Mouse Models of Follicular and Papillary Thyroid Cancer Progression

A significant number of well-differentiated thyroid cancers progress or recur, becoming resistant to current therapeutic options. Mouse models recapitulating the genetic and histological features of advanced thyroid cancer have been an invaluable tool to dissect the mechanisms involved in the progression from indolent, well differentiated tumors to aggressive, poorly differentiated carcinomas, and to identify novel therapeutic targets. In this review, we focus on the lessons learned from models of epithelial cell-derived thyroid cancer showing progression from hyperplastic lesions to locally invasive and metastatic carcinomas

Gene Expression Analysis of an EGFR Indirectly Related Pathway Identified PTEN and MMP9 as Reliable Diagnostic Markers for Human Glial Tumor Specimens

In this study the mRNA levels of five EGFR indirectly related genes, EGFR, HB-EGF, ADAM17, PTEN, and MMP9, have been assessed by Real-time PCR in a panel of 37 glioblastoma multiforme specimens and in 5 normal brain samples; as a result, in glioblastoma, ADAM17 and PTEN expression was significantly lower than in normal brain samples, and, in particular, a statistically significant inverse correlation was found between PTEN and MMP9 mRNA levels. To verify if this correlation was conserved in gliomas, PTEN and MMP9 expression was further investigated in an additional panel of 16 anaplastic astrocytoma specimens and, in parallel, in different human normal and astrocytic tumor cell lines. In anaplastic astrocytomas PTEN expression was significantly higher than in glioblastoma multiforme, but no significant correlation was found between PTEN and MMP9 expression. PTEN and MMP9 mRNA levels were also employed to identify subgroups of specimens within the different glioma malignancy grades and to define a gene expression-based diagnostic classification scheme. In conclusion, this gene expression survey highlighted that the combined measurement of PTEN and MMP9 transcripts might represent a novel reliable tool for the differential diagnosis of high-grade gliomas, and it also suggested a functional link involving these genes in glial tumors

The impact of adding sugars to milk and fruit on adiposity and diet quality in children: A cross-sectional and longitudinal analysis of the identification and prevention of dietary-and lifestyle-induced health effects in children and infants (IDEFICS) study

Sugar, particularly as free sugars or sugar-sweetened beverages, significantly contributes to total energy intake, and, possibly, to increased body weight. Excessive consumption may be considered as a proxy of poor diet quality. However, no previous studies evaluated the association between the habit of adding sugars to “healthy” foods, such as plain milk and fresh fruit, and indicators of adiposity and/or dietary quality in children. To answer to these research questions, we Panalysed the European cohort of children participating in the IDEFICS study. Anthropometric variables, frequency of consumption of sugars added to milk and fruit (SAMF), and scores of adherence to healthy dietary pattern (HDAS) were assessed at baseline in 9829 children stratified according to age and sex. From this cohort, 6929 children were investigated again after two years follow-up. At baseline, a direct association between SAMF categories and adiposity indexes was observed only in children aged 6–<10 years, while the lower frequency of SAMF consumption was significantly associated with a higher HDAS. At the two year follow-up, children with higher baseline SAMF consumption showed significantly higher increases in all the anthropometric variables measured, with the exception of girls 6–<10 years old. The inverse association between SAMF categories and HDAS was still present at the two years follow-up in all age and sex groups. Our results suggest that the habit to adding sugars to foods that are commonly perceived as healthy may impact the adherence to healthy dietary guidelines and increase in adiposity risk as well

Thyrocyte-specific inactivation of p53 and Pten results in anaplastic thyroid carcinomas faithfully recapitulating human tumors

Anaplastic thyroid carcinoma (ATC) is the most aggressive form of thyroid cancer, and often derives from pre-existing well-differentiated tumors. Despite a relatively low prevalence, it accounts for a disproportionate number of thyroid cancer-related deaths, due to its resistance to any therapeutic approach. Here we describe the first mouse model of ATC, obtained by combining in the mouse thyroid follicular cells two molecular hallmarks of human ATC: activation of PI3K (via Pten deletion) and inactivation of p53. By 9 months of age, over 75% of the compound mutant mice develop aggressive, undifferentiated thyroid tumors that evolve from pre-existing follicular hyperplasia and carcinoma. These tumors display all the features of their human counterpart, including pleomorphism, epithelial-mesenchymal transition, aneuploidy, local invasion, and distant metastases. Expression profiling of the murine ATCs reveals a significant overlap with genes found deregulated in human ATC, including genes involved in mitosis control. Furthermore, similar to the human tumors, [Pten, p53]thyr−/− tumors and cells are highly glycolytic and remarkably sensitive to glycolysis inhibitors, which synergize with standard chemotherapy. Taken together, our results show that combined PI3K activation and p53 loss faithfully reproduce the development of thyroid anaplastic carcinomas, and provide a compelling rationale for targeting glycolysis to increase chemotherapy response in ATC patients

