RANKL/RANK/OPG system consists of three essential signaling molecules: i) the receptor activator of nuclear factor (NF)-kB-ligand (RANKL), ii) the receptor activator of NF-kB (RANK), and iii) the ...soluble decoy receptor osteoprotegerin (OPG). Although this system is critical for the regulation of osteoclast differentiation/activation and calcium release from the skeleton, different studies have elucidated its specific role in mammary gland physiology and hormone-driven epithelial proliferation during pregnancy. Of note, several data suggest that progesterone induces mammary RANKL expression in mice and humans. In turn, RANKL controls cell proliferation in breast epithelium under physiological conditions typically associated with higher serum progesterone levels, such as luteal phase of the menstrual cycle and pregnancy. Hence, RANKL/RANK system can be regarded as a major downstream mediator of progesterone-driven mammary epithelial cells proliferation, potentially contributing to breast cancer initiation and progression. Expression of RANKL, RANK, and OPG has been detected in breast cancer cell lines and in human primary breast cancers. To date, dysregulation of RANKL/RANK/OPG system at the skeletal level has been widely documented in the context of metastatic bone disease. In fact, RANKL inhibition through the RANKL-blocking human monoclonal antibody denosumab represents a well-established therapeutic option to prevent skeletal-related events in metastatic bone disease and adjuvant therapy-induced bone loss in breast cancer. On the other hand, the exact role of OPG in breast tumorigenesis is still unclear. This review focuses on molecular mechanisms linking RANKL/RANK/OPG system to mammary tumorigenesis, highlighting pre-clinical and clinical evidence for the potential efficacy of RANKL inhibition as a prevention strategy and adjuvant therapy in breast cancer settings.
Over the last few months, coronavirus disease 2019 (COVID-19) pandemic caused by the novel coronavirus SARS-CoV-2 has posed a serious threat to public health on a global scale. Given the current lack ...of an effective vaccine, several drugs have been repurposed for treatment and prophylaxis of COVID-19 in an attempt to find an effective cure.
The antimalarial drug hydroxychloroquine (HCQ) initially garnered widespread attention following the publication of preliminary results showing that this drug exerts an anti-SARS-CoV-2 activity in vitro.
To date, clinical evidence suggests lack of benefit from HCQ use for the treatment of hospitalized patients with COVID-19. In such patients, HCQ also appears to be associated with an increased risk of QT interval prolongation and potentially lethal ventricular arrhythmias. Therefore, FDA has recently revoked the Emergency Use Authorization (EUA) for emergency use of HCQ and chloroquine to treat COVID-19. Conversely, whether HCQ use may represent an effective prophylactic strategy against COVID-19 is a separate question that still remains to be answered. In addition, relevant aspects regarding the potential risks and benefits of HCQ need to be clarified, in pursuit of a rational use of this drug in the COVID-19 pandemic era.
Data mining is a promising new tool in mineral exploration. Here, we combined data-mining procedures with spatial prediction modeling for gold exploration targeting in the Buhweju area in ...southwestern Uganda. It was employed in a data-rich context of unavoidably partly redundant and correlated information that offered challenges in extracting significant relationships. Our study utilized a database of co-registered digital maps related to gold mineralization. It comprised Landsat TM, Shuttle Radar Topographic Mission (SRTM), and geophysical (radiometric and magnetic) datasets for geological and structural mapping. The locations of 15 orogenic gold deposits and 87 gold occurrences were obtained from the Geological Survey of Uganda database. These were considered direct evidence of the presence of gold mineralization. The geological and geophysical settings at the gold deposit/occurrences locations were based on geological units as host rocks, contacts, and structural elements, together with continuous field values of geophysics, radiometry, and other remotely sensed imagery. A gold exploration targeting proposition (
T
p
) was defined as: “That a point
p
within the study area contains a gold deposit given the presence of spatial evidence.” All outstanding combinations of spatial evidence were obtained using empirical likelihood ratios. With a data-mining strategy, the ratios were filtered and modeled to identify stronger spatial associations, to rank the study area according to the likelihood of future discoveries, to represent ranking quality, to estimate associated uncertainty, and to select prospective target areas. The empirical likelihood ratios facilitated a transparent strategy for generating
prediction patterns
and extracting small prospective target areas with higher likelihood of discovery and lower-ranking uncertainty. Conclusions are provided on the knowledge extraction for prospectivity with further data and the challenges of reducing the arbitrariness of decisional steps.
