Identifying MicroRNAs Suitable for Detection of Breast Cancer: A Systematic Review of Discovery Phases Studies on MicroRNA Expression Profiles.

The analysis of circulating tumor cells and tumor-derived materials, such as circulating tumor DNA, circulating miRNAs (cfmiRNAs), and extracellular vehicles provides crucial information in cancer research. CfmiRNAs, a group of short noncoding regulatory RNAs, have gained attention as diagnostic and prognostic biomarkers. This review focuses on the discovery phases of cfmiRNA studies in breast cancer patients, aiming to identify altered cfmiRNA levels compared to healthy controls. A systematic literature search was conducted, resulting in 16 eligible publications. The studies included a total of 585 breast cancer cases and 496 healthy controls, with diverse sample types and different cfmiRNA assay panels. Several cfmiRNAs, including MIR16, MIR191, MIR484, MIR106a, and MIR193b, showed differential expressions between breast cancer cases and healthy controls. However, the studies had a high risk of bias and lacked standardized protocols. The findings highlight the need for robust study designs, standardized procedures, and larger sample sizes in discovery phase studies. Furthermore, the identified cfmiRNAs can serve as potential candidates for further validation studies in different populations. Improving the design and implementation of cfmiRNA research in liquid biopsies may enhance their clinical diagnostic utility in breast cancer patients.

[The wave train of COVID-19 infections]. / COVID-19: il treno di onde dei contagi.

The present work studies the epidemic curve of COVID-19 in Italy between September 2020 and mid-June 2021 in terms of poussées, that is successive waves. There is obviously only one pandemic, although the virus has spread in the form of several variants, but the daily incidence trend can also be read in terms of overlapping of events that are different from each other or, in any case, induced by various phenomena. It can be hypothesized that in this way a succession of various waves was generated, which are modelled here using appropriate adaptation curves used in the study of epidemic data. Each curve corresponds approximately to the situation that would have occurred if no element had intervened to prevent the decrease of infections after the relative peak, while their overlap is considered to describe the subsequent increases. This interpolation has no predictive purpose, being purely descriptive over the time window under consideration. The discrepancies between the superposition of the modelling curves and the real epidemic curve are therefore also highlighted, especially in the transition periods between the various poussées. Finally, the analysis carried out allows to match the trend of the epidemic in the period considered with, on one hand, the series of events and, on the other, with the containment measures adopted which may have determined the succession of increases and decreases in the incidence of infections.

[Rt or RDt, that is the question!] / Rt or RDt, that is the question!

The article compares two of the most followed indices in the monitoring of COVID-19 epidemic cases: the Rt and the RDt indices. The first was disseminated by the Italian National Institute of Health (ISS) and the second, which is more usable due to the lower difficulty of calculation and the availability of data, was adopted by various regional and local institutions.The rationale for the Rt index refers to that for the R0 index, the basic reproduction number, which is used by infectivologists as a measure of contagiousness of a given infectious agent in a completely susceptible population. The RDt index, on the other hand, is borrowed from the techniques of time series analysis for the trend of an event measurement that develops as a function of time. The RDt index does not take into account the time of infection, but the date of the diagnosis of positivity and for this reason it is defined as diagnostic replication index, as it aims to describe the intensity of the development of frequency for cases recognized as positive in the population.The comparison between different possible applications of the methods and the use of different types of monitoring data was limited to four areas for which complete individual data were available in March and April 2020. The main problems in the use of Rt, which is based on the date of symptoms onset, arise from the lack of completeness of this information due both to the difficulty in the recording and to the absence in asymptomatic subjects.The general trend of RDt, at least at an intermediate lag of 6 or 7 days, is very similar to that of Rt, as confirmed by the very high value of the correlation index between the two indices. The maximum correlation between Rt and RDt is reached at lag 7 with a value of R exceeding 0.97 (R2=0.944).The two indices, albeit formally distinct, are both valid; they show specific aspects of the phenomenon, but provide basically similar information to the public health decision-maker. Their distinction lies not so much in the method of calculation, rather in the use of different information, i.e., the beginning of symptoms and the swabs outcome.Therefore, it is not appropriate to make a judgment of preference for one of the two indices, but only to invite people to understand their different potentials so that they can choose the one they consider the most appropriate for the purpose they want to use it for.

