OBJECTIVE: Can we identify genetic variants associated with ectopic pregnancy by undertaking the first genome-wide association study (GWAS) leveraging two large-scale biobank initiatives?
CONCLUSIONS: We identified two novel genome-wide significant associations with ectopic pregnancy, highlighting MUC1 (mucin 1) as the most plausible affected gene.
BACKGROUND: Ectopic pregnancy is an important cause of maternal morbidity and mortality worldwide. Despite being a common early pregnancy complication, the genetic predisposition to this condition remains understudied and no large scale genetic studies have been performed so far.
METHODS: A GWAS meta-analysis including 7070 women with ectopic pregnancy and 248 810 controls from Estonian Biobank and the FinnGen study.
METHODS: We identified ectopic pregnancy cases from national registers by ICD (International Classification of Disease) codes (ICD-10 O00), and all remaining women were considered controls. We carried out standard GWAS meta-analysis and additionally annotated GWAS signals, analysed co-localization with quantitative trait loci, estimated genetic correlations and identified associated phenotypes to characterize the genetic signals, as well as to analyse the genetic and phenotypic relationships with the condition.
RESULTS: We identified two genome-wide significant loci on chromosomes 1 (rs4971091, P = 5.32×10-9) and 10 (rs11598956, P = 2.41×10-8) potentially associated with ectopic pregnancy. Follow-up analyses propose MUC1, which codes for an epithelial glycoprotein with an important role in barrier function, as the most likely candidate gene for the association on chromosome 1. We also characterize the phenotypic and genetic correlations with other phenotypes, identifying a genetic correlation with smoking and diseases of the (genito)urinary and gastrointestinal system, and phenotypic correlations with various reproductive health diagnoses, reflecting the previously known epidemiological associations.
METHODS: The GWAS meta-analysis summary statistics are available from the GWAS Catalogue (GCST90272883).
CONCLUSIONS: The main limitation is that the findings are based on European-based ancestry populations, with limited data on other populations, and we only captured maternal genomes. Additionally, further larger meta-analysis or independent studies are needed to validate these findings.
CONCLUSIONS: This study encourages the use of large-scale genetic datasets to unravel genetic factors linked to ectopic pregnancy, which is difficult to study in experimental settings. Increased sample size might bring additional genetic factors associating with ectopic pregnancy and inform its heritability. Altogether, our results provide more insight into the biology of ectopic pregnancy and, accordingly, the biological processes governing embryo implantation.
BACKGROUND: N.P.G. was supported by MATER Marie Sklodowska-Curie which received funding from the European Union\'s Horizon 2020 research and innovation program under grant agreement No. 813707. This study was funded by European Union through the European Regional Development Fund Project No. 2014-2020.4.01.15-0012 GENTRANSMED. Computations were performed in the High-Performance Computing Center of University of Tartu. The authors declare no competing interests.

This study tried to achieve active targeting of Muc1 in cancer; the surface of PEGylated liposomal doxorubicin (PLD/Doxil®) was decorated with FA12 peptide.
According to docking results, FA12 was selected for this study, among four different peptides. MD simulation was also conducted as an additional confirmation of the binding interaction between FA12 and Muc1. Liposomal formulations were prepared; 1HNMR and HPLC techniques were used to verify peptide conjugation to DSPE-PEG2000-COOH. Afterward, DSPE-PEG2000-FA12 was post-inserted into the PLD at 50, 100, 200, and 400 peptides per liposome. The size, zeta potential, release profile, cytotoxicity (IC50), and cell uptake (using fluorescence microscopy and flow cytometry) were evaluated. In vivo biodistribution and antitumor activities were studied on mice bearing C-26 colon carcinoma.
Cell uptake and cytotoxicity results revealed that PLD-100 (targeted PLD with 100 FA12 per liposome) could significantly enhance cellular binding. Furthermore, PLD-100 demonstrated higher antitumor efficacy, indicating more remarkable survival compared to PLD and other targeted PLDs. PLD-100 exhibited higher doxorubicin tumor accumulation compared to PLD.
FA12 peptide is a promising targeting ligand for PLD to treat cancers with a high level of Muc1 expression and merits further investigations.
In this work, we used an antimicrobial peptide, FA12, to target Muc1 glycoprotein on the surface of colon cancer cells. The interaction between the peptide and Muc1 as a receptor was verified by molecular dynamics simulation. FA12 peptide was affixed to the surface of the liposomal form of doxorubicin (PLD) specifically to facilitate drug delivery transfer to the tumor site. The main benefits of this novel formulation were improvement of therapeutic efficacy and enhancement of survival time in mice bearing colon cancer.[Figure: see text].

