP array (∼238K SNPs, Sty I). IBD analysis was performed using the PLink software. Results: There is longer IBD segment length associated with FH+ ESCC compared with control groups. The 27 IBD segments in FH+ ESCC samples having no overlap with control/Hapmap may encompass the potential cancer-susceptibility loci and should be further examined. However, no strong evidence for founder effect was observed by IBD approach for hereditary ESCC in Henan population. Conclusions: The increased length of germline genomic homozygosity association with hereditary ESCC in Henan is observed. Due to the small sample size in the current study, the association is considered hypothesis-generating only. The importance of these IBD segments to the etiology and development of ESCC in high risk areas require further study with an expanded sample size for validation. Acknowledgements: This work was supported by the Research Grants Council of the Hong Kong Special Administrative Region, People's Republic of China (HKU 3/06C to M.L.L.). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2637. doi:1538-7445.AM2012-2637

A comparative longitudinal quality of life study using the Spitzer quality of life index in a randomized multicenter phase III trial (FFCD 9102): chemoradiation followed by surgery compared with chemoradiation alone in locally advanced squamous resectable thoracic esophageal cancer

Spleen tyrosine kinase (Syk) is a nonreceptor tyrosine kinase and often aberrantly expressed in human cancers. However, Syk expression pattern has not yet been investigated in nasopharyngeal carcinoma (NPC). Samples of 223 NPC tissues were immunohistochemically stained for Syk expression and survival analysis was then performed. Interaction and co-localization of Syk with Epstein-Barr virus encoded latent membrane protein 2A (LMP2A) was explored. High expression of Syk was detected in 24% of NPC cases, and correlated significantly with T classification, local recurrence, a lower 5-year survival rate, and a lower 5-year disease-free survival (DFS) rate. Syk expression was a significant, independent prognosis predictor for patients with NPC. LMP2A induced Syk expression in NPC and LMP2A high expression correlated with Syk high expression in NPC clinical samples. High expression of Syk, which results partly from LMP2A expression in NPC, is associated with tumor recurrence and poor prognosis of patients with NPC.

Gut microbiota are reported to be associated with the incidence and prognosis of Esophageal cancer (EC) but their genetic association is unclear. We carried out a bidirectional MR analysis to assess the causal relationship between EC and gut microbiota from fecal samples. The microbiome genome-wide association studies (GWAS) data of 18,340 individuals provided by MiBioGen consortium and the EC GWAS data (740 esophageal cancers cases and 372 016 controls) provided by UK Biobank were respectively utilized as exposure and/or outcome data. Reliable single nucleotide polymorphisms (SNPs) were obtained after rigorous screening. A bidirectional Mendelian randomization (MR) analysis was conducted using the inverse-variance weighted (IVW) method. The sensitivity analyses including the MR-Egger method, weighted median, weighed mode and leave-one-out method were performed to examine the stability, heterogeneity and pleiotropy of the results. Forward MR analysis revealed the increase in abundance of the microbial trait by each standard deviation was associated with a higher risk of EC (Coprobacter (OR = 1.001,95%CI = 1.000-1.002, P = .0281, FDR = 0.0424); Ruminococcus1(OR = 1.001,95%CI = 1.000-1.002, P = .0318, FDR = 0.0424); Senegalimassilia (OR = 1.002,95%CI = 1.000-1.003, P = .0062, FDR = 0.0372); Veillonella (OR = 1.001,95%CI = 1.000-1.002, P = .0182, FDR = 0.0372)) or a lower risk of EC (Eubacterium oxidoreducens (OR = 0.999, 95%CI = 0.998-1.000, P = .0379, FDR = 00 433); Lachnospira (OR = 0.998,95%CI = 0.996-1.000, P = .0186, FDR = 0.0372); Romboutsia (OR = 0.999,95%CI = 0.998-1.000, P = .0482, FDR = 0.0482); Turicibacter (OR = 0.999,95%CI = 0.998-1.000, P = .0133, FDR = 0.0372)). Reverse MR analysis showed that genetic liability to EC was also causally linked toincreased susceptibility of changes in the gut microbiome (genera Eggerthella (Beta = 37.63,95%CI = 4.76-70.50, P = .0248, FDR = 0.0331); Coprococcus 2 (Beta = 23.90,95%CI = 1.65-46.15, P = .0353, FDR = 0.0353); Christensenellaceae R.7 (Beta = 22.75,95%CI = 4.22-41.28, P = .0161, FDR = 0.0322); Intestinimonas (Beta = -33.24,95%CI = -54.90-11.58, P = .0026, FDR = 0.0104)). Our findings supported a bidirectionally causal relationship between gut microbiota and EC, implying the potential role of gut microbiota in preventing the occurrence and development of EC.

