Is SARS-CoV-2-induced disease a decisive factor influencing testosterone in males? Findings from a case-control ex post facto study.

BACKGROUND: Whether the observed lower total testosterone (tT) levels in male patients with COVID-19 are caused by a direct impact of SARS-CoV-2 infection or are collateral phenomena shared by other systemic inflammatory conditions has not yet been clarified. OBJECTIVES: To investigate the independent role of COVID-19 in reducing circulating tT levels in men. MATERIALS AND METHODS: We compared demographic, clinical, and hormonal values of patients with laboratory confirmed COVID-19 admitted during the first wave of the pandemic with a cohort of consecutive male patients admitted to the intensive care unit (ICU) of the same academic center because of severe acute respiratory distress syndrome (ARDS) but without SARS-CoV-2 infection and no previous history of COVID-19. Linear regression model tested the independent impact of COVID-19 on circulating tT levels. Logistic regression model was used to test predictors of death in the entire cohort. RESULTS: Of 286 patients with COVID-19, 70 men had been admitted to the ICU ( = cases) and were compared to 79 patients equally admitted to ICU because of severe ARDS but negative for SARS-CoV-2 infection and without previous history of COVID-19 ( = controls). Controls were further grouped into noninfective (n = 49) and infective-ARDS (n = 30) patients. At baseline, controls were older (p = 0.01) and had more comorbidities (p < 0.0001). Overall, cases admitted to ICU had significantly lower circulating tT levels compared to controls (0.9 nmol/L vs. 2.1 nmol/L; vs. 1.2 nmol/L; p = 0.03). At linear regression, being negative for COVID-19 was associated with higher tT levels (Coeff: 2.13; 95% confidence interval - CI 0.71-3.56; p = 0.004) after adjusting for age, BMI, comorbidities and IL-6 levels. Only age and IL-6 levels emerged to be associated with higher risk of death regardless of COVID-19 status. CONCLUSIONS: This case-control ex post facto study showed lower tT levels in men with COVID-19 compared to those without COVID-19 despite both groups have been equally admitted to ICU for severe ARDS, thus suggesting a possible direct impact of SARS-CoV-2 infection toward circulating tT levels and a consequent more severe clinical outcome.

Whole exome data prioritization unveils the hidden weight of Mendelian causes of male infertility. A report from the first Italian cohort.

Almost 40% of infertile men cases are classified as idiopathic when tested negative to the current diagnostic routine based on the screening of karyotype, Y chromosome microdeletions and CFTR mutations in men with azoospermia or oligozoospermia. Rare monogenic forms of infertility are not routinely evaluated. In this study we aim to investigate the unknown potential genetic causes in couples with pure male idiopathic infertility by applying variant prioritization to whole exome sequencing (WES) in a cohort of 99 idiopathic Italian patients. The ad-hoc manually curated gene library prioritizes genes already known to be associated with more common and rare syndromic and non-syndromic male infertility forms. Twelve monogenic cases (12.1%) were identified in the whole cohort of patients. Of these, three patients had variants related to mild androgen insensitivity syndrome, two in genes related to hypogonadotropic hypogonadism, and six in genes related to spermatogenic failure, while one patient is mutant in PKD1. These results suggest that NGS combined with our manually curated pipeline for variant prioritization and classification can uncover a considerable number of Mendelian causes of infertility even in a small cohort of patients.

Testosterone in males with COVID-19: a 12-month cohort study.