Cortical dynamics in visual areas induced by the first use of multifocal contact lenses in presbyopes

A common non-spectacle strategy to correct presbyopia is to provide simultaneous images with multifocal optical designs. Understanding the neuroadaptation mechanisms behind multifocal devices usage would have important clinical implications, such as predicting whether patients will be able to tolerate multifocal optics. The aim of this study was to evaluate the brain correlates during the initial wear of multifocal contact lenses (CLs) using high-density visual evoked potential (VEP) measures. Fifteen presbyopes (mean age 51.8 ± 2.6 years) who had previously not used multifocal CLs were enrolled. VEP measures were achieved while participants looked at arrays of 0.5 logMAR Sloan letters in three different optical conditions arranged with CLs: monofocal condition with the optical power appropriate for the distance viewing; multifocal correction with medium addition; and multifocal correction with low addition. An ANOVA for repeated measures showed that the amplitude of the C1 and N1 components significantly dropped with both multifocal low and medium addition CL conditions compared to monofocal CLs. The P1 and P2 components showed opposite behavior with an increase in amplitudes for multifocal compared to monofocal conditions. VEP data indicated that multifocal presbyopia corrections produce a loss of feedforward activity in the primary visual cortex that is compensated by extra feedback activity in extrastriate areas only, in both early and late visual processing

Umbilical cord mesenchymal stem cells modulate dextran sulphate sodium induced acute colitis in immunodeficient mice.

Inflammatory bowel diseases (IBD) are complex multi-factorial diseases with increasing incidence worldwide but their treatment is far from satisfactory. Unconventional strategies have consequently been investigated, proposing the use of stem cells as an effective alternative approach to IBD. In the present study we examined the protective potential of exogenously administered human umbilical cord derived mesenchymal stem cells (UCMSCs) against Dextran Sulphate Sodium (DSS) induced acute colitis in immunodeficient NOD.CB17-Prkdc scid/J mice with particular attention to endoplasmic reticulum (ER) stress. METHODS: UCMSCs were injected in NOD.CB17-Prkdc scid/J via the tail vein at day 1 and 4 after DSS administration. To verify attenuation of DSS induced damage by UCMSCs, Disease Activity Index (DAI) and body weight changes was monitored daily. Moreover, colon length, histological changes, myeloperoxidase and catalase activities, metalloproteinase (MMP) 2 and 9 expression and endoplasmic reticulum (ER) stress related proteins were evaluated on day 7. RESULTS: UCMSCs administration to immunodeficient NOD.CB17-Prkdc scid/J mice after DSS damage significantly reduced DAI (1.45\u2009\ub1\u20090.16 vs 2.08\u2009\ub1\u20090.18, p\u20093-fold), which were significantly reduced in mice receiving UCMSCs. Moreover, positive modulation in ER stress related proteins was observed after UCMSC administration. CONCLUSIONS: Our results demonstrated that UCMSCs are able to prevent DSS-induced colitis in immunodeficient mice. Using these mice we demonstrated that our UCMSCs have a direct preventive effect other than the T-cell immunomodulatory properties which are already known. Moreover we demonstrated a key function of MMPs and ER stress in the establishment of colitis suggesting them to be potential therapeutic targets in IBD treatment

Branes in AdS and pp-wave spacetimes

We find half supersymmetric AdS-embeddings in AdS_5 x S^5 corresponding to all quarter BPS orthogonal intersections of D3-branes with Dp-branes. A particular case is the Karch-Randall embedding AdS_4 x S^2. We explicitly prove that these embeddings are supersymmetric by showing that the kappa symmetry projections are compatible with half of the target space Killing spinors and argue that all these cases lead to AdS/dCFT dualities involving a CFT with a defect. We also find an asymptotically AdS_4 x S^2 embedding that corresponds to a holographic RG-flow on the defect. We then consider the pp-wave limit of the supersymmetric AdS-embeddings and show how it leads to half supersymmetric D-brane embeddings in the pp-wave background. We systematically analyze D-brane embeddings in the pp-wave background along with their supersymmetry. We construct all supersymmetric D-branes wrapped along the light-cone using operators in the dual gauge theory: the open string states are constructed using defect fields. We also find supersymmetric D1 (monopoles) and D3 (giant gravitons) branes that wrap only one of the light-cone directions. These correspond to non-perturbative states in the dual gauge theory.Comment: 57 pages, 1 figure; corrections and addition

The rapid spread of SARS-COV-2 Omicron variant in Italy reflected early through wastewater surveillance