Marginal Time-Dependent Causal Effects in Mediation Analysis With Survival Data.

The main aim of mediation analysis is to study the direct and indirect effects of an exposure on an outcome. To date, the literature on mediation analysis with multiple mediators has mainly focused on continuous and dichotomous outcomes. However, the development of methods for multiple mediation analysis of survival outcomes is still limited. Here we extend to survival outcomes a method for multiple mediation analysis based on the computation of appropriate weights. The approach considered has the advantages of not requiring specific models for mediators, allowing nonindependent mediators of any nature, and not relying on the assumption of rare outcomes. Simulation studies show good performance of the proposed estimator in terms of bias and coverage probability. The method is further applied to an example from a published study on prostate cancer mortality aimed at understanding the extent to which the effect of DNA methyltransferase 3b (DNMT3b) genotype on mortality was explained by DNA methylation and tumor aggressiveness. This approach can be used to quantify the marginal time-dependent direct and indirect effects carried by multiple indirect pathways, and software code is provided to facilitate its application.

New insights on occupational exposure and bladder cancer risk: a pooled analysis of two Italian case-control studies.

PURPOSE: The main risk factor for bladder cancer (BC) is cigarette smoking, but also occupational exposure to carcinogens is relevant, causing about 4-10% of BC. We aimed at investigating the association between BC risk, occupations held in the past and exposure to occupational carcinogens, also assessing whether these associations were influenced by tumour grade. METHODS: We pooled data from two Italian case-control studies on male BC, analyzing 893 cases and 978 controls. Occupations were classified using the International Standard Classification of Occupations and exposure to carcinogens was assigned using a validated Job Exposure Matrix. Logistic regression approach was used as well as a semi-Bayesian model, based on a priori information on exposure. RESULTS: A significantly increased BC risk was found for chemical engineering technicians, postmen, and lathe operators, but only, for the latter, the association remained significant after Bayesian control for type I error. Among carcinogens, cadmium and trichloroethylene were associated with BC. When analyzing data by grade, exposure to these carcinogens was associated with low-grade BC only. CONCLUSIONS: Our results suggest that monitoring workplaces to prevent exposure to carcinogenic agents is still an important task, which should be still given adequate importance in public health.

Nonsuppressing normal thymus on chemical-shift MR imaging and anterior mediastinal lymphoma: differentiation with diffusion-weighted MR imaging by using the apparent diffusion coefficient.

OBJECTIVES: To prospectively evaluate usefulness of the apparent diffusion coefficient (ADC) in differentiating anterior mediastinal lymphoma from nonsuppressing normal thymus on chemical-shift MR, and to look at the relationship between patient age and ADC. METHODS: Seventy-three young subjects (25 men, 48 women; age range, 9-29 years), who underwent chemical-shift MR and diffusion-weighted MR were divided into a normal thymus group (group A, 40 subjects), and a lymphoma group (group B, 33 patients). For group A, all subjects had normal thymus with no suppression on opposed-phase chemical-shift MR. Two readers measured the signal intensity index (SII) and ADC. Differences in SII and ADC between groups were tested using t-test. ADC was correlated with age using Pearson correlation coefficient. RESULTS: Mean SII±standard deviation was 2.7±1.8% for group A and 2.2±2.4% for group B, with no significant difference between groups (P=.270). Mean ADC was 2.48±0.38x10-3mm2/s for group A and 1.24±0.23x10-3mm2/s for group B. A significant difference between groups was found (P<.001), with no overlap in range. Lastly, significant correlation was found between age and ADC (r=0.935, P<.001) in group A. CONCLUSIONS: ADC of diffusion-weighted MR is a noninvasive and accurate parameter for differentiating lymphoma from nonsuppressing thymus on chemical-shift MR in young subjects. KEY POINTS: • SII cannot differentiate mediastinal lymphoma from nonsuppressing normal thymus at visual assessment • ADC is useful for distinguishing nonsuppressing normal thymus from mediastinal lymphoma • ADC is more accurate than transverse-diameter and surface-area in this discrimination • ADC of normal thymus is age dependent and increases with increasing age.