Previous research has found a link between the temperature of food and beverages and the risk of esophageal cancer (EC). A causal relationship between the two has not been well established. Herein, we used Mendelian randomization (MR) analysis to assess the causal effect of temperature preference for hot beverages on EC risk. Genome-wide association studies (GWAS) data for hot beverage temperature preference were obtained from the UK biobank. There were 457,873 European and 2,617 East Asian participants included. GWAS data for EC were obtained from the Integrative Epidemiology Unit (IEU) project database. Two datasets from the European population and two datasets from the East Asian population were included. Totally, 4,426 EC cases and 1,202,270 control subjects were included. The "TwoSampleMR" R package was used to conduct a two-sample MR analysis. A random-effect inverse variance weighted (IVW) was used as the main analytical method to estimate the causal effect, and various sensitivity analyses, including MR Egger, weighted median, simple mode, and weighted mode, were used to examine the potential violation of the second and third MR assumptions. Meta-analyses were performed to further confirm the results. Sixty-eight single nucleotide polymorphisms (SNPs) from the European population and 11 SNPs from the East Asian population were used for MR analysis. No significant causal effect was found between hot beverage temperature preference and EC risk in the European population {for the ieu-b-4960 dataset, inverse variance weighted odds ratio (ORIVW) =1.00 [95% confidence interval (CI): 0.99-1.00], P=0.54; for the ebi-a-GCST90018841 dataset, ORIVW =0.35 (95% CI: 0.10-1.29), P=0.12} or in the East Asian population [for the bbj-a-117 dataset, ORIVW =1.09 (95% CI: 0.80-1.48), P=0.59; for the ebi-a-GCST90018621 dataset, ORIVW =0.11 (95% CI: 0.82-1.50), P=0.49]. Meta-analyses of the European population datasets and the Asian population datasets showed consistent results. The current MR analysis provides new genetic evidence for a null causal relationship between hot beverage temperature preference and EC, both in the European population and the East Asian population. Evidence to prevent EC by reducing the intake of hot beverages is insufficient.

Esophageal cancer has recent shown a higher incidence but lower 5-year survival rate after normal clinical treatment in China. The aim of this study was to observe whether the inhibition of miR-196a affects esophageal cancer cell growth by modulating the nuclear factor-κB target gene and to detect the possible cooperative therapeutic effects on esophageal cancer by knocking down miR-196a expression combined with the specific inhibitor of nuclear factor-κB target genes. Thus, anti-miR-196a or sotrastaurin, a protein kinase C (PKC) inhibitor, were used to alter PKC expression. We found that miR-196a knockdown or PKC inhibition by sotrastaurin changed PKC expression which then reduced esophageal cancer cell proliferation and downregulated proliferating cell nuclear antigen expression via the classical B-cell receptor-PKC nuclear factor-κB pathway but not the alternative pathway; in addition, miR-196a inhibition can increase the caspase level and induce esophageal cancer cell apoptosis. Our current results provided the evidence that miR-196a was related to the classical nuclear factor-κB pathway, and these new findings proved the potential therapeutic effect of miR-196a in targeted therapy for clinical esophageal cancer patients.

Esophageal cancer (EC) is the sixth leading cause of cancer deaths worldwide with a low 5-year survival rate. More effective chemotherapeutic drugs, either new or repurposing ones, are urgently needed. Disulfiram (DSF) is a safe and public domain drug for alcohol addiction treatment and later shown to have anti-cancer capability, especially when administrated together with copper. The present study is to test the hypothesis that a newly developed copper-cysteamine (Cu-Cy) nanoparticles (NPs) can enhance the anti-tumor effect of DSF on esophageal cancer with reduced risk of copper poisoning. Our results showed that Cu-Cy NPs could greatly facilitate DSF to inhibit cell proliferation in cultured human esophageal cancer cells. Interestingly, the combined inhibitory function could be further enhanced when DSF and Cu-Cy NPs were present at an optimal molar ratio of 1:4. The results of the change in physical color, UV-vis absorption and fluorescence spectra, X-ray diffraction patterns, and FTIR spectra from a mixture of DSF and Cu-Cy NPs suggest a possible reaction between DSF and Cu-Cy NPs and the formation of new materials. Furthermore, cellular mechanistic studies revealed that the combination of DSF and Cu-Cy NPs resulted in reactive oxygen species (ROS) accumulation, and blocked nuclear translocation of NF-ƙB (p65) in esophageal cancer cells. Moreover, in xenograft nude mice, combined administration of DSF and Cu-Cy NPs greatly inhibited tumor growth without noticeable histological toxicity, while any single agent at the same doses presented no inhibitory function. Together, this study demonstrates an effective anti-cancer function of combined treatment of DSF and Cu-Cy NPs in vitro and in vivo, which could be a promising new chemotherapy for esophageal cancer patients.