Type 1 diabetes (T1D) is a chronic autoimmune disease leading to immune-mediated destruction of pancreatic beta cells, resulting in the need for insulin therapy. The incidence of T1D is increasing ...worldwide, thus prompting researchers to investigate novel immunomodulatory strategies to halt autoimmunity and modify disease progression. T1D is considered as a multifactorial disease, in which genetic predisposition and environmental factors interact to promote the triggering of autoimmune responses against beta cells. Over the last decades, it has become clear that vitamin D exerts anti-inflammatory and immunomodulatory effects, apart from its well-established role in the regulation of calcium homeostasis and bone metabolism. Importantly, the global incidence of vitamin D deficiency is also dramatically increasing and epidemiologic evidence suggests an involvement of vitamin D deficiency in T1D pathogenesis. Polymorphisms in genes critical for vitamin D metabolism have also been shown to modulate the risk of T1D. Moreover, several studies have investigated the role of vitamin D (in different doses and formulations) as a potential adjuvant immunomodulatory therapy in patients with new-onset and established T1D. This review aims to present the current knowledge on the immunomodulatory effects of vitamin D and summarize the clinical interventional studies investigating its use for prevention or treatment of T1D.
Background Presenting signs and symptoms of pulmonary embolism (PE) are nonspecific, favoring a large use of second-line diagnostic tests such as multidetector CT pulmonary angiography (MCTPA), thus ...exposing patients to high-dose radiation and to potential serious complications. We investigated the diagnostic performance of multiorgan ultrasonography (lung, heart, and leg vein ultrasonography) and whether multiorgan ultrasonography combined to Wells score and D-dimer could safely reduce MCTPA tests. Methods Consecutive adult patients suspected of PE and with a Wells score > 4 or a positive D-dimer result were prospectively enrolled in three EDs. Final diagnosis was obtained with MCTPA. Multiorgan ultrasonography was performed before MCTPA and considered diagnostic for PE if one or more subpleural infarcts, right ventricular dilatation, or DVT was detected. If multiorgan ultrasonography was negative for PE, an alternative ultrasonography diagnosis was sought. Accuracies of each single-organ and multiorgan ultrasonography were calculated. Results PE was diagnosed in 110 of 357 enrolled patients (30.8%). Multiorgan ultrasonography yielded a sensitivity of 90% and a specificity of 86.2%, lung ultrasonography 60.9% and 95.9%, heart ultrasonography 32.7% and 90.9%, and vein ultrasonography 52.7% and 97.6%, respectively. Among the 132 patients (37%) with multiorgan ultrasonography negative for PE plus an alternative ultrasonographic diagnosis or plus a negative D-dimer result, no patients received PE as a final diagnosis. Conclusions Multiorgan ultrasonography is more sensitive than single-organ ultrasonography, increases the accuracy of clinical pretest probability estimation in patients with suspected PE, and may safely reduce the MCTPA burden. Trial registry ClinicalTrials.gov ; No.: NCT01635257; URL: www.clinicaltrials.gov
Abstract Objective Elevated aldosterone is associated with increased risk of atherosclerosis complications, whereas treatment with mineralocorticoid receptor (MR) antagonists decreases the rate of ...cardiovascular events. Here we test the hypothesis that aldosterone promotes early atherosclerosis by modulating intercellular adhesion molecule-1 (ICAM-1) expression and investigate the molecular mechanisms by which aldosterone regulates ICAM-1 expression. Methods and results Apolipoprotein-E (ApoE)−/− mice fed an atherogenic diet and treated with aldosterone for 4 weeks showed increased vascular expression of ICAM-1, paralleled by enhanced atherosclerotic plaque size in the aortic root. Moreover, aldosterone treatment resulted in increased plaque lipid and inflammatory cell content, consistent with an unstable plaque phenotype. ApoE/ICAM-1 double knockout (ApoE−/− /ICAM-1−/− ) littermates were protected from the aldosterone-induced increase in plaque size, lipid content and macrophage infiltration. Since aldosterone is known to regulate ICAM-1 transcription via MR in human endothelial cells, we explored MR regulation of the ICAM-1 promoter. Luciferase reporter assays performed in HUVECs using deletion constructs of the human ICAM-1 gene promoter showed that a region containing a predicted MR-responsive element (MRE) is required for MR-dependent transcriptional regulation of ICAM-1. Conclusions Pro-atherogenic effects of aldosterone are mediated by increased ICAM-1 expression, through transcriptional regulation by endothelial MR. These data enhance our understanding of the molecular mechanism by which MR activation promotes atherosclerosis complications.