Transient elastography for non-invasive evaluation of post-transplant liver graft fibrosis in children.

As graft survival in pediatric LT is often affected by progressive fibrosis, numerous centers carry out protocol liver biopsies. Follow-up biopsy protocols differ from center to center, but all biopsies are progressively spaced out, as time from transplant increases. Therefore, there is a need for non-invasive techniques to evaluate graft fibrosis progression in those children who have no clinical or serological signs of liver damage. Indirect markers, such as the APRI, should be relied on with caution because their sensitivity in predicting fibrosis can be strongly influenced by the etiology of liver disease, severity of fibrosis, and patient age. A valid alternative could be TE, a non-invasive technique already validated in adults, which estimates the stiffness of the cylindrical volume of liver tissue, 100-fold the size of a standard needle biopsy sample. The aims of this study were to evaluate the reliability of TE in children after LT and to compare both the TE and the APRI index results with the histological scores of fibrosis on liver biopsies. A total of 36 pediatric LT recipients were studied. All patients underwent both TE and biopsy within a year (median interval -0.012 months) at an interval from LT of 0.36 to 19.47 years (median 3.02 years). Fibrosis was assessed on the biopsy specimens at histology and staged according to METAVIR. There was a statistically significant correlation between TE stiffness values and METAVIR scores (P = .005). The diagnostic accuracy of TE for the diagnosis of significant fibrosis (F ≥ 2) was measured as the area under the curve (AUROC = 0.865), and it demonstrated that the method had a good diagnostic performance. APRI was not so accurate in assessing graft fibrosis when compared to METAVIR (AUROC = 0.592). A liver stiffness cutoff value of 5.6 kPa at TE was identified as the best predictor for a significant graft fibrosis (METAVIR F ≥ 2) on liver biopsy, with a 75% sensitivity, a 95.8% specificity, a 90% positive predictive value, and an 88.5% negative predictive value. These data suggest that TE may represent a non-invasive, reliable tool for the assessment of graft fibrosis in the follow-up of LT children, alerting the clinicians to the indication for a liver biopsy, with the aim of reducing the number of protocol liver biopsies.

A computational analysis of S-(2-succino)cysteine sites in proteins.

The adduction of fumaric acid to the sulfhydryl group of certain cysteine (Cys) residues in proteins via a Michael-like reaction leads to the formation of S-(2-succino)cysteine (2SC) sites. Although its role remains to be fully understood, this post-translational Cys modification (protein succination) has been implicated in the pathogenesis of diabetes/obesity and fumarate hydratase-related diseases. In this study, theoretical approaches to address sequence- and 3D-structure-based features possibly underlying the specificity of protein succination have been applied to perform the first analysis of the available data on the succinate proteome. A total of 182 succinated proteins, 205 modifiable, and 1750 non-modifiable sites have been examined. The rate of 2SC sites per protein ranged from 1 to 3, and the overall relative abundance of modifiable sites was 10.8%. Modifiable and non-modifiable sites were not distinguishable when the hydrophobicity of the Cys-flaking peptides, the acid dissociation constant value of the sulfhydryl groups, and the secondary structure of the Cys-containing segments were compared. By contrast, significant differences were determined when the accessibility of the sulphur atoms and the amino acid composition of the Cys-flaking peptides were analysed. Based on these findings, a sequence-based score function has been evaluated as a descriptor for Cys residues. In conclusion, our results indicate that modifiable and non-modifiable sites form heterogeneous subsets when features often discussed to describe Cys reactivity are examined. However, they also suggest that some differences exist, which may constitute the baseline for further investigations aimed at the development of predictive methods for 2SC sites in proteins.