BACKGROUND: Male patients with COVID-19 have been found with reduced serum total testosterone (tT) levels and with more severe clinical outcomes. OBJECTIVES: To assess total testosterone (tT) levels and the probability of recovering eugonadal tT levels during a minimum 12-month timespan in a cohort of men who have been followed over time after the recovery from laboratory-confirmed COVID-19. MATERIALS AND METHODS: Demographic, clinical and hormonal values were collected for the overall cohort. Hypogonadism was defined as tT ≤9.2 nmol/l. The Charlson Comorbidity Index was used to score health-significant comorbidities. Descriptive statistics was used to compare hormonal levels at baseline versus 7-month (FU1) versus 12-month (FU2) follow-up, respectively. Multivariate cox proportional hazards regression model was used to identify the potential predictors of eugonadism recovery over time among patients with hypogonadism at the time of infection. RESULTS: Of the original cohort of 286 patients, follow-up data were available for 121 (42.3%) at FU1 and 63 (22%) patients at FU2, respectively. Higher median interquartile range (IQR) tT levels were detected at FU2 (13.8 (12.3-15.3) nmol/L) versus FU1 (10.2 [9.3-10.9] nmol/L) and versus baseline (3.6 [3.02-4.02] nmol/L) (all p < 0.0001), whilst both LH and E2 levels significantly decreased over the same time frame (all p ≤ 0.01). Circulating IL-6 levels further decreased at FU2 compared to FU1 levels (19.3 vs. 72.8 pg/ml) (p = 0.02). At multivariable cox regression analyses, baseline tT level (HR 1.19; p = 0.03 [1.02-1.4]) was independently associated with the probability of tT level normalization over time, after adjusting for potential confounders. CONCLUSIONS: Circulating tT levels keep increasing over time in men after COVID-19. Still, almost 30% of men who recovered from COVID-19 had low circulating T levels suggestive for a condition of hypogonadism at a minimum 12-month follow-up.

Combined plasma levels of IL-10 and testosterone, but not soluble HLA-G5, predict the risk of death in COVID-19 patients.

BACKGROUND: The identification of biomarkers correlated with coronavirus disease 2019 (COVID-19) outcomes is a relevant need for clinical management. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterized by elevated interleukin (IL)-6, IL-10, HLA-G, and impaired testosterone production. OBJECTIVES: We aimed at defining the combined impact of sex hormones, interleukin-10, and HLA-G on COVID-19 pathophysiology and their relationship in male patients. MATERIALS AND METHODS: We measured by chemiluminescence immunoassay, electrochemiluminescent assays, and enzyme-linked immunosorbent assay circulating total testosterone, 17ß-estradiol (E2 ), IL-10, and -HLAG5 as well as SARS-CoV-2 S1/S2 Immunoglobulin G from 292 healthy controls and 111 COVID-19 patients with different disease severity at hospital admission, and in 53 COVID-19 patients at 7-month follow-up. RESULTS AND DISCUSSION: We found significantly higher levels of IL-10, HLA-G, and E2 in COVID-19 patients compared to healthy controls and an inverse correlation between IL-10 and testosterone, with IL-10, progressively increasing and testosterone progressively decreasing with disease severity. This correlation was lost at the 7-month follow-up. The risk of death in COVID-19 patients with low testosterone increased in the presence of high IL-10. A negative correlation between SARS-CoV-2 Immunoglobulin G and HLA-G or IL-10 at hospitalization was observed. At the 7-month follow-up, IL-10 and testosterone normalized, and  HLA-G decreased. CONCLUSION: Our findings indicate that combined evaluation of IL-10 and testosterone predicts the risk of death in men with COVID-19 and support the hypothesis that IL-10 fails to suppress excessive inflammation by promoting viral spreading.

Radiomic and gEnomic approaches for the enhanced DIagnosis of clear cell REnal Cancer (REDIRECt): a translational pilot methodological study.

