Interferon alpha and rapamycin inhibit the growth of pheochromocytoma PC12 line in vitro

Wstęp: Guzy chromochłonne (pheochromocytoma/paraganglioma) należą do łagodnych lub złośliwych nowotworów neuroendokrynnych.Wobec niezadowalającej skuteczności standardowych sposobów leczenia pacjentów z rozsianą postacią choroby, wciąż poszukuje się nowych metod terapii, w tym możliwości skutecznego leczenia celowanego. W związku ze wzmożonym unaczynieniem tych nowotworów, preparaty o działaniu antyangiogennym mogą potencjalnie stanowić nową grupę leków stosowanych w leczeniu pheochromocytoma/paraganglioma.Materiał i metody: W badaniu oceniano wpływ różnych angiomodulatorów: VEGF (naczyniowo-środbłonkowy czynnik wzrostu) orazpięciu endo- i egzogennych czynników antyangiogennych (endostatyna; IFN-alfa [interferon alfa]; rapamycyna — inhibitor szlaku mTOR[mammalian target of rapamycin]; JV1-36 and SU5416 [semaxinib]) na wzrost szczurzej linii pheochromocytoma PC12.Wyniki: IFN-alfa (105 U/mL) silnie hamował wzrost komórek PC12 w hodowli 72 h, nasilając apoptozę i hamując cykl komórkowy. Rapamycynaw szerokim zakresie stężeń (10-5 to 10-8 M) nieznacznie zmniejszała żywotność komórek PC12, a w stężeniu 10-5 M także hamowałaich proliferację. VEGF, endostatyna oraz JV1-36 nie wpływały na wzrost lini PC12.Wnioski: W badaniu po raz pierwszy wykazano, że IFN-alfa hamuje wzrost linii komórkowej pheochromocytoma PC12, a także potwierdzonohamujący wpływ rapamycyny wobec tej linii komórkowej. Uzyskane wyniki sugerują zatem, że IFN-alfa oraz inhibitory szlakumTOR mogą być potencjalnie skuteczne w leczeniu złośliwych postaci guzów chromochłonnych i zachęcają do dalszych badań w tymkierunku.(Endokrynol Pol 2013; 64 (5): 368–374)Introduction: Pheochromocytomas are benign or malignant neuroendocrine tumours. The unsatisfactory efficacy of the traditionaltherapeutic methods for patients with metastatic disease results in a continuing search for more effective and targeted agents. Due to theincreased vascularisation of these tumours, inhibitors of angiogenesis could be potentially a new group of drugs in pheochromocytoma/paraganglioma therapy.Material and methods: The aim of this study was to evaluate the influence of angiomodulators: VEGF (vascular endothelial growth factor)and five endogenous and exogenous antiangiogenic compounds (endostatin; IFN-alpha [interferon alpha]; rapamycin — mTOR [mammaliantarget of rapamycin] inhibitor; JV1-36 and SU5416 (semaxinib]) on the growth of rat pheochromocytoma PC12 cell line.Results: IFN-alpha (105 U/mL) strongly inhibited PC12 growth in a 72 h culture, increasing apoptosis and arresting the cell cycle. Rapamycinin a wide range of concentrations (10-5 to 10-8 M) induced a slight inhibitory effect on PC12 viability and decreased cell proliferation at theconcentration of 10-5 M. VEGF, endostatin and JV1-36 did not influence the growth of PC12.onclusions: The study has shown for the first time that IFN-a inhibited the growth of pheochromocytoma PC12 line and confirmed theinhibitory action of rapamycin on these cells. The results suggest that IFN-alpha and mTOR inhibitors could be potentially effective in thetherapy of malignant pheochromocytoma, and encourage further study in this field.(Endokrynol Pol 2013; 64 (5): 368–374

Willingness to vaccinate among adults, and factors associated with vaccine acceptance of COVID-19 vaccines in a nationwide study in Poland between March 2021 and April 2022

