IntroductionInfections may play a role in the etiology of childhood cancer and immunizations may be protective because vaccinations stimulate the immune system. Observational studies reported inconsistent associations between vaccination and risk of childhood cancer. Since a synthesis of the evidence is lacking, we conducted a meta-analysis stratified by histological and site-specific cancer.MethodsWe performed a systematic review (CRD42020148579) following PRISMA guidelines and searched for literature in MEDLINE, Embase, and the Science Citation Index databases. We identified in three literature databases 7,594 different articles of which 35 met the inclusion criteria allowing for 27 analyses of 11 cancer outcomes after exposure to nine different types of vaccinations. We calculated summary odds ratios (ORs) and 95% confidence intervals (CIs) using random effects models.ResultsWe observed four inverse associations between childhood leukemia and certain vaccines as well as the number of vaccinations: OR 0.49 (95% CI = 0.32 to 0.74) for leukemia death after bacillus Calmette–Guérin vaccination; OR 0.76 (95% CI = 0.65 to 0.90) for acute lymphoblastic leukemia after Haemophilus influenzae type b vaccination; OR 0.57 (95% CI = 0.36 to 0.88) for leukemia; and OR 0.62 (95% CI = 0.46 to 0.85) for acute lymphoblastic leukemia after three or more vaccinations of any type. All other conducted analyses did not show any associations.DiscussionThe results are consistent with the hypothesis that vaccinations reduce the risk of childhood leukemia. However, the robustness and validity of these results is limited due to the small number, substantial heterogeneity, and methodological limitations of available studies.
Background Exposure to ionizing radiation induces complex stress responses in cells, which can lead to adverse health effects such as cancer. Although a variety of studies investigated gene expression and affected pathways in human fibroblasts after exposure to ionizing radiation, the understanding of underlying mechanisms and biological effects is still incomplete due to different experimental settings and small sample sizes. Therefore, this study aims to identify the time point with the highest number of differentially expressed genes and corresponding pathways in primary human fibroblasts after irradiation at two preselected time points. Methods Fibroblasts from skin biopsies of 15 cell donors were exposed to a high (2Gy) and a low (0.05Gy) dose of X-rays. RNA was extracted and sequenced 2 h and 4 h after exposure. Differentially expressed genes with an adjusted p-value < 0.05 were flagged and used for pathway analyses including prediction of upstream and downstream effects. Principal component analyses were used to examine the effect of two different sequencing runs on quality metrics and variation in expression and alignment and for explorative analysis of the radiation dose and time point of analysis. Results More genes were differentially expressed 4 h after exposure to low and high doses of radiation than after 2 h. In experiments with high dose irradiation and RNA sequencing after 4 h, inactivation of the FAT10 cancer signaling pathway and activation of gluconeogenesis I, glycolysis I, and prostanoid biosynthesis was observed taking p-value (< 0.05) and (in) activating z-score (≥2.00 or ≤ − 2.00) into account. Two hours after high dose irradiation, inactivation of small cell lung cancer signaling was observed. For low dose irradiation experiments, we did not detect any significant (p < 0.05 and z-score ≥ 2.00 or ≤ − 2.00) activated or inactivated pathways for both time points. Conclusions Compared to 2 h after irradiation, a higher number of differentially expressed genes were found 4 h after exposure to low and high dose ionizing radiation. Differences in gene expression were related to signal transduction pathways of the DNA damage response after 2 h and to metabolic pathways, that might implicate cellular senescence, after 4 h. The time point 4 h will be used to conduct further irradiation experiments in a larger sample.
Background Therapy for a first primary neoplasm (FPN) in childhood with high doses of ionizing radiation is an established risk factor for second primary neoplasms (SPN). An association between exposure to low doses and childhood cancer is also suggested; however, results are inconsistent. As only subgroups of children with FPNs develop SPNs, an interaction between radiation, genetic, and other risk factors is presumed to influence cancer development. Objective Therefore, the population-based, nested case-control study KiKme aims to identify differences in genetic predisposition and radiation response between childhood cancer survivors with and without SPNs as well as cancer-free controls. Methods We conducted a population-based, nested case-control study KiKme. Besides questionnaire information, skin biopsies and saliva samples are available. By measuring individual reactions to different exposures to radiation (eg, 0.05 and 2 Gray) in normal somatic cells of the same person, our design enables us to create several exposure scenarios for the same person simultaneously and measure several different molecular markers (eg, DNA, messenger RNA, long noncoding RNA, copy number variation). Results Since 2013, 101 of 247 invited SPN patients, 340 of 1729 invited FPN patients, and 150 of 246 invited cancer-free controls were recruited and matched by age and sex. Childhood cancer patients were additionally matched by tumor morphology, year of diagnosis, and age at diagnosis. Participants reported on lifestyle, socioeconomical, and anthropometric factors, as well as on medical radiation history, health, and family history of diseases (n=556). Primary human fibroblasts from skin biopsies of the participants were cultivated (n=499) and cryopreserved (n=3886). DNA was extracted from fibroblasts (n=488) and saliva (n=510). Conclusions This molecular-epidemiological study is the first to combine observational epidemiological research with standardized experimental components in primary human skin fibroblasts to identify genetic predispositions related to ionizing radiation in childhood and SPNs. In the future, fibroblasts of the participants will be used for standardized irradiation experiments, which will inform analysis of the case-control study and vice versa. Differences between participants will be identified using several molecular markers. With its innovative combination of experimental and observational components, this new study will provide valuable data to forward research on radiation-related risk factors in childhood cancer and SPNs. International Registered Report Identifier (IRRID) DERR1-10.2196/32395