OBJECTIVE: This study was designed to compare the antitumor effects of anti-human MUC1 monoclonal antibody with those of anti-human CA199 monoclonal antibody coupled with drug-loaded polybutylcyanoacrylate nanoparticles on human pancreatic cancer cell lines and pancreatic cancer-bearing model animals and to screen more efficient targeting molecules.
METHODS: Gemcitabine-loaded nanospheres were prepared by emulsion polymerization (GEM-PBCA-NP), and then, anti-MUC1 monoclonal antibody was coupled with GEM-PBCA-NP (MUC1-GEM-PBCA-NP), and anti-human CA199 monoclonal antibody was coupled with GEM-PBCA-NP (CA199-GEM-PBCA-NP), using the chemical crosslinking method. The cell-killing rates were detected using MTT assay. The changes in the tumor cell cycle and apoptosis after treatment were detected using flow cytometry. Then, the subcutaneous planting method was adopted to establish an animal model of pancreatic cancer: two nanometer microspheres were injected into the body of nude mice via the tail vein; the tumor suppression effect was detected after treatment; then, the groups were compared.
RESULTS: In vitro, the cell-killing rate of each experimental group was significantly different from that of the control group (P < 05). The MUC1-GEM-PBCA-NP group had a significantly higher cell-killing rate than the other groups (P < 05). The apoptosis rate of the MUC1-GEM-PBCA-NP treatment group was significantly higher than that of other groups (P < 05). In vivo, the tumor inhibition rate of the MUC1-GEM-PBCA-NP treatment group was 72.69% ± 4.29%, which was significantly higher than those of other groups (P < 0.05). The tumor inhibition rate of the CA199-GEM-PBCA-NP treatment group was 56.58% ± 5.11%, which was significantly higher than those of other control groups (P < 0.05). At the end of treatment, the average tumor mass of the MUC1-GEM-PBCA-NP treatment group was 433.55 ± 12.49 mg, which was significantly lower than those of other groups (P < 0.05).
CONCLUSIONS: Compared with CA199-GEM-PBCA-NP, MUC1-GEM-PBCA-NP is more effective in vitro and in vivo. MUC1 could be a target molecule in treating pancreatic cancer.

OBJECTIVE: Overexpression of mucin1 is found in head and neck squamous cell carcinoma tissues compared with adjacent non-neoplastic tissues and higher levels are associated with metastasis and invasion. The expression level of mucin1 in saliva of normal individuals, oral potentially malignant disorders and oral squamous cell carcinoma patients and its correlation to clinical and histological variables was evaluated.
METHODS: Forty oral potentially malignant disorders, 40 oral squamous cell carcinoma subjects, and 20 age matched-controls were included. Stimulated salivary samples were collected from all participants, and mucin1 expression was measured by real-time PCR.
RESULTS: Mucin1 expression in saliva was significantly elevated in oral potentially malignant disorders when compared with controls. Similarly, mucin1 expression was significantly elevated in oral squamous cell carcinoma group when compared with oral potentially malignant disorders and controls. Mucin1 expression in OSCC patient showed significant positive correlations with T classification and distant Metastasis. Mucin1 expression in oral potentially malignant disorders patients showed significant positive correlations with degree of dysplasia.
CONCLUSIONS: The expression level of mucin1 in saliva might be a potential biomarker for diagnosing oral potentially malignant disorders and oral squamous cell carcinoma.

