Netter's Introduzione all'imaging

Questo libro è rivolto agli studenti del primo e secondo anno del corso di laurea in Medicina e Chirurgia e agli studenti di altri corsi di laurea che affrontano per la prima volta lo studio dell’anatomia e della radiologia. L’imaging di solito è in stretto rapporto con l’anatomia e con le tecniche di apprendimento note come “problem-based”, e fornisce un rilevante e interessante aiuto per lo studio delle normali strutture anatomiche e delle loro funzioni. Usualmente, nei testi per il primo anno di Medicina sono presenti molte tipologie di immagini e sezioni anatomiche, accompagnate da descrizioni di base delle principali tecniche di imaging, ma spesso è difficile trovare spiegazioni alle domande che gli studenti si pongono a proposito dell’imaging. Il principale obiettivo di questo libro è di creare una risorsa più vasta, che gli studenti dei primi anni possano usare per le lezioni introduttive sull’imaging, per l’apprendimento “problem-based” e per altri contesti basati sull’uso dell’imaging

Upregulation of SOCS-1 by Nutlin-3 in acute myeloid leukemia cells but not in primary normal cells

OBJECTIVE: It has been shown that SOCS-1 plays an important role in the proper control of cytokine/growth factor responses and acts as a tumor suppressor in acute myeloid leukemias. Therefore, the objective of the present study was to evaluate the in vitro effect of treatment with Nutlin-3, a small molecule inhibitor of the MDM2/p53 interaction, on the expression of the suppressor of cytokine signaling 1 in primary acute myeloid leukemia cells and in myeloid cell lines with differential p53 status. METHOD: The expression of the suppressor of cytokine signaling 1 was quantitatively analyzed by real-time PCR in myeloid p53wild-type (OCI and MOLM) and p53null HL-60, leukemic cell lines, in patient-derived acute myeloid leukemia blasts, and in primary normal cell types, such as macrophages, endothelial cells, and bone marrow mesenchymal stem cells. The p53-dependence of the suppressor of cytokine signaling 1 upregulation that is induced by Nutlin-3 was analyzed in experiments performed using siRNA for p53, while the functional upregulation of the suppressor of cytokine signaling 1 was analyzed by assessing the levels of phosphorylated STAT-3. RESULTS: Nutlin-3 significantly upregulated the transcription of the suppressor of cytokine signaling 1 in p53wild-type OCI and MOLM but not in p53deleted p53null HL60, myeloid leukemic cell lines, as well as in primary acute myeloid leukemia blasts. Conversely, and somewhat unexpectedly, Nutlin-3 did not modulate the suppressor of cytokine signaling 1 expression in primary normal macrophages, endothelial cells, and bone marrow mesenchymal stem cells. The p53-dependent upregulation of the suppressor of cytokine signaling 1 by Nutlin-3 was associated with the downregulation of phosphorylated STAT-3, a major molecular target of the suppressor of cytokine signaling 1. CONCLUSION: Overall, our data suggest a potential role for the suppressor of cytokine signaling 1 as a therapeutic target of Nutlin-3 in p53 wild-type acute myeloid leukemias

Sex/Gender-Specific Imbalance in CVD: Could Physical Activity Help to Improve Clinical Outcome Targeting CVD Molecular Mechanisms in Women?

In the last two decades, new insights have been gained regarding sex/gender-related differences in cardiovascular disease (CVD). CVD represents the leading cause of death worldwide in both men and women, accounting for at least one-third of all deaths in women and half of deaths in women over 50 years in developing countries. Important sex-related differences in prevalence, presentation, management, and outcomes of different CVDs have been recently discovered, demonstrating sex/gender-specific pathophysiologic features in the presentation and prognosis of CVD in men and women. A large amount of evidence has highlighted the role of sex hormones in protecting women from CVDs, providing an advantage over men that is lost when women reach the menopause stage. This hormonal-dependent shift of sex-related CVD risk consequently affects the overall CVD epidemiology, particularly in light of the increasing trend of population aging. The benefits of physical activity have been recognized for a long time as a powerful preventive approach for both CVD prevention and aging-related morbidity control. Exercise training is indeed a potent physiological stimulus, which reduces primary and secondary cardiovascular events. However, the underlying mechanisms of these positive effects, including from a sex/gender perspective, still need to be fully elucidated. The aim of this work is to provide a review of the evidence linking sex/gender-related differences in CVD, including sex/gender-specific molecular mediators, to explore whether sex- and gender-tailored physical activity may be used as an effective tool to prevent CVD and improve clinical outcomes in women

Vaginal Lactoferrin Modulates PGE 2

Inflammation plays an important role in pregnancy, and cytokine and matrix metalloproteases (MMPs) imbalance has been associated with premature rupture of membranes and increased risk of preterm delivery. Previous studies have demonstrated that lactoferrin (LF), an iron-binding protein with anti-inflammatory properties, is able to decrease amniotic fluid (AF) levels of IL-6. Therefore, we aimed to evaluate the effect of vaginal LF administration on amniotic fluid PGE2 level and MMP-TIMP system in women undergoing genetic amniocentesis. One hundred and eleven women were randomly divided into controls (n = 57) or treated with LF 4 hours before amniocentesis (n = 54). Amniotic fluid PGE2, active MMP-9 and MMP-2, and TIMP-1 and TIMP-2 concentrations were determined by commercially available assays and the values were normalized by AF creatinine concentration. PGE2, active MMP-9, and its inhibitor TIMP-1 were lower in LF-treated group than in controls (p < 0.01, p < 0.005, and p < 0.001, resp.). Conversely, active MMP-2 (p < 0.0001) and MMP-2/TIMP-2 molar ratio (p < 0.001) were increased, whilst TIMP-2 was unchanged. Our data suggest that LF administration is able to modulate the inflammatory response following amniocentesis, which may counteract cytokine and prostanoid imbalance that leads to abortion. This trial is registered with Clinical Trial number NCT02695563