This contribution exposes the relative uncertainties associated with prediction patterns of landslide susceptibility. The patterns are based on relationships between direct and indirect spatial ...evidence of landslide occurrences. In a spatial database constructed for the modeling, direct evidence is the presence of landslide trigger areas, while indirect evidence is the presence of corresponding multivariate context in the form of digital maps. Five mathematical modeling functions are applied to capture and integrate evidence, indirect and direct, for separating landslide-presence areas from the areas of landslide assumed absence. Empirical likelihood ratios are used first to represent the spatial relationships. These are then combined by the models into prediction scores, ordered, equal-area ranked, displayed, and synthesized as prediction-rate curves. A critical task is assessing how uncertainty levels vary across the different prediction patterns, i.e., the modeling results visualized as fixed, colored groups of ranks. This is obtained by a strategy of iterative cross validation that uses only part of the direct evidence to model the pattern and the rest to validate it as a predictor. The conducted experiments in a mountainous area in northern Italy point at a research challenge that can now be confronted with relative rank-based statistics and iterative cross-validation processes. The uncertainty properties of prediction patterns are mostly unknown nevertheless they are critical for interpreting and justifying prediction results.
Summary
Objectives Ageing in men is associated with a gradual decline in serum testosterone levels and a concomitant loss of muscle mass, accumulation of central adiposity, impaired mobility and ...increased risk of bone fractures. Whether androgen treatment might be beneficial in these subjects is still under debate. We have carried out a systematic review of randomized controlled trials (RCTs) evaluating the effects of testosterone (T) administration to middle‐aged and ageing men on body composition, muscle strength, bone density, markers of bone metabolism and serum lipid profile.
Data source A comprehensive search of all published randomized clinical trials was performed using the MEDLINE, Cochrane Library, EMBASE and Current Contents databases.
Review methods Guided by prespecified criteria, software‐assisted data ion and quality assessed by two independent reviewers, 29 RCTs were found to be eligible. For each investigated variable, we reported the results of pooled estimates of testosterone treatment using the random effect model of meta‐analysis. Heterogeneity, reproducibility and consistency of the findings across studies were explored using sensitivity and meta‐regression analysis.
Results Overall, 1083 subjects were evaluated, 625 randomized to T, 427 to placebo and 31 to observation (control group). Weighted mean age was 64·5 years (range 49·9–77·6) and mean serum testosterone was 10·9 nmol/l (range 7·8–19). Testosterone treatment produced: (i) a reduction of 1·6 kg (CI: 2·5–0·6) of total body fat, corresponding to −6·2% (CI: 9·2–3·3) variation of initial body fat, (ii) an increase in fat free mass of 1·6 kg (CI: 0·6–2·6), corresponding to +2·7% (CI: 1·1–4·4) increase over baseline and (iii) no change in body weight. The effects of T on muscle strength were heterogeneous, showing a tendency towards improvement only at the leg/knee extension and handgrip of the dominant arm (pooled effect size = 0·3 standard mean difference (SMD), CI: −0·0 to 0·6). Testosterone improved bone mineral density (BMD) at the lumbar spine by +3·7% (CI: 1·0–6·4%) compared to placebo, but not at the femoral neck, and produced a consistent reduction in bone resorption markers (pooled effect size = −0·6 SMD, CI: −1·0 to −0·2). Testosterone also reduced total cholesterol by 0·23 mmol/l (CI: −0·37 to −0·10), especially in men with lower baseline T concentrations, with no change in low density lipoprotein (LDL)‐cholesterol. A significant reduction of high density lipoprotein (HDL)‐cholesterol was found only in studies with higher mean T‐values at baseline (−0·085 mmol/l, CI: −0·017 to −0·003). Sensitivity and meta‐regression analysis revealed that the dose/type of T used, in particular the possibility of aromatization, explained the heterogeneity in findings observed on bone density and HDL‐cholesterol among studies.