Background: The combination of radiomic and transcriptomic approaches for patients diagnosed with small clear-cell renal cell carcinoma (ccRCC) might improve decision making. In this pilot and methodological study, we investigate whether imaging features obtained from computed tomography (CT) may correlate with gene expression patterns in ccRCC patients. Methods: Samples from 6 patients who underwent partial nephrectomy for unilateral non-metastatic ccRCC were included in this pilot cohort. Transcriptomic analysis was conducted through RNA-sequencing on tumor samples, while radiologic features were obtained from pre-operative 4-phase contrast-enhanced CT. To evaluate the heterogeneity of the transcriptome, after a 1,000 re-sampling via bootstrapping, a first Principal Component Analyses (PCA) were fitted with all transcripts and a second ones with transcripts deriving from a list of 369 genes known to be associated with ccRCC from The Cancer Genome Atlas (TCGA). Significant pathways in each Principal Components for the 50 genes with the highest loadings absolute values were assessed with pathways enrichment analysis. In addition, Pearson's correlation coefficients among radiomic features themselves and between radiomic features and transcripts expression values were computed. Results: The transcriptomes of the analysed samples showed a high grade of heterogeneity. However, we found four radiogenomic patterns, in which the correlation between radiomic features and transcripts were statistically significant. Conclusions: We showed that radiogenomic approach is feasible, however its clinical meaning should be further investigated.

Testosterone in males with COVID-19: A 7-month cohort study.

BACKGROUND: Circulating testosterone levels have been found to be reduced in men with severe acute respiratory syndrome coronavirus 2 infection, COVID-19, with lower levels being associated with more severe clinical outcomes. OBJECTIVES: We aimed to assess total testosterone levels and the prevalence of total testosterone still suggesting for hypogonadism at 7-month follow-up in a cohort of 121 men who recovered from laboratory-confirmed COVID-19. MATERIALS AND METHODS: Demographic, clinical, and hormonal values were collected for all patients. Hypogonadism was defined as total testosterone ≤9.2 nmol/L. The Charlson Comorbidity Index was used to score health-significant comorbidities. Descriptive statistics and multivariable linear and logistic regression models tested the association between clinical and laboratory variables and total testosterone levels at follow-up assessment. RESULTS: Circulating total testosterone levels increased at 7-month follow-up compared to hospital admittance (p < 0.0001), while luteinizing hormone and 17ß-estradiol levels significantly decreased (all p ≤ 0.02). Overall, total testosterone levels increased in 106 (87.6%) patients, but further decreased in 12 (9.9%) patients at follow-up, where a total testosterone level suggestive for hypogonadism was still observed in 66 (55%) patients. Baseline Charlson Comorbidity Index score (OR 0.36; p = 0.03 [0.14, 0.89]) was independently associated with total testosterone levels at 7-month follow-up, after adjusting for age, BMI, and IL-6 at hospital admittance. CONCLUSIONS: Although total testosterone levels increased over time after COVID-19, more than 50% of men who recovered from the disease still had circulating testosterone levels suggestive for a condition of hypogonadism at 7-month follow-up. In as many as 10% of cases, testosterone levels even further decreased. Of clinical relevance, the higher the burden of comorbid conditions at presentation, the lower the probability of testosterone levels recovery over time.

Severely low testosterone in males with COVID-19: A case-control study.

BACKGROUND: Circulating androgens could have a relevant pathobiological role in clinical outcomes in men with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19). OBJECTIVES: We aimed to assess: (a) circulating sex steroids levels in a cohort of 286 symptomatic men with laboratory-confirmed COVID-19 at hospital admission compared to a cohort of 281 healthy men; and (b) the association between serum testosterone levels (tT), COVID-19, and clinical outcomes. MATERIALS AND METHODS: Demographic, clinical, and hormonal values were collected for all patients. Hypogonadism was defined as tT ≤9.2 nmol/l. The Charlson Comorbidity Index (CCI) was used to score health-significant comorbidities. Severe clinical outcomes were defined as patients either transferred to intensive care unit (ICU) or death. Descriptive statistics and multivariable linear and logistic regression models tested the association between clinical and laboratory variables and tT levels. Univariable and multivariable logistic regression models tested the association between tT and severe clinical outcomes. RESULTS: Overall, a significantly lower levels of LH and tT were found in patients with COVID-19 compared to healthy controls (all p < 0.0001); conversely, healthy controls depicted lower values of circulating E2 (p < 0.001). Testosterone levels suggestive for hypogonadism were observed in 257 (89.8%) patients at hospital admission. In as many as 243 (85%) cases, hypogonadism was secondary. SARS-CoV-2 infection status was independently associated with lower tT levels (p < 0.0001) and greater risk of hypogonadism (p < 0.0001), after accounting for age, BMI, CCI, and IL-6 values. Lower tT levels were associated with higher risk of ICU admission and death outcomes (all p ≤ 0.05), after accounting for clinical and laboratory parameters. CONCLUSIONS: We unveil an independent association between SARS-CoV-2 infection status and secondary hypogonadism already at hospital admission, with lower testosterone levels predicting the most severe clinical outcomes.