IntroductionDespite the availability, safety and effectiveness of COVID-19 vaccines, Poland remains one of the six countries of the European Union with the lowest cumulative uptake of the vaccine's primary course in the general population. This study examined willingness to vaccinate and the associated factors in samples of unvaccinated and vaccinated adults between March 2021 and April 2022.MethodsData were collected using OBSER-CO, a nationwide, repeated cross-sectional study, conducted at four different time points (rounds). Data on willingness to vaccinate among the unvaccinated (at all rounds) and willingness to receive another dose in the vaccinated (at 2 rounds-after booster introduction), reasons for reluctance, sociodemographic, health, and behavioral factors were collected using a uniform questionnaire via computer-assisted telephone interviewing. In each round, more than 20,000 respondents were interviewed. To assess associations between factors and willingness to vaccinate, separate multivariable logistic regression models were fitted for each factor at each round and adjusted for confounders.ResultsBetween rounds 1 and 4 (March 2021–April 2022), in the unvaccinated, willingness to vaccinate declined from 73 to 12%, whereas in the vaccinated, willingness to receive another dose declined from 90 to 53%. The highest magnitude of decline between subsequent rounds occurred during the Omicron wave. Overall, concerns about side effects, effectiveness, and vaccine adverse effects were common but decreased over time. Age, gender, employment, place of residence, COVID-19 diagnosis or exposure, hospitalization, and participation in social activities were among the factors associated with willingness. However, associations changed over rounds highlighting the influence of different pandemic waves and variants.ConclusionWe observed a declining and multifactorial willingness to vaccinate in Poland, with vaccine attitudes dynamically changing across subsequent rounds. To address vaccine concerns, sustained health communication about COVID-19 vaccines is essential, especially after the emergence of new variants

Comparison of the clinical characteristics, glycemic control, and pregnancy outcomes between women with gestational diabetes mellitus in waves I and III of the COVID-19 pandemic: a reference center report

Objectives: The medical care of patients with gestational diabetes mellitus (GDM) during the COVID-19 pandemic was influenced by changing epidemiological conditions and government regulations. Aim — To compare the clinical pregnancy data of GDM women between waves I and III of the pandemic. Material and methods: We performed a retrospective analysis of medical records from the GDM clinic and compared the periods of March–May 2020 (wave I) and March–May 2021 (wave III). Results: Women with GDM during wave I (n = 119) compared to wave III (n = 116) were older (33.0 ± 4.7 vs 32.1 ± 4.8 years; p = 0.07), booked later (21.8 ± 8.4 vs 20.3 ± 8.5 weeks; p = 0.17), and had their last appointment earlier (35.5 ± 2.0 vs 35.7 ± 3.2 weeks; p < 0.01). Telemedicine consultations were used more frequently during wave I (46.8% vs 24.1%; p < 0.01), while insulin therapy was used less often (64.7% vs 80.2%; p < 0.01). Mean fasting self-measured glucose did not differ (4.8 ± 0.3 vs 4.8 ± 0.3 mmol/L; p = 0.49), but higher postprandial glucose was reported during wave I (6.6 ± 0.9 vs 6.3 ± 0.6 mmol/l; p < 0.01). Pregnancy outcome data were available for 77 wave I pregnancies and 75 wave III pregnancies. The groups were similar in terms of gestational week of delivery (38.3 ± 1.4 vs 38.1 ± 1.6 weeks), cesarean sections (58.4% vs 61.3%), APGAR scores (9.7 ± 1.0 vs 9.7 ± 1.0 pts), and birth weights (3306.6 ± 457.6 g vs 3243.9 ± 496.8 g) (p = NS for all). The mean wave I neonate length was slightly higher (54.3 ± 2.6 cm vs 53.3 ± 2.6 cm; p = 0.04). Conclusions: We identified differences between wave I and wave III pregnancies for several clinical characteristics. However, nearly all pregnancy outcomes were found to be similar

Lifestyle, dietary factors and antibody levels to oral bacteria in cancer-free participants of a European cohort study

