Antibody-drug conjugates (ADC) against cancer stem-like cells (CSC) - Is there still room for optimism?

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

Association of non-alcoholic fatty liver disease and cardiometabolic risk factors with early atherosclerosis in an adult population in Southern Italy

Aim. The prevalence of risk factors for cardiovascular and metabolic diseases was investigated in an adult population of the city of Cittanova, Southern Italy. Methods. The study was conducted among 992 randomly selected adults aged 18-75 years, between April 2009 and January 2011. Results. Prevalence rates of non-alcoholic fatty liver disease (NAFLD), overweight, obesity, and metabolic syndrome (MS) were 24.8%, 41.5%, 27.1%, and 34.4%, respectively. For the components of MS, prevalence of central obesity was 47.4%, impaired fasting glucose (IFG) 34.7%; hypertension 53.7%, low high-density lipoprotein (HDL) cholesterol 34.2%, and hypertriglyceridemia 27.2%. Conclusions. Hypertension, central obesity, IFG, low HDL cholesterol, hypertriglyceridemia, MS, and increased carotid artery intima-media thickness (IMT) were significantly associated with NAFLD after adjustment for age and sex. With additional adjustment for body mass index (BMI), IMT and MS (depending on the prevalence ratio that was investigated), the positive association between the NAFLD and increased IMT lost statistical significance, while that with body mass index (BMI) and MS remained significant

Cardiovascular risk factors, nonalcoholic fatty liver disease, and carotid artery intima-media thickness in an adolescent population in southern Italy

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), gamma-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

A century of trends in adult human height

Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5-22.7) and 16.5 cm (13.3-19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8-144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries

Metabolically healthy obesity and high carotid intima-media thickness in children and adolescents: International childhood vascular structure evaluation Consortium

OBJECTIVE It has been argued that metabolically healthy obesity (MHO) does not increase cardiovascular disease (CVD) risk. This study examines the association of MHO with carotid intima-media thickness (cIMT), a proxy of CVD risk, in children and adolescents. RESEARCH DESIGN AND METHODS Data were available for 3,497 children and adolescents aged 6–17 years from five population-based cross-sectional studies in Brazil, China, Greece, Italy, and Spain. Weight status categories (normal, overweight, and obese) were defined using BMI cutoffs from the International Obesity Task Force. Metabolic status (defined as “healthy” [no risk factors] or “unhealthy” [one or more risk factors]) was based on four CVD risk factors: elevated blood pressure, elevated triglyceride levels, reduced HDL cholesterol, and elevated fasting glucose. High cIMT was defined as cIMT ‡90th percentile for sex, age, and study population. Logistic regression model was used to examine the association of weight and metabolic status with high cIMT, with adjustment for sex, age, race/ethnicity, and study center. RESULTS In comparison with metabolically healthy normal weight, odds ratios (ORs) for high cIMT were 2.29 (95% CI 1.58–3.32) for metabolically healthy overweight and 3.91 (2.46–6.21) for MHO. ORs for high cIMT were 1.44 (1.03–2.02) for unhealthy normal weight, 3.49 (2.51–4.85) for unhealthy overweight, and 6.96 (5.05–9.61) for unhealthy obesity. CONCLUSIONS Among children and adolescents, cIMT was higher for both MHO and metabolically healthy overweight compared with metabolically healthy normal weight. Our findings reinforce the need for weight control in children and adolescents irrespective of their metabolic status. © 2018 by the American Diabetes Association

Use of Static Cutoffs of Hypertension to Determine High cIMT in Children and Adolescents: An International Collaboration Study

Background: Pediatric hypertension is typically defined as blood pressure ≥ sex-, age-, and height-specific 95th percentile (high) cutoffs. Given the number of strata, there are hundreds of cutoffs for defining elevated and high blood pressure that make it cumbersome to use in clinical practice. This study aimed to evaluate the utility of the static cutoffs for pediatric hypertension (120/80 mm Hg for children and 130/80 mm Hg for adolescents) in determining high carotid intimamedia thickness (cIMT) in children and adolescents. Methods: Data were from 6 population-based cross-sectional studies in Brazil, China, Greece, Italy, Spain, and the United Kingdom. A total of 4280 children and adolescents, aged 6 to 17 years, were included. High cIMT was defined as cIMT ≥ sex-, age- and cohort-specific 90th percentile cutoffs. Results: Compared with normal blood pressure, hypertension defined using the percentile-based cutoffs from 2017 American Academy of Pediatrics guideline, and the static cutoffs were associated with similar higher odds for high cIMT (percentile-based cutoffs: odds ratio [OR], 1.46, 95% confidence interval [CI], 1.15-1.86; static cutoffs: OR, 1.65, 95% CI, 1.25-2.17), after adjustment for sex, age, race/ethnicity, body mass index, high-density lipoprotein-cholesterol, triglyceride, and fasting blood glucose. The similar utility of 2 definitions in determining high cIMT was further confirmed by area under the receiver operating characteristic curve and net reclassification improvement methods (P for difference &gt; 0.05). Conclusion: Static cutoffs (120/80 mm Hg for children, 130/80 mm Hg for adolescents) performed similarly compared with percentile-based cutoffs in determining high cIMT, supporting the use of static cutoffs in identifying pediatric hypertension in clinical practice. © 2020 Canadian Cardiovascular Societ

The process of care in residential facilities. A national survey in Italy

Background: Although residential facilities (RFs) have largely replaced mental hospitals (MHs) in most developed countries for the long-term residential care of severely impaired patients, the process of care in RFs has not been well studied. The aim of this paper is to investigate the process of care in 265 RFs, representing 19.3% of all RFs in Italy, and to devise a classification of RFs based on process characteristics. Methods: Structured interviews were conducted with the manager and staff of each RF. Residents were evaluated using standardized rating instruments. Results: Most RFs had specific admission criteria, with one third having a waiting list that averaged about 3 months. There was no formal limitation to the length of stay in three quarters of RFs, and turnover rates were very low. Although a homelike atmosphere was found in many RFs, most facilities had restrictive rules on patients' daily lives and behaviours. RFs carried out several external activities targeted at integrating patients within the local community. Standardized assessment instruments and written treatment plans were rarely used. A cluster analysis based on the levels of restrictiveness and the standardization of the process of care classified RFs into five groups that differed with respect to daily staff coverage, size, geographical distribution and proportion of former MH residents. No significant intercluster differences were associated with the current clinical and psychosocial characteristics of residents, or with several other outcome variables. Conclusions: This study provides naturalistic evidence of the heterogeneity of the process of residential care on a large scale. Future efforts should focus on developing an empirical classification of RFs, as well as on national and international standards of care and staffing to address patients' needs