The expression and biological role of IL33 in colon cancer is poorly understood. In this study, we show that IL33 is expressed by vascular endothelial cells and tumor cells in the human colon cancer microenvironment. Administration of human IL33 and overexpression of murine IL33 enhanced human and murine colon cancer cell growth in vivo, respectively. IL33 stimulated cell sphere formation and prevented chemotherapy-induced tumor apoptosis. Mechanistically, IL33 activated core stem cell genes NANOG, NOTCH3, and OCT3/4 via the ST2 signaling pathway, and induced phosphorylation of c-Jun N terminal kinase (JNK) activation and enhanced binding of c-Jun to the promoters of the core stem cell genes. Moreover, IL33 recruited macrophages into the cancer microenvironment and stimulated them to produce prostaglandin E2, which supported colon cancer stemness and tumor growth. Clinically, tumor IL33 expression associated with poor survival in patients with metastatic colon cancer. Thus, IL33 dually targets tumor cells and macrophages and endows stem-like qualities to colon cancer cells to promote carcinogenesis. Collectively, our work reveals an immune-associated mechanism that extrinsically confers cancer cell stemness properties. Targeting the IL33 signaling pathway may offer an opportunity to treat patients with metastatic cancer.

Hereditary mutations in BRCA1/2 genes increase the risk of breast cancer by 60–80% and ovarian cancer by about 20–40% in female carriers. Detection of inherited mutations in asymptomatic carriers allows for the implementation of appropriate preventive measures. BRCA1/2 genotyping is also important for poly(adenosine diphosphate)-ribose polymerase (PARP) inhibitor administration. This work addresses the need for next-generation sequencing (NGS) technology for the detection of BRCA1/2 mutations in Poland where until recently mostly founder mutations have been tested, and whether BRCA diagnostics should be extended beyond the panel of founder mutations in this population. The study comprises 2931 patients who were referred for genetic counseling and tested for founder and recurrent mutations in BRCA1 (5382insC (c.5266dupC; p.Gln1756Profs), c.5370C>T (c.5251C>T; p.R1751*), 300T>G (c.181T>G; p.Cys61Gly), 185delAG (c.68_69delAG; p.Glu23Valfs), and 4153delA (c.4035delA; p.Glu1346Lysfs)) by high-resolution melting/Sanger sequencing. A total of 103 (3.5%) mutations were detected, including 53 (51%) in healthy subjects and 50 (49%) in cancer patients. Then, based on more stringent clinical and pedigree criteria, sequencing of all BRCA1/2 exons was performed in 454 (16%) patients without founder mutations by NGS, which detected 58 mutations (12.8%), 40 (8.8%) of which were pathogenic. In 14 (3.1%) subjects, variants of uncertain significance (VUS) were detected, and in four (0.9%) subjects, the detected mutations were benign. In total, 161 mutations were detected using our two-step algorithm (founder test and NGS), of which 64% were founder mutations, 25% were NGS-detected pathogenic mutations, 9% were VUS, and 2% were benign. In addition, 38 mutations not yet reported in the Polish population were detected. In total, founder mutations accounted for only 64% of all detected mutations, and the remaining mutations (36%) were dispersed across the BRCA1/2 gene sequences. Thus, in Poland, testing for constitutional mutations in BRCA1/2 should be carried out in two stages, where NGS is performed in qualifying subjects if founder mutations are not identified.

Excessive accumulation of body fat (BF) promotes obesity, whilst posing a significant health hazard. There being no agreed, optimal quantifying methods, application of BF variable in clinical practice is not deemed an effective assessment option. The study, involving 4,735 patients (33.6% men), aged 45–64, aimed to identify optimal cut-off values for anthropometric indicators of obesity to evaluate cardiometabolic risk. A minimum P-value approach was applied to calculate the cut-offs for BF%. Threshold values for body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height (WHTR) ratio, facilitating optimal differentiation of cardiometabolic risk, were based on BF%, expressed as a binary classifier. The newly estimated cut-off values for predicting cardiometabolic risk, based on BMI, were lower than the referential obesity thresholds, whereas the threshold values of WC, WHR, and WHTR were higher. Apart from dyslipidemia, the odds of cardiometabolic disorders were higher, when the anthropometric indicators under study exceeded the cut-off points in both sexes. The proposed cut-offs proved instrumental in predicting cardiometabolic risk, whilst highlighting diagnostic and clinical potential of BF%, whereas BMI boasted the highest predictive potential. Cardiometabolic risk also proved significantly higher even in the overweight patients.

Background: Reliable obesity assessment is essential in evaluating the risk of cardiovascular risk factors (CRFs). Non-availability of clearly defined cutoffs for body fat percentage (BF%), as well as a widespread application of surrogate measures for obesity assessment, may result in incorrect prediction of cardio-metabolic risk. Purpose: The study aimed to determine optimal cutoff points for BF%, with a view of predicting the CRFs related to obesity. Patients and Methods: The study involved 4735 (33.6% of men) individuals, the Polish-Norwegian Study (PONS) participants, aged 45-64. BF% was measured with the aid of bioelectrical impedance analysis (BIA) method. The gender-specific cutoffs of BF% were found with respect to at least one CRF. A P-value approach, and receiver operating characteristic curve analyses were pursued for BF% cutoffs , which optimally differentiated normal from the risk groups. The associations between BF% and CRFs were determined by logistic regression models. Results: The cutoffs for BF% were established as 25.8% for men and 37.1% for women. With the exception of dyslipidemia, in men and women whose BF% was above the cutoffs , the odds for developing CRFs ranged 2-4 times higher than those whose BF% was below the cutoffs. Conclusion: Controlling BF% below the thresholds indicating an increased health hazard may be instrumental in appreciably reducing overall exposure to developing cardiometabolic risk.

ObjectiveThe study was designed to address the following three key areas, that is, (1) evaluate overall level of physical activity in the residents of a mid-sized, Central-European city, (2) compliance level with WHO’s recommendations on physical activity in leisure time and (3) actual impact of select socioeconomic factors on the physical activity level within the study population.MethodsAssessment of the source data collected for 4619 participants (1532 men and 3087 women, aged 45–65 years; mean age 56.41±5.31 years) was completed. Three levels of physical activity, and compliance level with pertinent WHO recommendations was evaluated, based on International Physical Activity Questionnaire (long form). Multilevel logistic regression models of socioeconomic factors associated with moderate-level, high-level physical activity, and WHO recommendations were developed.ResultsData analyses revealed that 6.19% of the study participants (n=286) engaged in low-level physical activity, 48.86%—in moderate-level activity, while high-level activity was reported in 44.94% of them. Compliance with pertinent WHO recommendations was higher in men aged 44–55 years, boasting upper-level education, living without a partner and in the persons with a net income over €1140 per household.ConclusionsOverall level of physical activity in the residents of a mid-sized, Central-European city was established as moderate. Pertinent WHO recommendations on physical activity were met by 4.2% of the subjects only.