Abdominal adiposity is not a mediator of the protective effect of Mediterranean diet on colorectal cancer.

Adherence to the Mediterranean diet (MD) has a preventive effect on colorectal cancer (CRC). Several biological mechanisms have been hypothesized to explain this effect, but the involvement of clinical mediators has not been experimentally proven. We examined the role of abdominal adiposity (i.e., waist-to-hip ratio, WHR) as a potential mediator of the relationship between the MD and CRC in the Italian centres of the European Prospective Investigation into Cancer and Nutrition. We evaluated the effect of the Italian Mediterranean Index (IMI) on WHR and of WHR on CRC risk. We then estimated the natural indirect effect (NIE, mediated by WHR) and the pure direct effect (PDE, unmediated) of IMI on CRC risk using mediation analyses, considering age, sex, education, physical activity, smoking and EPIC centre as confounders. Increased IMI was associated with significantly decreased odds of high WHR (odds ratio [OR] for an IMI of 6-11 vs. 0-1: 0.88, 95% confidence interval [CI]: 0.81-0.97). There was a positive relationship between WHR and CRC (hazard ratio [HR] for high vs. low WHR: 1.34, 95%CI: 1.09-1.66). The total effect of IMI was protective on CRC risk and was mainly explained by the PDE (HR for an IMI of 6-11 vs. 0-1: 0.51, 95%CI: 0.31-0.83), whereas the NIE was 1.00 (95%CI: 0.94-1.10). In this Mediterranean cohort, the protective effect of the MD on the development of CRC was not mediated by abdominal adiposity. Since this is the first study to investigate the mediating effect of abdominal obesity, other studies are needed to replicate this result.

Diet and endometrial cancer: a focus on the role of fruit and vegetable intake, Mediterranean diet and dietary inflammatory index in the endometrial cancer risk.

BACKGROUND: Endometrial cancer is the fourth most common cancer in European women. The major risk factors for endometrial cancer are related to the exposure of endometrium to estrogens not opposed to progestogens, that can lead to a chronic endometrial inflammation. Diet may play a role in cancer risk by modulating chronic inflammation. METHODS: In the framework of a case-control study, we recruited 297 women with newly diagnosed endometrial cancer and 307 controls from Northern Italy. Using logistic regression, we investigated the role of fruit and vegetable intake, adherence to the Mediterranean diet (MD), and the dietary inflammatory index (DII) in endometrial cancer risk. RESULTS: Women in the highest quintile of vegetable intake had a statistically significantly lower endometrial cancer risk (adjusted OR 5th quintile vs 1st quintile: 0.34, 95% CI 0.17-0.68). Women with high adherence to the MD had a risk of endometrial cancer that was about half that of women with low adherence to the MD (adjusted OR: 0.51, 95% CI 0.39-0.86). A protective effect was detected for all the lower quintiles of DII, with the highest protective effect seen for the lowest quintile (adjusted OR 5th quintile vs 1st quintile: 3.28, 95% CI 1.30-8.26). CONCLUSIONS: These results suggest that high vegetable intake, adherence to the MD, and a low DII are related to a lower endometrial cancer risk, with several putative connected biological mechanisms that strengthen the biological plausibility of this association.

Diffusion-weighted quantitative MRI of pleural abnormalities: Intra- and interobserver variability in the apparent diffusion coefficient measurements.