Polyacrylate/polyacrylate-PEG biomaterials obtained by high internal phase emulsions (HIPEs) with tailorable drug release and effective mechanical and biological properties.

The paper focuses on the preparation of polyacrylate based biomaterials designed as patches for dermal/transdermal drug delivery using materials obtained by the high internal phase emulsion (HIPE) technique. In particular, butyl acrylate and glycidyl methacrylate were selected, respectively, as backbone and functional monomer while two different crosslinkers, bifunctional or trifunctional, were used to form the covalent network. The influence of PEG on the main properties of the materials was also investigated. The obtained materials show a characteristic and interconnected internal structure as confirmed by SEM studies. By an industrial point of view, an interesting feature of this system is that it can be shaped as needed, in any form and thickness. The physiochemically characterized materials showed a tailorable curcumin (model of hydrophobic drugs) drug release, effective mechanical properties and cell viability and resulted neither pro nor anti-angiogenic as demonstrated in vivo by the chick embryo choriallantoic membrane (CAM) assay. Based on these results, the obtained polyHIPEs could be proposed as devices for dermal/transdermal drug delivery and/or for the direct application on wounded skin.

Comparative Analysis of Porcine and Human Thoracic Aortic Stiffness.

OBJECTIVES: To compare porcine and human thoracic aortic stiffness using the available literature. METHODS: The available literature was searched for studies reporting data on porcine or human thoracic aortic mechanical behaviour. A four fibre constitutive model was used to transform the data from included studies. Thus, equi-biaxial stress stretch curves were generated to calculate circumferential and longitudinal aortic stiffness. Analysis was performed separately for the ascending and descending thoracic aorta. Data on human aortic stiffness were divided by age <60 or ≥60 years. Porcine and human aortic stiffness were compared. RESULTS: Eleven studies were included, six reported on young porcine aortas, four on human aortas of various ages, and one reported on both. In the ascending aorta, circumferential and longitudinal stiffness were 0.42±0.08 MPa and 0.37±0.06 MPa for porcine aortas (4-9 months) versus 0.55±0.15 MPa and 0.45±0.08 MPa for humans <60 years, and 1.02±0.59 MPa and 1.03±0.54 MPa for humans ≥60 years. In the descending aorta, circumferential and longitudinal stiffness were 0.46±0.03 MPa and 0.44±0.01 MPa for porcine aortas (4-10 months) versus 1.04±0.70 MPa and 1.24±0.76 MPa for humans <60 years, and 3.15±3.31 MPa and 1.17±0.31 MPa for humans ≥60 years. CONCLUSIONS: The stiffness of young porcine aortic tissue shows good correspondence with human tissue aged <60 years, especially in the ascending aorta. Young porcine aortic tissue is less stiff than human aortic tissue aged ≥60 years.

Effects of clinico-pathological risk factors on in-vitro mechanical properties of human dilated ascending aorta.