Background The etiology and most risk factors for a sporadic first primary neoplasm in childhood or subsequent second primary neoplasms are still unknown. One established causal factor for therapy-associated second primary neoplasms is the exposure to ionizing radiation during radiation therapy as a mainstay of cancer treatment. Second primary neoplasms occur in 8% of all cancer survivors within 30 years after the first diagnosis in Germany, but the underlying factors for intrinsic susceptibilities have not yet been clarified. Thus, the purpose of this nested case–control study was the investigation and comparison of gene expression and affected pathways in primary fibroblasts of childhood cancer survivors with a first primary neoplasm only or with at least one subsequent second primary neoplasm, and controls without neoplasms after exposure to a low and a high dose of ionizing radiation. Methods Primary fibroblasts were obtained from skin biopsies from 52 adult donors with a first primary neoplasm in childhood (N1), 52 with at least one additional primary neoplasm (N2+), as well as 52 without cancer (N0) from the KiKme study. Cultured fibroblasts were exposed to a high [2 Gray (Gy)] and a low dose (0.05 Gy) of X-rays. Messenger ribonucleic acid was extracted 4 h after exposure and Illumina-sequenced. Differentially expressed genes (DEGs) were computed using limma for R, selected at a false discovery rate level of 0.05, and further analyzed for pathway enrichment (right-tailed Fisher’s Exact Test) and (in-) activation (z ≥|2|) using Ingenuity Pathway Analysis. Results After 0.05 Gy, least DEGs were found in N0 (n = 236), compared to N1 (n = 653) and N2+ (n = 694). The top DEGs with regard to the adjusted p-value were upregulated in fibroblasts across all donor groups (SESN1, MDM2, CDKN1A, TIGAR, BTG2, BLOC1S2, PPM1D, PHLDB3, FBXO22, AEN, TRIAP1, and POLH). Here, we observed activation of p53 Signaling in N0 and to a lesser extent in N1, but not in N2+. Only in N0, DNA (excision-) repair (involved genes: CDKN1A, PPM1D, and DDB2) was predicted to be a downstream function, while molecular networks in N2+ were associated with cancer, as well as injury and abnormalities (among others, downregulation of MSH6, CCNE2, and CHUK). After 2 Gy, the number of DEGs was similar in fibroblasts of all donor groups and genes with the highest absolute log2 fold-change were upregulated throughout (CDKN1A, TIGAR, HSPA4L, MDM2, BLOC1SD2, PPM1D, SESN1, BTG2, FBXO22, PCNA, and TRIAP1). Here, the p53 Signaling-Pathway was activated in fibroblasts of all donor groups. The Mitotic Roles of Polo Like Kinase-Pathway was inactivated in N1 and N2+. Molecular Mechanisms of Cancer were affected in fibroblasts of all donor groups. P53 was predicted to be an upstream regulator in fibroblasts of all donor groups and E2F1 in N1 and N2+. Results of the downstream analysis were senescence in N0 and N2+, transformation of cells in N0, and no significant effects in N1. Seven genes were differentially expressed in reaction to 2 Gy dependent on the donor group (LINC00601, COBLL1, SESN2, BIN3, TNFRSF10A, EEF1AKNMT, and BTG2). Conclusion Our results show dose-dependent differences in the radiation response between N1/N2+ and N0. While mechanisms against genotoxic stress were activated to the same extent after a high dose in all groups, the radiation response was impaired after a low dose in N1/N2+, suggesting an increased risk for adverse effects including carcinogenesis, particularly in N2+.
Background: Aim of this study was to describe the proportion of hypertension among Zanzibari of different age-groups and to detect possible correlates of this non-communicable disease.Methods: In 2013 a cross-sectional survey was conducted in Unguja Island, Zanzibar. A total of 235 randomly selected households, including 1,229 (2 to 95 years) eligible study participants, were examined. Association between objectively assessed obesity markers, salt intake and hypertension were investigated. Estimates of 24 h sodium and potassium excretion from a single morning spot urine specimen were calculated and used as surrogate for salt intake. The association between overweight/obesity and hypertension in different age-groups was assessed in multilevel logistic regression models. Further associations between salt intake and hypertension were analyzed.Results: Measures of systolic and diastolic blood pressure as well as proportion of overweight/obesity and hypertension both increased with age. Overweight and obesity were significantly associated with hypertension in adults. Moreover, thinness seems to be associated with hypertension as well. We observed a significantly reduced chance of hypertension for higher urinary sodium-to-potassium compared to a lower ratio in children.Conclusion: Overweight/obesity and hypertension were highly prevalent (>47% of adults >40 years are overweight or obese and >69% are hypertensive in the same age group) in our sample. Weight status was confirmed as a correlate of high blood pressure in our sample from Zanzibar, Tanzania. To early and effectively prevent related severe cardiovascular outcomes, screening strategies but also monitoring strategies are required for this population.
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