The SARS-CoV-2 Omicron variant emerged in South Africa in November 2021, and has later been identified worldwide, raising serious concerns. A real-time RT-PCR assay was designed for the rapid screening of the Omicron variant, targeting characteristic mutations of the spike gene. The assay was used to test 737 sewage samples collected throughout Italy (19/21 Regions) between 11 November and 25 December 2021, with the aim of assessing the spread of the Omicron variant in the country. Positive samples were also tested with a real-time RT-PCR developed by the European Commission, Joint Research Centre (JRC), and through nested RT-PCR followed by Sanger sequencing. Overall, 115 samples tested positive for Omicron SARS-CoV-2 variant. The first occurrence was detected on 7 December, in Veneto, North Italy. Later on, the variant spread extremely fast in three weeks, with prevalence of positive wastewater samples rising from 1.0% (1/104 samples) in the week 5–11 December, to 17.5% (25/143 samples) in the week 12–18, to 65.9% (89/135 samples) in the week 19–25, in line with the increase in cases of infection with the Omicron variant observed during December in Italy. Similarly, the number of Regions/Autonomous Provinces in which the variant was detected increased fromone in the first week, to 11 in the second, and to 17 in the last one. The presence of the Omicron variant was confirmed by the JRC real-time RT-PCR in 79.1% (91/115) of the positive samples, and by Sanger sequencing in 66% (64/97) of PCR amplicons

Rising rural body-mass index is the main driver of the global obesity epidemic in adults

Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities(.)(1,2) This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity(3-6). Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017-and more than 80% in some low- and middle-income regions-was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing-and in some countries reversal-of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.Peer reviewe

Height and body-mass index trajectories of school-aged children and adolescents from 1985 to 2019 in 200 countries and territories: a pooled analysis of 2181 population-based studies with 65 million participants

Summary Background Comparable global data on health and nutrition of school-aged children and adolescents are scarce. We aimed to estimate age trajectories and time trends in mean height and mean body-mass index (BMI), which measures weight gain beyond what is expected from height gain, for school-aged children and adolescents. Methods For this pooled analysis, we used a database of cardiometabolic risk factors collated by the Non-Communicable Disease Risk Factor Collaboration. We applied a Bayesian hierarchical model to estimate trends from 1985 to 2019 in mean height and mean BMI in 1-year age groups for ages 5–19 years. The model allowed for non-linear changes over time in mean height and mean BMI and for non-linear changes with age of children and adolescents, including periods of rapid growth during adolescence. Findings We pooled data from 2181 population-based studies, with measurements of height and weight in 65 million participants in 200 countries and territories. In 2019, we estimated a difference of 20 cm or higher in mean height of 19-year-old adolescents between countries with the tallest populations (the Netherlands, Montenegro, Estonia, and Bosnia and Herzegovina for boys; and the Netherlands, Montenegro, Denmark, and Iceland for girls) and those with the shortest populations (Timor-Leste, Laos, Solomon Islands, and Papua New Guinea for boys; and Guatemala, Bangladesh, Nepal, and Timor-Leste for girls). In the same year, the difference between the highest mean BMI (in Pacific island countries, Kuwait, Bahrain, The Bahamas, Chile, the USA, and New Zealand for both boys and girls and in South Africa for girls) and lowest mean BMI (in India, Bangladesh, Timor-Leste, Ethiopia, and Chad for boys and girls; and in Japan and Romania for girls) was approximately 9–10 kg/m2. In some countries, children aged 5 years started with healthier height or BMI than the global median and, in some cases, as healthy as the best performing countries, but they became progressively less healthy compared with their comparators as they grew older by not growing as tall (eg, boys in Austria and Barbados, and girls in Belgium and Puerto Rico) or gaining too much weight for their height (eg, girls and boys in Kuwait, Bahrain, Fiji, Jamaica, and Mexico; and girls in South Africa and New Zealand). In other countries, growing children overtook the height of their comparators (eg, Latvia, Czech Republic, Morocco, and Iran) or curbed their weight gain (eg, Italy, France, and Croatia) in late childhood and adolescence. When changes in both height and BMI were considered, girls in South Korea, Vietnam, Saudi Arabia, Turkey, and some central Asian countries (eg, Armenia and Azerbaijan), and boys in central and western Europe (eg, Portugal, Denmark, Poland, and Montenegro) had the healthiest changes in anthropometric status over the past 3·5 decades because, compared with children and adolescents in other countries, they had a much larger gain in height than they did in BMI. The unhealthiest changes—gaining too little height, too much weight for their height compared with children in other countries, or both—occurred in many countries in sub-Saharan Africa, New Zealand, and the USA for boys and girls; in Malaysia and some Pacific island nations for boys; and in Mexico for girls. Interpretation The height and BMI trajectories over age and time of school-aged children and adolescents are highly variable across countries, which indicates heterogeneous nutritional quality and lifelong health advantages and risks