Ascending aorta aneurysms (AsAA) are associated with a degeneration of the aortic wall tissue, which leads to changes in tissue mechanical properties. Risk factors for the development of the AsAA disease are recognized in patient age and gender, valve type, hypertension, diabetes mellitus, smoking history, and a prior diagnosis of Marfan syndrome. The present study aims to assess how such clinico-pathological factors can affect the mechanical properties of human dilated ascending aorta. Specimens of AsAA are excised from 68 patients who underwent elective AsAA surgical repair and stretched until rupture during the execution of uniaxial tensile tests. Experimental stress-stretch curves are used to determine tissue mechanical properties (stress and stretch at failure point and at transition point, low and high elastic modulus). Data are divided into groups according to region (anterior vs posterior), direction (circumferential vs longitudinal), and then according to age (young vs old), gender (male vs female), valve type (tricuspid aortic valve, TAV, vs bicuspid aortic valve, BAV), and presence of hypertension, diabetes mellitus, and/or Marfan syndrome (yes/no). Moreover, data are grouped according to the critical value of body mass index (BMI), maximum AsAA diameter, and aortic stiffness index (ASI), respectively. Finally, a non-parametric statistical analysis is performed to find possible significant differences and correlations between mechanical properties and clinico-pathological data. Our results confirm the anisotropy and heterogeneity of the AsAA tissue and highlight that ageing and hypertension make the AsAA tissue weaker and less extensible, whereas the valve type affects the tissue strength with higher values in BAV than in TAV patients. No effects of gender, critical BMI, critical maximum AsAA diameter, critical ASI, smoking status, and presence of diabetes mellitus, and Marfan syndrome are evidenced.

Design of a Bioabsorbable Multilayered Patch for Esophagus Tissue Engineering.

A gold standard for esophagus reconstruction is not still available. The present work aims to design a polymer patch combining synthetic polylactide-co-polycaprolacton and chitosan biopolymers, tailoring patch properties to esophageal tissue characteristics by a temperature-induced precipitation method, to get multilayered patches (1L, 2L, and 3L). Characterization shows stable multilayered patches (1L and 2L) by selection of copolymer type, and their M w . In vitro investigation of the functional patch properties in simulated physiologic and pathologic conditions demonstrates that the chitosan layer (patch 3L) decreases patch stability and cell adhesion, while improves cell proliferation. Patches 2L and 3L comply with physiological esophageal pressure (3-5 kPa) and elongation (20%).

A Regression Method Based on Noninvasive Clinical Data to Predict the Mechanical Behavior of Ascending Aorta Aneurysmal Tissue.

Goal: Ascending aorta aneurysms represent a severe life-threatening condition associated with asymptomatic risk of rupture. Prediction of aneurysm evolution and rupture is one of the hottest investigation topics in cardiovascular science, and the decision on when and whether to surgically operate is still an open question. We propose an approach for estimating the patient-specific ultimate mechanical properties and stress-stretch characteristics based on noninvasive data. Methods: As for the characteristics, we consider a nonlinear constitutive model of the aortic wall and assume patient-specific model coefficients. Through a regression model, we build the response surfaces of ultimate stress, ultimate stretch, and model coefficients in function of patient data that are commonly available in the clinical practice. We apply the approach to a dataset of 59 patients. Results: The approach is fair and accurate response surfaces can be obtained for both ultimate properties and model coefficients. Conclusion: Prediction errors are acceptable, even though a larger patient dataset will be required to stabilize the surfaces, making it possible to apply the approach in the clinical practice. Significance: A fair prediction of the patient aortic mechanical behavior, based on clinical information noninvasively acquired, would improve the decision process and lead to more effective treatments.Goal: Ascending aorta aneurysms represent a severe life-threatening condition associated with asymptomatic risk of rupture. Prediction of aneurysm evolution and rupture is one of the hottest investigation topics in cardiovascular science, and the decision on when and whether to surgically operate is still an open question. We propose an approach for estimating the patient-specific ultimate mechanical properties and stress-stretch characteristics based on noninvasive data. Methods: As for the characteristics, we consider a nonlinear constitutive model of the aortic wall and assume patient-specific model coefficients. Through a regression model, we build the response surfaces of ultimate stress, ultimate stretch, and model coefficients in function of patient data that are commonly available in the clinical practice. We apply the approach to a dataset of 59 patients. Results: The approach is fair and accurate response surfaces can be obtained for both ultimate properties and model coefficients. Conclusion: Prediction errors are acceptable, even though a larger patient dataset will be required to stabilize the surfaces, making it possible to apply the approach in the clinical practice. Significance: A fair prediction of the patient aortic mechanical behavior, based on clinical information noninvasively acquired, would improve the decision process and lead to more effective treatments.