PURPOSE: To assess intra- and interobserver variability in the apparent diffusion coefficient (ADC) measurements of pleural abnormalities. MATERIALS AND METHODS: Diffusion-weighted magnetic resonance imaging was performed in 34 patients to characterize pleural abnormalities, with a 1.5T unit at b values of 0/150/500/800 sec/mm2 . In two sessions held 3 months apart, on perfusion-free ADC maps, two independent readers measured the ADC of pleural abnormalities (two readings for each reader in each case) using different methods of region-of-interest (ROI) positioning. In three methods, freehand ROIs were drawn within tumor boundaries to encompass the entire lesion on one or more axial slices (whole tumor volume [WTV], three slices observer-defined [TSOD], single-slice [SS]), while in two methods one or more ROIs were placed on the more restricted areas (multiple small round ROI [MSR], one small round ROI [OSR]). Measurement variability between readings by each reader (intraobserver repeatability) and between readers in first reading (interobserver repeatability) were assessed using intraclass correlation coefficient (ICC) and coefficient of variation (CoV). Analysis of variance (ANOVA) was performed to compare ADC values between the different methods. The measurement time of each case for all methods in first reading was recorded and compared between methods and readers. RESULTS: All methods demonstrated good (MSR, OSR) and excellent (WTV, TSOD, SS) intra- and interreader agreement, with best and worst repeatability in WTV (lower ICC, 0.977; higher CoV, 3.5%) and OSR (lower ICC, 0.625; higher CoV, 22.8%), respectively. The lower 95% confidence interval of ICC resulted in fair to moderate agreement for OSR (up to 0.379) and in excellent agreement for WTV, TSV, and SS (up to 0.918). ADC values of OSR and MSR were significantly lower compared to other methods (P < 0.001). The OSR and SS required less measurement time (10 and 21/22 sec, respectively) compared to the others (P < 0.0001), while the WTV required the longest measurement time (132/134 sec) (P < 0.0001). CONCLUSION: ADC measurements of pleural abnormalities are repeatable. The SS method has excellent repeatability, similar to WTV, but requires significantly less measurement time. Thus, its use should be preferred in clinical practice. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. MAGN. RESON. IMAGING 2017;46:769-782.

Apparent diffusion coefficient measurements in diffusion-weighted magnetic resonance imaging of the anterior mediastinum: inter-observer reproducibility of five different methods of region-of-interest positioning.

OBJECTIVES: To investigate inter-reader reproducibility of five different region-of-interest (ROI) protocols for apparent diffusion coefficient (ADC) measurements in the anterior mediastinum. METHODS: In eighty-one subjects, on ADC mapping, two readers measured the ADC using five methods of ROI positioning that encompassed the entire tissue (whole tissue volume [WTV], three slices observer-defined [TSOD], single-slice [SS]) or the more restricted areas (one small round ROI [OSR]), multiple small round ROI [MSR]). Inter-observer variability was assessed with interclass correlation coefficient (ICC), coefficient of variation (CoV), and Bland-Altman analysis. Nonparametric tests were performed to compare the ADC between ROI methods. The measurement time was recorded and compared between ROI methods. RESULTS: All methods showed excellent inter-reader agreement with best and worst reproducibility in WTV and OSR, respectively (ICC, 0.937/0.874; CoV, 7.3 %/16.8 %; limits of agreement, ±0.44/±0.77 × 10-3 mm2/s). ADC values of OSR and MSR were significantly lower compared to the other methods in both readers (p < 0.001). The SS and OSR methods required less measurement time (14 ± 2 s) compared to the others (p < 0.0001), while the WTV method required the longest measurement time (90 ± 56 and 77 ± 49 s for each reader) (p < 0.0001). CONCLUSIONS: All methods demonstrate excellent inter-observer reproducibility with the best agreement in WTV, although it requires the longest measurement time. KEY POINTS: • All ROI protocols show excellent inter-observer reproducibility. • WTV measurements provide the most reproducible ADC values. • ROI size and positioning influence ADC measurements in the anterior mediastinum. • ADC values of OSR and MSR are significantly lower than other methods. • OSR and WTV methods require the shortest and longest measurement time, respectively.

