Carcinoma cells that undergo an epithelial-mesenchymal transition (EMT) and display a predominantly mesenchymal phenotype (hereafter EMT tumor cells) are associated with immune exclusion and immune ...deviation in the tumor microenvironment (TME). A large body of evidence has shown that EMT tumor cells and immune cells can reciprocally influence each other, with EMT cells promoting immune exclusion and deviation and immune cells promoting, under certain circumstances, the induction of EMT in tumor cells. This cross-talk between EMT tumor cells and immune cells can occur both between EMT tumor cells and cells of either the native or adaptive immune system. In this article, we review this evidence and the functional consequences of it. We also discuss some recent evidence showing that tumor cells and cells of the immune system respond to similar stimuli, activate the expression of partially overlapping gene sets, and acquire, at least in part, identical functionalities such as migration and invasion. The possible significance of these symmetrical changes in the cross-talk between EMT tumor cells and immune cells is addressed. Eventually, we also discuss possible therapeutic opportunities that may derive from disrupting this cross-talk.
Cancer stem-like cells (CSC) represent a subpopulation of tumor cells with peculiar functionalities that distinguish them from the bulk of tumor cells, most notably their tumor-initiating potential ...and drug resistance. Given these properties, it appears logical that CSCs have become an important target for many pharma companies. Antibody-drug conjugates (ADC) have emerged over the last decade as one of the most promising new tools for the selective ablation of tumor cells. Three ADCs have already received regulatory approval and many others are in different phases of clinical development. Not surprisingly, also a considerable number of anti-CSC ADCs have been described in the literature and some of these have entered clinical development. Several of these ADCs, however, have yielded disappointing results in clinical studies. This is similar to the results obtained with other anti-CSC drug candidates, including native antibodies, that have been investigated in the clinic. In this article we review the anti-CSC ADCs that have been described in the literature and, in the following, we discuss reasons that may underlie the failures in clinical trials that have been observed. Possible reasons relate to the biology of CSCs themselves, including their heterogeneity, the lack of strictly CSC-specific markers, and the capacity to interconvert between CSCs and non-CSCs; second, inherent limitations of some classes of cytotoxins that have been used for the construction of ADCs; third, the inadequacy of animal models in predicting efficacy in humans. We conclude suggesting some possibilities to address these limitations.
Metabolic syndrome (MetS) is becoming prevalent in the pediatric population. The existing pediatric MetS definitions (e.g., the International Diabetes Federation (IDF) definition and the modified ...National Cholesterol Education Program (NCEP) definition) involve complex cut-offs, precluding fast risk assessment in clinical practice.We proposed a simplified definition for assessing MetS risk in youths aged 6-17 years, and compared its performance with two existing widely used pediatric definitions (the IDF definition, and the NCEP definition) in 10 pediatric populations from 9 countries globally (n = 19,426) using the receiver operating characteristic (ROC) curve analyses. In general, the total MetS prevalence of 6.2% based on the simplified definition was roughly halfway between that of 4.2% and 7.7% estimated from the IDF and NCEP definitions, respectively. The ROC curve analyses showed a good agreement between the simplified definition and two existing definitions: the total area under the curve (95% confidence interval) of the proposed simplified definition for identifying MetS risk achieved 0.91 (0.89-0.92) and 0.79 (0.78-0.81) when using the IDF or NCEP definition as the gold standard, respectively.The proposed simplified definition may be useful for pediatricians to quickly identify MetS risk and cardiometabolic risk factors (CMRFs) clustering in clinical practice, and allow direct comparison of pediatric MetS prevalence across different populations, facilitating consistent pediatric MetS risk monitoring and the development of evidence-based pediatric MetS prevention strategies globally.
Waist-to-height ratio (WHtR) has been proposed as a simple and effective screening tool for assessing central obesity and cardiometabolic risk in both adult and pediatric populations. However, ...evidence suggests that the use of a uniform WHtR cut-off of 0.50 may not be universally optimal for pediatric populations globally. We aimed to determine the optimal cut-offs of WHtR in children and adolescents with increased cardiometabolic risk across different countries worldwide.
We used ten population-based cross-sectional data on 24,605 children and adolescents aged 6-18 years from Brazil, China, Greece, Iran, Italy, Korea, South Africa, Spain, the UK, and the USA for establishing optimal WHtR cut-offs. We performed an external independent test (9,619 children and adolescents aged 6-18 years who came from other six countries) to validate the optimal WHtR cut-offs based on the predicting performance for at least two or three cardiometabolic risk factors.
Based on receiver operator characteristic curve analyses of various WHtR cut-offs to discriminate those with ≥ 2 cardiometabolic risk factors, the relatively optimal percentile cut-offs of WHtR in the normal weight subsample population in each country did not always coincide with a single fixed percentile, but varied from the 75
to 95
percentiles across the ten countries. However, these relatively optimal percentile values tended to cluster irrespective of sex, metabolic syndrome (MetS) criteria used, and WC measurement position. In general, using ≥ 2 cardiometabolic risk factors as the predictive outcome, the relatively optimal WHtR cut-off was around 0.50 in European and the US youths but was lower, around 0.46, in Asian, African, and South American youths. Secondary analyses that directly tested WHtR values ranging from 0.42 to 0.56 at 0.01 increments largely confirmed the results of the main analyses. In addition, the proposed cut-offs of 0.50 and 0.46 for two specific pediatric populations, respectively, showed a good performance in predicting ≥ 2 or ≥ 3 cardiometabolic risk factors in external independent test populations from six countries (Brazil, China, Germany, Italy, Korea, and the USA).
The proposed international WHtR cut-offs are easy and useful to identify central obesity and cardiometabolic risk in children and adolescents globally, thus allowing international comparison across populations.