Impact of thoracic endovascular aortic repair on radial strain in an ex vivo porcine model.

Objectives: To quantify the impact of thoracic endovascular aortic repair (TEVAR) on radial aortic strain with the aim of elucidating stent-graft-induced stiffening and complications. Methods: Twenty fresh thoracic porcine aortas were connected to a mock circulatory loop driven by a centrifugal flow pump. A high-definition camera captured diameters at five different pressure levels (100, 120, 140, 160, and 180 mmHg), before and after TEVAR. Three oversizing groups were created: 0-9% ( n = 7), 10-19% ( n = 6), and 20-29% ( n = 6). Radial strain (or deformation) derived from diameter amplitude divided by baseline diameter at 100 mmHg. Uniaxial tensile testing evaluated Young's moduli of the specimens. Results: Radial strain was reduced after TEVAR within the stented segment by 49.4 ± 24.0% ( P < 0.001). As result, a strain mismatch was observed between the stented segment and the proximal non-stented segment (7.0 ± 2.5% vs 11.8 ± 3.9%, P < 0.001), whereas the distal non-stented segment was unaffected ( P = 0.99). Stent-graft oversizing did not significantly affect the amount of strain reduction ( P = 0.30). Tensile testing showed that the thoracic aortas tended to be more elastic proximally than distally ( P = 0.11). Conclusions: TEVAR stiffened the thoracic aorta by 2-fold. Such segmental stiffening may diminish the Windkessel function considerably and might be associated with TEVAR-related complications, including stent-graft-induced dissection and aneurysmal dilatation. These data may have implications for future stent-graft design, in particular for TEVAR of the highly compliant proximal thoracic aorta.

An experimental investigation of the impact of thoracic endovascular aortic repair on longitudinal strain.

OBJECTIVES: To investigate the impact of thoracic endovascular aortic repair (TEVAR) on longitudinal strain and assess aortic tensile properties in order to better understand complications associated with TEVAR. METHODS: Twenty fresh thoracic porcine aortas were harvested and connected to a mock circulatory loop driven by a centrifugal flow pump at body temperature. Length measurements were conducted before and after TEVAR through aortic marking, high-definition imaging and custom-developed software under physiological pressure conditions (i.e. between 100 and 180 mmHg with 20 mmHg increments). Longitudinal strain was derived from length amplitude divided by the baseline length at 100 mmHg. Three groups of stent-graft oversizing were created (0-9, 10-19 and 20-29%). Finally, elastic properties of the aortic samples were assessed in both longitudinal and circumferential directions through uniaxial tensile testing. Longitudinal strain was compared before and after TEVAR, and stress-to-rupture was compared among specimens and locations. RESULTS: TEVAR induced a longitudinal strain decrease from 11.9 to 5.6% (P< 0.001) in the stented segments and a longitudinal strain mismatch between stented (5.6%) and non-stented segments (9.1%, P< 0.001). Stent-graft oversizing did not affect the magnitude of strain reduction (P= 0.77). Tensile testing showed that peak stress-to-rupture was lower for longitudinal (1.4 ± 0.4 MPa) than for circumferential fragments (2.3 ± 0.4 MPa, P< 0.001). In addition, longitudinal fragments were more prone to rupture proximally than distally (P= 0.01). CONCLUSIONS: This experimental study showed that TEVAR acutely stiffens the aorta in the longitudinal direction and thereby induces a strain mismatch, while tensile testing confirmed that longitudinal aortic fragments are most prone to rupture, particularly close to the arch. Such an acute strain mismatch of potentially vulnerable tissue might play a role in TEVAR-related complications, including retrograde dissection and aneurysm formation. The finding that TEVAR stiffens the aorta longitudinally may also shed light on systemic complications following TEVAR, such as hypertension and cardiac remodelling. These observations may imply the need for further improvement of stent-graft designs.