Diffusion-weighted magnetic resonance imaging of thymoma: ability of the Apparent Diffusion Coefficient in predicting the World Health Organization (WHO) classification and the Masaoka-Koga staging system and its prognostic significance on disease-free survival.

OBJECTIVES: To evaluate the usefulness of diffusion-weighted magnetic resonance for distinguishing thymomas according to WHO and Masaoka-Koga classifications and in predicting disease-free survival (DFS) by using the apparent diffusion coefficient (ADC). METHODS: Forty-one patients were grouped based on WHO (low-risk vs. high-risk) and Masaoka-Koga (early vs. advanced) classifications. For prognosis, seven patients with recurrence at follow-up were grouped separately from healthy subjects. Differences on ADC levels between groups were tested using Student-t testing. Logistic regression models and areas under the ROC curve (AUROC) were estimated. RESULTS: Mean ADC values were different between groups of WHO (low-risk = 1.58 ± 0.20 × 10(-3)mm(2)/sec; high-risk = 1.21 ± 0.23 × 10(-3)mm(2)/sec; p < 0.0001) and Masaoka-Koga (early = 1.43 ± 0.26 × 10(-3)mm(2)/sec; advanced = 1.31 ± 0.31 × 10(-3)mm(2)/sec; p = 0.016) classifications. Mean ADC of type-B3 (1.05 ± 0.17 × 10(-3)mm(2)/sec) was lower than type-B2 (1.32 ± 0.20 × 10(-3)mm(2)/sec; p = 0.023). AUROC in discriminating groups was 0.864 for WHO classification (cut-point = 1.309 × 10(-3)mm(2)/sec; accuracy = 78.1 %) and 0.730 for Masaoka-Koga classification (cut-point = 1.243 × 10(-3)mm(2)/sec; accuracy = 73.2 %). Logistic regression models and two-way ANOVA were significant for WHO classification (odds ratio[OR] = 0.93, p = 0.007; p < 0.001), but not for Masaoka-Koga classification (OR = 0.98, p = 0.31; p = 0.38). ADC levels were significantly associated with DFS recurrence rate being higher for patients with ADC ≤ 1.299 × 10(-3)mm(2)/sec (p = 0.001; AUROC, 0.834; accuracy = 78.0 %). CONCLUSIONS: ADC helps to differentiate high-risk from low-risk thymomas and discriminates the more aggressive type-B3. Primary tumour ADC is a prognostic indicator of recurrence. KEY POINTS: • DW-MRI is useful in characterizing thymomas and in predicting disease-free survival. • ADC can differentiate low-risk from high-risk thymomas based on different histological composition • The cutoff-ADC-value of 1.309 × 10 (-3) mm (2) /sec is proposed as optimal cut-point for this differentiation • The ADC ability in predicting Masaoka-Koga stage is uncertain and needs further validations • ADC has prognostic value on disease-free survival and helps in stratification of risk.

Risk of second primary malignancies in women with breast cancer: Results from the European prospective investigation into cancer and nutrition (EPIC).

Women with a diagnosis of breast cancer are at increased risk of second primary cancers, and the identification of risk factors for the latter may have clinical implications. We have followed-up for 11 years 10,045 women with invasive breast cancer from a European cohort, and identified 492 second primary cancers, including 140 contralateral breast cancers. Expected and observed cases and Standardized Incidence Ratios (SIR) were estimated using Aalen-Johansen Markovian methods. Information on various risk factors was obtained from detailed questionnaires and anthropometric measurements. Cox proportional hazards regression models were used to estimate the role of risk factors. Women with breast cancer had a 30% excess risk for second malignancies (95% confidence interval-CI 18-42) after excluding contralateral breast cancers. Risk was particularly elevated for colorectal cancer (SIR, 1.71, 95% CI 1.43-2.00), lymphoma (SIR 1.80, 95% CI 1.31-2.40), melanoma (2.12; 1.63-2.70), endometrium (2.18; 1.75-2.70) and kidney cancers (2.40; 1.57-3.52). Risk of second malignancies was positively associated with age at first cancer, body mass index and smoking status, while it was inversely associated with education, post-menopausal status and a history of full-term pregnancy. We describe in a large cohort of women with breast cancer a 30% excess of second primaries. Among risk factors for breast cancer, a history of full-term pregnancy was inversely associated with the risk of second primary cancer.