Background—Increasing evidence suggests that oral microbiota play a pivotal role in chronic diseases, in addition to the well-established role in periodontal disease. Moreover, recent studies suggest that oral bacteria may also be involved in carcinogenesis; periodontal disease has been linked several cancers. In this study, we examined whether lifestyle factors have an impact on antibody levels to oral bacteria. Methods—Data on demographic characteristics, lifestyle factors, and medical conditions were obtained at the time of blood sample collection. For the current analysis, we measured antibody levels to 25 oral bacteria in 395 cancer-free individuals using an immunoblot array. Combined total immunglobin G (IgG) levels were obtained by summing concentrations for all oral bacteria measured. Results—IgG antibody levels were substantially lower among current and former smokers (1697 and 1677 ng/mL, respectively) than never smokers (1960 ng/mL; p-trend = 0.01), but did not vary by other factors, including BMI, diabetes, physical activity, or by dietary factors, after adjusting for age, sex, education, country and smoking status. The highest levels of total IgG were found among individuals with low education (2419 ng/mL). Conclusions—Our findings on smoking are consistent with previous studies and support the notion that smokers have a compromised humoral immune response. Moreover, other major factors known to be associated with inflammatory markers, including obesity, were not associated with antibody levels to a large number of oral bacteria

Pre-diagnostic copper and zinc biomarkers and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort.

Adequate intake of copper and zinc, two essential micronutrients, are important for antioxidant functions. Their imbalance may have implications for development of diseases like colorectal cancer (CRC), where oxidative stress is thought to be etiologically involved. As evidence from prospective epidemiologic studies is lacking, we conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to investigate the association between circulating levels of copper and zinc, and their calculated ratio, with risk of CRC development. Copper and zinc levels were measured by reflection X-ray fluorescence spectrometer in 966 cases and 966 matched controls. Multivariable adjusted odds ratios (OR) and 95% confidence intervals (CI) were calculated using conditional logistic regression and are presented for the fifth versus first quintile. Higher circulating concentration of copper was associated with a raised CRC risk (OR = 1.50; 95% CI: 1.06, 2.13; P-trend = 0.02) whereas an inverse association with cancer risk was observed for higher zinc levels (OR = 0.65; 95% CI: 0.43, 0.97; P-trend = 0.07). Consequently, the ratio of copper/zinc was positively associated with CRC (OR = 1.70; 95% CI: 1.20, 2.40; P-trend = 0.0005). In subgroup analyses by follow-up time, the associations remained statistically significant only in those diagnosed within 2 years of blood collection. In conclusion, these data suggest that copper or copper levels in relation to zinc (copper to zinc ratio) become imbalanced in the process of CRC development. Mechanistic studies into the underlying mechanisms of regulation and action are required to further examine a possible role for higher copper and copper/zinc ratio levels in CRC development and progression

The Potential Role of Vitamin D Enhanced Foods in Improving Vitamin D Status

Low vitamin D intake and status have been reported worldwide and many studies have suggested that this low status may be involved in the development of several chronic diseases. There are a limited number of natural dietary sources of vitamin D leading to a real need for alternatives to improve dietary intake. Enhancement of foods with vitamin D is a possible mode for ensuring increased consumption and thus improved vitamin D status. The present review examines studies investigating effects of vitamin D enhanced foods in humans and the feasibility of the approach is discussed

Association of Plasma Vitamin D Metabolites With Incident Type 2 Diabetes: EPIC-InterAct Case-Cohort Study.