UNASSIGNED: The Mucin-family protein, MUC1, impacts on carcinogenesis and tumor invasion. We evaluated the impact of MUC1 expression on outcome in a cohort of 158 patients with resected pancreatic ductal adenocarcinomas (PDAC) in the CONKO-001 study (adjuvant gemcitabine [gem] vs. observation [obs]).
UNASSIGNED: The percentage of MUC1-positive tumor cells by immunohistochemistry (IHC) and the staining intensity were evaluated by two observers blinded to outcome. The numeric values of both parameters were multiplied, resulting in an immunoreactivity score (IRS) ranging from 0 to 12. The level of MUC1 expression was defined as follows: IRS 0-4 (low) vs IRS >4 (high). Outcomes in terms of disease-free (DFS) and overall survival (OS) were evaluated by Kaplan-Meier method, log-rank tests and Cox regressions.
UNASSIGNED: In total, tumors of 158 study patients were eligible for immunohistochemistry of MUC1. High cytoplasmic MUC1 expression was associated with impaired DFS and OS in the overall study population (hazard ratio (HR) for DFS: 0.49, 95% CI 0.31 to 0.78, p = .003; HR for OS: 0.46, 95% CI 0.29 to 0.73, p = .001). In the study arms, prognostic effects of MUC1 were also evident in the observation group (HR for DFS: 0.55; 95% CI 0.29 to 1.04, p = .062; HR for OS: 0.34, 95% CI 0.17 to 0.67, p = .001) and trending in the gem group (HR for DFS: 0.48, 95% CI 0.24 to 0.95, p = .041; HR for OS: 0.56, 95% CI 0.28 to1.11, p = .093).
UNASSIGNED: Our data suggest that MUC1 expression is a powerful prognostic marker in patients with PDAC after curatively intended resection.

The prognosis of patients with advanced pancreatic cancer is poor. In the present phase I/II study, we have evaluated the safety and the feasibility of Wilms\' tumor 1 (WT1) and/or mucin1 (MUC1) peptide-pulsed dendritic cell (DC) vaccination in combination with chemotherapy in patients with advanced or relapsed pancreatic ductal adenocarcinoma (PDAC). Sixty-five eligible patients were enrolled. No severe adverse events related to the vaccinations were observed. Objective response rate and disease control rate was 12.3% and 50.8%, respectively. Median progression-free survival and overall survival were 4.9 and 9.6 months, respectively. DC vaccinations augmented WT1- and MUC1-specific immunity which might be related to clinical outcome. These results indicate that DC-based immunotherapy combined with a conventional chemotherapy is safe and feasible for patients in advanced stage of PDAC.

Luteolin is a natural flavonoid possessing certain beneficial pharmacological properties, including anti-oxidant, anti-inflammatory, anti-microbial and anti-cancer properties. The majority of types of gastric cancer with chronic gastritis are caused by infection with Helicobacter pylori (H. pylori). The present study evaluated the effect of luteolin on a number of selected factors that are potentially involved in gastric cancer development. The study was performed using gastric cancer CRL-1739 cells treated with 30 µM luteolin and H. pylori alone or combined. ELISA and reverse transcription PCR were used to assess the expression levels of MUC1, GalNAcα-R (Tn antigen) and NeuAcα2-3Galβ1-3GalNAc-R (sT antigen), ADAM-17, IL-8, IL-10 and NF-κB. H. pylori and luteolin independently and in combination significantly reduced the expression levels of the extracellular domain of MUC1 in gastric cancer cells compared with the untreated control cells. ADAM-17 expression was reduced by treatment with the pathogen and luteolin. Additionally, both factors reduced sT antigen expression. Treatment with 30 ≤M luteolin significantly induced IL-8 expression at the mRNA and protein level, and the mRNA expression levels of IL-10 and NF-κB compared with the control. Both H. pylori and luteolin induced IL-8 protein expression. The present preliminary results suggest that luteolin may be used to treat patients with gastric cancer.