[Dietary habits and social differences: the experience of EPIC-Italy]. / Abitudini alimentari e disuguaglianze sociali: l'esperienza della collaborazione EPIC-Italia.

OBJECTIVES: to investigate the impact of socioeconomic status on dietary habits in Italy. DESIGN: large Italian multicentric prospective cohort study. SETTING AND PARTICIPANTS: more than 45,000 subjects recruited between 1993 and 1998 in five Italian centres (Turin, Varese, Florence, Naples, and Ragusa). Dietary habits, educational level, and other characteristics were collected at baseline using standardised questionnaires. MAIN OUTCOME MEASURES: dietary habits collected for the EPIC study, grouped by food type and summarised by a Mediterranean dietary index. RESULTS: we observed differences in dietary habits and in lifestyle habits by tertile of educational level. Principally, we noticed a positive association between higher education and healthy dietary habits (reduction in intake of processed meat, bread and rice, sweet drinks; increase in intake of fruit and vegetables, yoghurt, fish, olive oil, and tea). CONCLUSION: a relationship between educational level and dietary habits is confirmed also in Italy, even if differences due to gender and residence area are present. This study shows an important role of dietary habits in health inequalities of the population with lower socioeconomic status.

Mediating Role of Lifestyle Behaviors in the Association between Education and Cancer: Results from the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Many studies have shown that socioeconomic position (SEP) is associated with the incidence of malignant tumors at different sites. This study aims to estimate the association between educational level (as proxy for SEP) and cancer incidence and to understand whether the observed associations might be partially explained by lifestyle behaviors. METHODS: The analyses were performed on data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, globally and by sex. We used Cox proportional hazards models together with mediation analysis to disentangle the total effect (TE) of educational level [measured through the Relative Index of Inequality (RII)] on cancer incidence into pure direct (PDE) and total indirect (TIE) effect, unexplained and explained by mediators, respectively. PDE and TIE were then combined to compute the proportions mediated (PM). RESULTS: After an average of 14 years of follow-up, 52,422 malignant tumors were ascertained. Low educated participants showed higher risk of developing stomach, lung, kidney (in women), and bladder (in men) cancers, and, conversely, lower risk of melanoma and breast cancer (in post-menopausal women), when compared with more educated participants. Mediation analyses showed that portions of the TE of RII on cancer could be explained by site-specific related lifestyle behaviors for stomach, lung, and breast (in women). CONCLUSIONS: Cancer incidence in Europe is determined at least in part by a socioeconomically stratified distribution of risk factors. IMPACT: These observational findings support policies to reduce cancer occurrence by altering mediators, such as lifestyle behaviors, particularly focusing on underprivileged strata of the population.

Reticulocyte parameters: markers of early response to oral treatment in children with severe iron-deficiency anemia.

The aim of the present study was to determine the effects of exclusive oral iron supplementation (iron sulphate 2 mg/kg/die) in asymptomatic children with severe iron-deficiency anemia [median hemoglobin (Hb) level before treatment 6.3 g/dL; range 4.5 to 7 g/dL] and to investigate the accuracy of Hb, reticulocyte hemoglobin content (CHr), and absolute reticulocyte count (ARC) as markers for monitoring early response to treatment. The increase in ARC and CHr was statistically significant at day +3. There was a significant association between suitable logarithmic functions of the percentage increase in CHr and ARC at day +3 and the fraction of required Hb increase compared with baseline to reach the mean reference value for age and sex at day +14. If these results are confirmed in a larger population, ARC and CHr could be considered affordable and widely available markers to detect early responders to oral iron therapy, and to switch unresponsive children to parenteral iron supplementation or transfusion.