BACKGROUND: Existing evidence for the prospective association of vitamin D status with type 2 diabetes (T2D) is focused almost exclusively on circulating total 25-hydroxyvitamin D [25(OH)D] without distinction between its subtypes: nonepimeric and epimeric 25(OH)D3 stereoisomers, and 25(OH)D2, the minor component of 25(OH)D. We aimed to investigate the prospective associations of circulating levels of the sum and each of these three metabolites with incident T2D. METHODS: This analysis in the European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study for T2D included 9671 incident T2D cases and 13,562 subcohort members. Plasma vitamin D metabolites were quantified by liquid chromatography-mass spectrometry. We used a multivariable Prentice-weighted Cox regression to estimate hazard ratios (HRs) of T2D for each metabolite. Analyses were performed separately within country, and estimates were combined across countries using random-effects meta-analysis. RESULTS: The mean concentrations (SD) of total 25(OH)D, nonepimeric 25(OH)D3, epimeric 25(OH)D3, and 25(OH)D2 were 41.1 (17.2), 40.7 (17.3), 2.13 (1.31), and 8.16 (6.52) nmol/L, respectively. Plasma total 25(OH)D and nonepimeric 25(OH)D3 were inversely associated with incident T2D [multivariable-adjusted HR per 1 SD = 0.81 (95% CI, 0.77, 0.86) for both variables], whereas epimeric 25(OH)D3 was positively associated [per 1 SD HR = 1.16 (1.09, 1.25)]. There was no statistically significant association with T2D for 25(OH)D2 [per 1 SD HR = 0.94 (0.76, 1.18)]. CONCLUSIONS: Plasma nonepimeric 25(OH)D3 was inversely associated with incident T2D, consistent with it being the major metabolite contributing to total 25(OH)D. The positive association of the epimeric form of 25(OH)D3 with incident T2D provides novel information to assess the biological relevance of vitamin D epimerization and vitamin D subtypes in diabetes etiology.The InterAct project was funded by the European Union Framework 6 (LSHM_CT_2006_037197). Biomarker measurements for vitamin D metabolites were funded jointly by the InterAct project, the MRC Cambridge Initiative (RG71466, SJAH/004) and the EPIC-CVD project. EPIC-CVD has been supported by the European Union Framework 7 (HEALTH-F2-2012-279233), the European Research Council (268834), the UK Medical Research Council (G0800270 and MR/L003120/1), the British Heart Foundation (SP/09/002 and RG/08/014 and RG13/13/30194) and the UK National Institute of Health Research. In addition, InterAct investigators acknowledge funding from the following agencies: Medical Research Council Epidemiology Unit MC_UU_12015/1 and MC_UU_12015/5, NIHR Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014), Regional Government of Asturias and Regional Governments of Basque Country. Dr. Ivonne Sluijs is supported by the Junior Dr. Dekker grant (2015T019) from the Dutch Heart Foundation. Dr. Guy Fagherazzi is supported by the French Research Agency (Agence Nationale de la Recherche) via an “Investissement d’Avenir” grant (investment for the future grant, ANR-10-COHO-0006) and by the IDEX Paris Saclay Nutriperso Project. This project has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 701708

Timing of eating across ten European countries - results from the European Prospective Investigation into Cancer and Nutrition (EPIC) calibration study

Objective To examine timing of eating across ten European countries. Design Cross-sectional analysis of the European Prospective Investigation into Cancer and Nutrition (EPIC) calibration study using standardized 24 h diet recalls collected during 1995-2000. Eleven predefined food consumption occasions were assessed during the recall interview. We present time of consumption of meals and snacks as well as the later:earlier energy intake ratio, with earlier and later intakes defined as 06.00-14.00 and 15.00-24.00 hours, respectively. Type III tests were used to examine associations of sociodemographic, lifestyle and health variables with timing of energy intake. Setting Ten Western European countries. Subjects In total, 22 985 women and 13 035 men aged 35-74 years (n 36 020). Results A south-north gradient was observed for timing of eating, with later consumption of meals and snacks in Mediterranean countries compared with Central and Northern European countries. However, the energy load was reversed, with the later:earlier energy intake ratio ranging from 0 center dot 68 (France) to 1 center dot 39 (Norway) among women, and from 0 center dot 71 (Greece) to 1 center dot 35 (the Netherlands) among men. Among women, country, age, education, marital status, smoking, day of recall and season were all independently associated with timing of energy intake (all PPeer reviewe