The tumor microenvironment produces different types of stimuli capable of endowing tumor cells with an aggressive behavior that is characterized by increased motility, invasiveness and propensity to ...metastasize, gain of a tumor‐initiating phenotype, and drug resistance. The following classes of stimuli have been reported to promote such a malignant phenotype: (i) solid‐ or fluid‐induced stress; (ii) altered composition of the extracellular matrix; (iii) hypoxia and low pH; (iv) innate and adaptive immune responses; (v) antitumor drugs. The simultaneous presence of more than one of these stimuli, as likely occurs in vivo, may lead to synergistic interactions in the induction of malignant traits. In many cases, the gain of a malignant phenotype is not the result of a direct effect of the stimuli on tumor cells but, rather, a stimulus‐promoted cross‐talk between tumor cells and other cell types within the tumor microenvironment. This cross‐talk is mainly mediated by two classes of molecules: paracrine factors and adhesion receptors. Stimuli that promote a malignant phenotype can promote additional outcomes in tumor cells, including autophagy and cell death. We summarize here the available evidence about the variables that induce tumor cells to take one or the other of these roads in response to the same stimuli. At the end of this review, we address some unanswered questions in this domain and indicate future directions of research.
Obesity and exposure to cardiovascular risk factors during adolescence may be associated with the development of atherosclerosis and cardiovascular diseases later in life. The objective of the study ...was to investigate whether any excess body weight, including moderate overweight, is associated with a more severe cardiovascular risk profile and signs of early atherosclerosis in a pediatric population.
A cross-sectional study was conducted among 646 adolescents ages 11 to 13 years from several primary schools of Reggio Calabria, Italy. Body mass index, waist circumference, blood pressure, glucose, insulin, homeostatic model assessment of insulin resistance, total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, triglycerides, and C-reactive protein (CRP) were determined. All of the subjects underwent carotid ultrasonography for the measurement of intima-media thickness. Complete clinical data were available from 575 subjects.
Overweight was similarly frequent in boys and girls (31.2% vs 31.0%), whereas prevalence of obesity was higher in boys (18.4% vs 10.1%). Subjects with lower levels of HDL and higher levels of triglycerides, insulin, and CRP plasma were observed more frequently among overweight and obese subjects than nonoverweight. At multivariate analysis, HDL cholesterol, insulin, and CRP were associated (P < 0.05) with overweight and obesity in girls, whereas in boys, insulin and CRP were associated (P < 0.05) with overweight and obesity, and LDL cholesterol with obesity. The association between overweight or obesity and increased intima-media thickness, a sign of early atherosclerosis, was present in girls (P < 0.05) and was close to statistical significance in obese boys (P = 0.07).
Overweight and obese adolescents have a higher prevalence of cardiovascular risk factors and show signs of early atherosclerosis. In girls, in particular, overweight is sufficient to determine a more severe cardiovascular risk profile.
The objective of this study was to determine, in an adolescent population, the prevalence of nonalcoholic fatty liver disease (NAFLD) and the association of NAFLD and cardiovascular risk factors with ...carotid artery intima-media thickness (IMT), a marker of subclinical atherosclerosis. The authors conducted a population-based study among 642 randomly selected adolescents aged 11–13 years in Reggio Calabria, southern Italy, between November 2007 and October 2008. Prevalences of overweight and obesity were 30.5% and 13.5%, respectively. The overall prevalence of NAFLD was 12.5%, increasing to 23.0% in overweight/obese adolescents. In univariate analysis, increased IMT was positively associated with the presence of NAFLD, body mass index (BMI), waist circumference, systolic blood pressure (all P's < 0.001), diastolic blood pressure (P = 0.006), γ-glutamyl transpeptidase (P = 0.006), alanine aminotransferase (P = 0.007), and C-reactive protein (P = 0.008) and was inversely associated with high density lipoprotein cholesterol (P < 0.001). In multivariate analysis, NAFLD (P = 0.002), BMI (P = 0.004), waist circumference (P = 0.003), and systolic blood pressure (P = 0.005) retained significant associations. The authors conclude that NAFLD, BMI, waist circumference, and systolic blood pressure are independent markers of increased IMT in a random sample of adolescents.
Serum biochemical liver tests (LTs) (ALT, AST, GGT) and platelet counts are often used to screen for chronic liver disease. Population-based data on abnormal LTs in Mediterranean areas are lacking. ...The prevalence and etiology of abnormal LTs were assessed from 2002 to 2003 in a 1 in 5 systematic random sample of the general population who were 12 years of age or older in Cittanova, a southern Italian town with 10,600 inhabitants. LTs, indices of metabolism, and markers of HBV and HCV infection were assayed and alcohol intake was recorded in the selected population. In virus-free individuals with abnormal LTs, LTs were retested, and upper abdominal echography and tests for other causes of liver damage were undertaken. Among the 1,645 individuals screened, the prevalence of anti-HCV was 6.5%; the prevalence was particularly high in individuals over 50 years of age. The corresponding prevalence for HBsAg was 0.8%. The overall prevalence of individuals with abnormal LTs was 12.7% (95% CI: 11.1-14.3). The probable cause of abnormal LTs was excessive alcohol in 45.6%, HCV in 18.6%, HBV in 1%, alcohol plus HCV and/or HBV in 8.8%, and rare diseases in 2%. In 24% of individuals with abnormal LTs, the probable cause was nonalcoholic fatty liver disease (NAFLD); in this subgroup, increased body weight, hypercholesterolemia, and hyperglycemia were common, and 63.3% of them had a bright liver at echography. In conclusion, in southern Italy, a Mediterranean area where dietary habits are different from those in industrialized areas, one eighth of the general population has abnormal LTs suggestive of possible liver damage; NAFLD appears to be emerging as a potentially important etiology of this presumed liver injury.
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