Conclusion The present analysis provides an estimate of the average treatment effects of testosterone therapy in middle‐aged men. Our findings are sufficiently strong to justify further interventional studies focused on alternative targets of androgenic treatment carrying more stringent clinical implications, in particular the cardiovascular, metabolic and neurological systems.
The mineralocorticoid receptor (MR) controls adipocyte function, but its role in the conversion of white adipose tissue (WAT) into thermogenic fat has not been elucidated. We investigated responses ...to the MR antagonists spironolactone (spiro; 20 mg/kg/d) and drospirenone (DRSP; 6 mg/kg/d) in C57BL/6 mice fed a high‐fat (HF) diet for 90 d. DRSP and spiro curbed HF diet‐induced impairment in glucose tolerance, and prevented body weight gain and white fat expansion. Notably, either MR antagonist induced up‐regulation of brown adipocyte‐specific transcripts and markedly increased protein levels of uncoupling protein 1 (UCP1) in visceral and inguinal fat depots when compared with the HF diet group. Positron emission tomography and magnetic resonance spectroscopy confirmed acquisition of brown fat features in WAT. Interestingly, MR antagonists markedly reduced the autophagic rate both in murine preadipocytes in vitro (10‐5 M) and in WAT depots in vivo, with a concomitant increase in UCP1 protein expression. Moreover, the autophagy repressor bafilomycin A1 (10‐8 M) mimicked the effect of MR antagonists, increasing UCP1 protein expression in primary preadipocytes. Hence, we showed that adipocyte MR regulates brown remodeling of WAT through a modulation of autophagy. These results provide a rationale for the use of MR antagonists to prevent the adverse metabolic consequences of adipocyte dysfunction.—Armani, A., Cinti, F., Marzolla, V., Morgan, J., Cranston, G. A., Antelmi, A., Carpinelli, G., Canese, R., Pagotto, U., Quarta, C., Malorni, W., Matarrese, P., Marconi, M., Fabbri, A., Rosano, G., Cinti, S., Young, M. J., Caprio, M. Mineralocorticoid receptor antagonism induces browning of white adipose tissue through impairment of autophagy and prevents adipocyte dysfunction in high‐fat‐diet‐fed mice. FASEB J. 28, 3745–3757 (2014). www.fasebj.org
This contribution discusses the problem of providing measures of significance of prediction results when the predictions were generated from spatial databases for landslide hazard mapping. The ...spatial databases usually contain map information on lithologic units, land-cover units, topographic elevation and derived attributes (slope, aspect, etc.) and the distribution in space and in time of clearly identified mass movements. In prediction modelling we transform the multi-layered database into an aggregation of functional values to obtain an index of propensity of the land to failure. Assuming then that the information in the database is sufficiently representative of the typical conditions in which the mass movements originated in space and in time, the problem then, is to confirm the validity of the results of some models over other ones, or of particular experiments that seem to use more significant data. A core point of measuring the significance of a prediction is that it allows interpreting the results. Without a validation no interpretation is possible, no support of the method or of the input information can be provided. In particular with validation, the added value can be assessed of a prediction either in a fixed time interval, or in an open-ended time or within the confined space of a study area. Validation must be of guidance in data collection and field practice for landslide hazard mapping.