Cancer of the esophagus is often diagnosed at a late stage and is related to severe morbidity and a low 5-year survival rate. Previous studies have reported low health-related quality of life and high suicide rates for these patients. The occurrence of psychiatric morbidity and thus the potential need for psychological support may vary over time after diagnosis. This has not been adequately studied in patients with newly diagnosed cancer of the esophagus or gastro-esophageal junction. The present study therefore aimed to prospectively evaluate the prevalence of psychiatric morbidity in 94 consecutive patients (median age 66, range 45-88 years) with all stages of disease. Psychiatric morbidity was evaluated with the Hospital Anxiety and Depression Scale (HADS) questionnaire at inclusion and 1, 2, 3, 6 and 12 months later. At inclusion, 42% of the patients had HADS scores indicating possible or probable anxiety disorder and/or depression. At all follow-ups except at 3 months, proportions of patients with possible/probable anxiety disorder were significantly lower than at inclusion. Among patients with a duration of tumor-specific symptoms exceeding 6 months pre-diagnosis, larger proportions of patients with a possible/probable anxiety disorder were found at the 1- and 6-month follow ups. The prevalence of possible/probable depression was greater among patients treated with a palliative intent than among those with a curative intent at inclusion. Patients who died during the study period scored worse for depression compared to the survivors. Apart from this, the proportion of patients with possible/probable psychiatric morbidity (anxiety and/or depression) was relatively stable over time and was unrelated to patient characteristics or clinical background, including the treatment regime. In conclusion, psychiatric morbidity is common among esophageal cancer patients, both at inclusion and over time, regardless of the cancer therapy given. The findings stress the importance of monitoring the patients' mental health and of offering adequate psychological care when needed.

An increasing number of cohort studies have indicated a correlation between lung diseases and esophageal cancer, but the exact causal relationship has not been definitively established. Therefore, the objective of this study is to assess the causal relationship between lung diseases and esophageal cancer. Single-nucleotide polymorphisms (SNPs) related to lung diseases such as asthma, chronic obstructive pulmonary disease (COPD), lung cancer, and idiopathic pulmonary fibrosis (IPF), along with outcomes data on esophageal cancer, were extracted from public genome-wide association studies (GWAS). A two-sample Mendelian randomization (MR) analysis was then performed using publicly available GWAS data to investigate the potential causal relationship. The effect estimates were primarily calculated using the fixed-effects inverse-variance-weighted method. Totally, 81 SNPs related to asthma among 218,792 participants in GWAS. Based on the primary causal effects model using MR analyses with the inverse variance weighted (IVW) method, asthma was demonstrated a significantly related to the risk of esophageal cancer (OR 1.0006; 95% CI 1.0003-1.0010, p = 0.001), while COPD (OR 1.0306; 95% CI 0.9504-1.1176, p = 0.466), lung cancer (OR 1.0003, 95% CI 0.9998-1.0008, p = 0.305), as well as IPF (OR 0.9999, 95% CI 0.9998-1.0000, p = 0.147), showed no significant correlation with esophageal cancer. The two-sample MR analysis conducted in this study revealed a positive causal relationship between asthma and esophageal cancer. In contrast, esophageal cancer demonstrated no significant correlation with COPD, lung cancer, or IPF. Further large-sample prospective studies are needed to validate these findings and to provide appropriate recommendations regarding esophageal cancer screening among patients with asthma.

Background:The most common life-threatening problem in population is gastrointestinal tract (GIT) cancer and its mortality rate is very high. Now a days Nanotechnology is a modern way of diagnosis and treatment. Nano-enzymes showed best diagnosis efficacy of treatment and disease progression Aims and objectives: The aims and objectives of current review were a comprehensive overview of Nano-enzymes in the diagnosis, prognosis, and treatment of gastrointestinal tract cancer. Practical Implications:Through Nano-enzymes different types of cancer may be diagnosis, prognosis, and treated. While the treatment of gastrointestinal tract cancer with Nano-enzymes showed best results. In this review, we outlined the many types of nanoparticles used to treat esophageal cancer. Conclusion:A common gastrointestinal cancer with a poor prognosis and a high fatality rate is esophageal cancer. Despite the development of multiple therapy approaches, patients with esophageal cancer still have a low 5-year survival rate. Traditional methods of delivering anti-cancer medications have some drawbacks, including no targeted administration and general toxicity. For the treatment of Esophageal cancer, nanoparticles offer a viable platform for drug delivery since they have a number of outstanding benefits, including less side effects, a longer circulation duration, and a preference for accumulating at the tumor site. These include polymers, micelles, liposomes, inorganic nanoparticles, and organic nanoparticles. In this review, we outlined the many types of nanoparticles used to treat esophageal cancer.