OBJECTIVE: We evaluated the safety, feasibility, and preliminary efficacy of Wilms tumor gene 1 (WT1) peptide and Mucin 1 (MUC1)-pulsed dendritic cell (DC) (WT1/MUC1-DC) vaccination as an adjuvant immunotherapy for surgically resectable pancreatic ductal adenocarcinoma (PDA) patients.
METHODS: Eligible patients were administered WT1/MUC1-DC vaccination at least seven times every 2 weeks with concomitant adjuvant chemotherapy after surgical resection of PDA.
RESULTS: Ten patients were enrolled and no Grade 2 or higher toxicities were associated with DC vaccination. The estimated overall survival (OS) and relapse-free survival (RFS) at 3-years from the time of surgical resection were 77.8% and 35.0%, respectively. Immunohistochemical analysis suggested a possible relationship between induction of WT1-specific cytotoxic T lymphocyte after DC vaccination and higher infiltration of CD3/CD4/CD8 lymphocytes in tumor tissues.
CONCLUSIONS: WT1/MUC1-DC vaccination in the adjuvant setting was safe and well-tolerated in PDA patients after tumor resection. A large-scale prospective study is warranted to evaluate the clinical benefit of this modality.

Hypokalemic periodic paralysis type 1 (OMIM; HOKPP1) and type 2 (OMIM; HOKPP2) are diseases of the muscle characterized by episodes of painless muscle weakness, and is associated with low potassium blood levels. Hyperthyroidism has been associated with thyrotoxic periodic paralysis (TTPP) (OMIM; TTPP1 and TTPP2), and genetic susceptibility has been implicated. In the present study, the clinical and epidemiological characteristics of patients with TTPP are described, together with their association with genetic variants reported previously in other populations. A prospective and a retrospective search of the medical records of patients who attended the emergency department at the Hospital Universitario \'Dr. Jose E. Gonzalez\' in Monterrey, Nuevo León, Mexico, and were diagnosed with TTPP was performed. A total of 16 gene variants in the genes MUC1, CACNA1S, KCNE3 and SCN4A, and nine ancestry informative markers (AIMs), were analysed by Multiplex TaqMan™ Open Array assay, and a genetic association study was performed. A total of 11 patients were recruited, comprising nine males and two females (age range, 19-52 years) and 64 control subjects. Only two cases (18%) had a previous diagnosis of hyperthyroidism; the rest were diagnosed subsequently with Graves\' disease. Based on the analysis, two DNA variants were found to potentially confer an increased risk for TTPP: S1PR1 rs3737576 [odds ratio (OR), 4.38; 95% confidence interval (CI), 1.08-17.76] and AIM rs2330442 (OR, 4.50; 95% CI, 1.21-16.69), and one variant was suggested to be possibly associated with TTPP, namely MUC1 rs4072037 (OR, 3.08; 95% CI, 0.841-1.38). However, there were no statistically significant associations between any of the 24 DNA variants and TTPP in a population from northeast Mexico.

OBJECTIVE: To investigate the clinical effects of MUC1 on papillary thyroid cancer (PTC) and explore the relationship between MUC1 expression and BRAF mutation.
METHODS: The data of 69 patients subjected to fine-needle aspiration biopsy in our hospital and 486 patient data downloaded from The Cancer Genome Atlas (TCGA) database were used. Univariate and multivariate analyses were performed.
RESULTS: The results on the 486 patients recorded in the TCGA indicated that high MUC1 expression was independently related to BRAF mutation, lymph node metastasis (LNM), and unifocal type. In the 69 fine-needle aspiration biopsy patients with PTC, high MUC1 expression was significantly related to LNM and extrathyroid extension (ETE). The result of Pearson\'s correlation coefficient showed that BRAF mutation and MUC1 expression were moderately correlated. Moreover, in the subgroup with low MUC1 expression, the patients with BRAF mutation had higher ETE frequency and LNM than those without BRAF mutation. In the subgroup with BRAF mutation, patients with high MUC1 expression exhibited higher ETE frequency than those with low MUC1 expression, and high MUC1 expression occurred in older patients. In the subgroup with BRAF wild-type mutation, patients with high MUC1 expression had a higher incidence of ETE and LNM than those with low expression.
CONCLUSIONS: We demonstrated that the MUC1 is an important oncogene in PTC and may have great significance on therapeutic cancer vaccine development.