Human dilated ascending aorta: Mechanical characterization via uniaxial tensile tests.

Aneurysms of the ascending aorta (AsAA), i.e., a progressive and localized dilatation of the first part of the aorta, represent a severe life-threatening condition, often occurring with no symptom. AsAA formation is associated with a degeneration of the aortic wall tissue, which leads to changes in the tissue mechanical properties, and in particular to increased wall stress and/or decreased wall ultimate strength. Nowadays, the decision to surgically operate is usually based on the AsAA diameter, although such a criterion is not always predictive. The present study focuses on the mechanical characterization of the AsAA tissues. Specimens were cut from portions of dilated ascending aorta excised from 46 patients through open-heart surgery. Peak strain, peak stress, and maximum elastic modulus (i.e., tissue stiffness) were measured from uniaxial stress-strain curves. Such (ultimate) mechanical properties were collected for different regions of the aortic wall (anterior and posterior) as well as for different specimen orientations (circumferential and longitudinal). Relationships of ultimate mechanical properties with patient age and sex were also investigated. The obtained results highlighted a significant anisotropy of the AsAA tissue (as also observed for healthy aortic tissues), with higher value of strength and stiffness in the circumferential than in the longitudinal direction. Higher strength and stiffness were also found in the posterior region with respect to the anterior one for the circumferential orientation, whereas an opposite result was found for the longitudinal orientation. A decreasing trend of ultimate mechanical properties with aging was also highlighted. Finally, a significant difference in the strength between male and female was observed only in the circumferential direction.

A clinically applicable stochastic approach for noninvasive estimation of aortic stiffness using computed tomography data.

The degeneration of the vascular wall tissue induces a change of the arterial stiffness, i.e., the capability of the vessel to distend under the pulsatile hemodynamic load. In the literature, the aortic stiffness is usually computed following a simple deterministic approach, in which only the maximum and the minimum values of arterial diameter and blood pressure over the cardiac cycle are considered. In this paper, we propose a stochastic approach to assess the stiffness, and its spatial variation, of a given aortic region exploiting patient-specific geometrical data derived from computed tomography angiography (CTA). In particular, the arterial stiffness is computed linking the aortic kinematic information derived from CTA with pressure waveforms, generated using a lumped parameter model of the arterial circulation. The proposed method is able to include the uncertainty of the input variables as well as to use the entire diameter and blood pressure waveforms over the cardiac cycle rather than only their maximum and minimum values. Although the efficiency and accuracy of the proposed method are tested on a single patient-specific case, the proposed approach is powerful and already possesses the ability to evaluate regional changes of stiffness in human aorta using noninvasive data. The final objective of our paper is to support the adoption of techniques such as CTA as a standard tool for diagnosis and treatment planning of aortic diseases.

CDC25A protein stability represents a previously unrecognized target of HER2 signaling in human breast cancer: implication for a potential clinical relevance in trastuzumab treatment.

The CDC25A-CDK2 pathway has been proposed as critical for the oncogenic action of human epidermal growth factor receptor 2 (HER2) in mammary epithelial cells. In particular, transgenic expression of CDC25A cooperates with HER2 in promoting mammary tumors, whereas CDC25A hemizygous loss attenuates the HER2-induced tumorigenesis penetrance. On the basis of this evidence of a synergism between HER2 and the cell cycle regulator CDC25A in a mouse model of mammary tumorigenesis, we investigated the role of CDC25A in human HER2-positive breast cancer and its possible implications in therapeutic response. HER2 status and CDC25A expression were assessed in 313 breast cancer patients and we found statistically significant correlation between HER2 and CDC25A (P = .007). Moreover, an HER2-positive breast cancer subgroup with high levels of CDC25A and very aggressive phenotype was identified (P = .005). Importantly, our in vitro studies on breast cancer cell lines showed that the HER2 inhibitor efficacy on cell growth and viability relied also on CDC25A expression and that such inhibition induces CDC25A down-regulation through phosphatidylinositol 3-kinase/protein kinase B pathway and DNA damage response activation. In line with this observation, we found a statistical significant association between CDC25A overexpression and trastuzumab-combined therapy response rate in two different HER2-positive cohorts of trastuzumab-treated patients in either metastatic or neoadjuvant setting (P = .018 for the metastatic cohort and P = .021 for the neoadjuvant cohort). Our findings highlight a link between HER2 and CDC25A that positively modulates HER2-targeted therapy response, suggesting that, in HER2-positive breast cancer patients, CDC25A overexpression affects trastuzumab sensitivity.