Usefulness of 99mTc-Pertechnetate SPECT-CT in Thyroid Tissue Volumetry: Phantom Studies and a Clinical Case Series.

BACKGROUND: An accurate measurement of the target volume is of primary importance in theragnostics of hyperthyroidism. OBJECTIVE: Our purpose was to evaluate the accuracy of a threshold-based isocontour extraction procedure for thyroid tissue volumetry from SPECT-CT. METHODS: Cylindrical vials with a fixed volume of 99mTcO4 at different activities were inserted into a neck phantom in two different thickness settings. Images were acquired by orienting the phantom in different positions, i.e., 40 planar images and 40 SPECT-CT. The fixed values of the isocontouring threshold for SPECT and SPECT-CT were calculated by means of linear and spline regression models. Mean, Median, Standard Deviation, Standard Error, Mean Absolute Percentage Error and Root Mean-Square Error were computed. Any difference between the planar method, SPECT and SPECT-CT and the effective volume was evaluated by means of ANOVA and posthoc tests. Moreover, planar and SPECT-CT acquisitions were performed in 8 patients with hyperthyroidism, considering relevant percentage differences greater than > 20% from the CT gold standard. RESULTS: Concerning phantom studies, the planar method shows higher values of each parameter than the other two methods. SPECT-CT shows lower variability. However, no significant differences were observed between SPECT and SPECT-CT measurements. In patients, relevant differences were found in 7 out of 9 lesions with the planar method, in 6 lesions with SPECT, but in only one with SPECT-CT. CONCLUSION: Our study confirms the superiority of SPECT in volume measurement if compared with the planar method. A more accurate measurement can be obtained from SPECT-CT.

How sample paths of leaky integrate-and-fire models are influenced by the presence of a firing threshold.

Neural membrane potential data are necessarily conditional on observation being prior to a firing time. In a stochastic leaky integrate-and-fire model, this corresponds to conditioning the process on not crossing a boundary. In the literature, simulation and estimation have almost always been done using unconditioned processes. In this letter, we determine the stochastic differential equations of a diffusion process conditioned to stay below a level S up to a fixed time t(1) and of a diffusion process conditioned to cross the boundary for the first time at t(1). This allows simulation of sample paths and identification of the corresponding mean process. Differences between the mean of free and conditioned processes are illustrated, as well as the role of noise in increasing these differences.

DNA methylation, colon cancer and Mediterranean diet: results from the EPIC-Italy cohort.

The biological mechanisms through which adherence to Mediterranean Diet (MD) protects against colon cancer (CC) are poorly understood. Evidence suggests that chronic inflammation may be implicated in the pathway. Both diet and CC are related to epigenetic regulation. We performed a nested case-control study on 161 pairs from the Italian component of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, in which we looked for the methylation signals in DNA extracted from leucocytes associated with both CC and MD in 995 CpGs located in 48 inflammation genes. The DNA methylation signals detected in this analysis were validated in a subgroup of 47 case-control pairs and further replicated (where validated) in 95 new pairs by means of pyrosequencing. Among the CpG sites selected a-priori in inflammation-related genes, seven CpG sites were found to be associated with CC status and with MD, in line with its protective effect. Only two CpG sites (cg17968347-SERPINE1 and cg20674490-RUNX3) were validated using bisulphite pyrosequencing and, after replication, we found that DNA methylation of cg20674490-RUNX3 may be a potential molecular mediator explaining the protective effect of MD on CC onset. The use of a 'meet-in-the-middle' approach to identify the overlap between exposure and predictive markers of disease is innovative in studies on the relationship between diet and cancer, in which exposure assessment is difficult and the mechanisms through which the nutrients exert their protective effect is largely unknown.