Cross-sectional exploration of maternal reports of food neophobia and pickiness in preschooler-mother dyads.

OBJECTIVE: To investigate cross-sectional associations of food neophobia and pickiness in preschoolers and in their mothers with regard also to food consumption, proposal of new foods, feeding, and weaning modes. DESIGN: Matched child and maternal data collected by means of self-report questionnaires administered to mothers. SETTING: Kindergartens of the City of Rome Municipality, Italy. SUBJECTS: One hundred twenty-seven mother-child pairs. Children were aged from 2 to 6 years. All participants were normal weight or obese. MEASURES OF OUTCOME: Mothers' and children's food neophobia and pickiness. RESULTS: Pickiness and neophobia were related within both children's (r(o) = 0.528, p = 0.001) and mothers' (r(o) = 0.186, p = 0.037) samples. Mothers' and children's neophobia and pickiness were significantly although modestly associated (neophobia r(o) = 0.223, p = 0.012; pickiness r(o) = 0.311, p = 0.001). Overweight and obese children were significantly more neophobic (18.8 ± 6.4 vs 15.7 ± 7.6; p = 0.03) and picky (6.87 ± 2.2 vs 5.72 ± 2.7; p = 0.03) than normal-weight children. CONCLUSIONS: Preschoolers' food neophobia and pickiness were correlated. Mothers and children displayed similarities in food neophobia, pickiness, and dietary habits. Genetics and environmental cues jointly contribute to shape preschoolers' attitudes toward familiar and unfamiliar foods. Hence, future longitudinal studies of larger samples are necessary to better define the role of genetics, parental feeding practices, and environmental characteristics in the development of food neophobia and pickiness.

Association of the OCTN1/1672T variant with increased risk for colorectal cancer in young individuals and ulcerative colitis patients.

BACKGROUND: Ulcerative colitis (UC) is associated with colorectal cancer. Chronic inflammation may also play a role in the pathogenesis of sporadic colorectal cancer (SCC), particularly in younger patients (<55 years). We evaluated whether single nucleotide polymorphisms of the OCTN1 and OCTN2 genes are associated with UC, SCC, and with UC cases with cancer progression (UCCP). METHODS: We evaluated the OCTN1 and OCTN2 polymorphisms in 200 patients with UC, 59 patients with UCCP, 200 patients with SCC, and 200 controls (HC). IL-8 expression was also assessed by real-time polymerase chain reaction (PCR). Additionally, we transfected human colon carcinoma Caco2 cells, homozygous for OCTN1/1672T variant, with the OCTN1/1672C allele and NF-κB activity was evaluated by luciferase based reporter assay and IL-8 mRNA expression by real-time PCR. RESULTS: OCTN2 polymorphisms did not present a significant association with any group of patients compared to normal controls. Conversely, homozygosity for the OCTN1/1672T variant was significantly associated with UC (P = 0.047 vs. HC), with UCCP (UCCP vs. HC, P < 0.001), and with SCC developing in early age (<55 years) (P = 0.021 vs. HC). Importantly, IL-8 mRNA expression was higher in UC and UCCP patients homozygous for the OCTN1 1672T variant compared to the other genotypes. Moreover, in Caco2 cells transfection of the OCTN1/1672C variant reduced the activity of the proinflammatory factor NF-κB. CONCLUSION: Our data demonstrate that OCTN1 could have a role in modulating the severity of chronic inflammation associated with SCC in early age and in UC patients, and that its polymorphisms may help to predict malignant progression of IBD.