MDM2/X inhibitors under clinical evaluation: Perspectives for the management of hematological malignancies and pediatric cancer

The two murine double minute (MDM) family members MDM2 and MDMX are at the center of an intense clinical assessment as molecular target for the management of cancer. Indeed, the two proteins act as regulators of P53, a well-known key controller of the cell cycle regulation and cell proliferation that, when altered, plays a direct role on cancer development and progression. Several evidence demonstrated that functional aberrations of P53 in tumors are in most cases the consequence of alterations on the MDM2 and MDMX regulatory proteins, in particular in patients with hematological malignancies where TP53 shows a relatively low frequency of mutation while MDM2 and MDMX are frequently found amplified/overexpressed. The pharmacological targeting of these two P53-regulators in order to restore or increase P53 expression and activity represents therefore a strategy for cancer therapy. From the discovery of the Nutlins in 2004, several compounds have been developed and reported with the ability of targeting the P53-MDM2/X axis by inhibiting MDM2 and/or MDMX. From natural compounds up to small molecules and stapled peptides, these MDM2/X pharmacological inhibitors have been extensively studied, revealing different biological features and different rate of efficacy when tested in in vitro and in vivo experimental tumor models. The data/evidence coming from the preclinical experimentation have allowed the identification of the most promising molecules and the setting of clinical studies for their evaluation as monotherapy or in therapeutic combination with conventional chemotherapy or with innovative therapeutic protocols in different tumor settings. Preliminary results have been recently published reporting data about safety, tolerability, potential side effects, and efficacy of such therapeutic approaches. In this light, the aim of this review is to give an updated overview about the state of the art of the clinical evaluation of MDM2/X inhibitor compounds with a special attention to hematological malignancies and to the potential for the management of pediatric cancers

Clinical perspectives of TRAIL: Insights into central nervous system disorders

The TNF-related apoptosis inducing ligand TRAIL is a member of the TNF superfamily that has been firstly studied and evaluated for its anti-cancer activity, and the insights into its biology have already led to the identification of several TRAIL-based anticancer strategies with strong clinical therapeutic potentials. Nonetheless, the TRAIL system is far more complex and it can lead to a wider range of biological effects other than the ability of inducing apoptosis in cancer cells. By virtue of the different receptors and the different signalling pathways involved, TRAIL plays indeed a role in the regulation of different processes of the innate and adaptive immune system and this feature makes it an intriguing molecule under consideration in the development/progression/treatment of several immunological disorders. In this context, central nervous system represents a peculiar anatomic site where, despite its "status" of immune-privileged site, both innate and adaptive inflammatory responses occur and are involved in several pathological conditions. A number of studies have evaluated the role of TRAIL and of TRAIL-related pathways as pro-inflammatory or protective stimuli, depending on the specific pathological condition, confirming a twofold nature of this molecule. In this light, the aim of this review is to summarize the main preclinical evidences of the potential/involvement of TRAIL molecule and TRAIL pathways for the treatment of central nervous system disorders and the key suggestions coming from their assessment in preclinical models as proof of concept for future clinical studies

Recombinant TRAIL induces miorelaxating activity in rat aortas, which is abrogated by the induction of diabetes mellitus

TNF-related apoptosis inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) family of cytokines, which exist either as type II membrane or as a soluble protein. Although the best-characterized activity of TRAIL is represented by its anti-cancer activity, it has been recently shown that TRAIL serum levels are decreased in patients affected by atherosclerotic cardiovascular disease raising the possibility that circulating soluble TRAIL might also affect vascular biology. In this respect, it has been previously shown that TRAIL induces the in vitro release of nitric oxide by vascular endothelial cells. In order to explore the in vivo relevance of these in vitro findings, we have assessed the vascular reactivity in response to recombinant TRAIL in a more intact paradigm. For this purpose, rings (4mm long) from rat thoracic aorta were obtained by both control (3-month-old male non-diabetic Wistar rats receiving vehicle infusion) and rats in which diabetes mellitus was induced by injecting 40 mg/kg streptozotocin (SZT). After sacrifice of the animals, aortas were harvested, cleaned of connective tissue and vascular reactivity was analyzed in ex vivo immediately after harvest. During submaximal contraction with phenylephrine, incubation of aortic segments in the presence of increasing (up to 1000 ng/ml) concentrations of recombinant human TRAIL, resulted in significant (p<0.01) vaso-relaxation. The effect was dose-dependent and was completely abolished by pre incubation of the rat aortic rings with L-NAME, clearly indicating that the NOS pathway played a key role in mediating the myo-relaxating activity of TRAIL. In parallel, we have investigated whether the induction of diabetes mellitus might affect the relaxating activity of aortic rings in response to TRAIL. Diabetes mellitus was induced by destruction of pancreatic islet cells by treating rats with SZT (40 mg/kg). Non-fasting blood glucose concentrations of both SZT-diabetic rats (SZT, n = 10) and age-matched control non-diabetic rats treated with vehicle (n = 10) were measured at days 5 and 15, when animals were sacrificed with CO2. The loss of insulin secretion triggered stable hyperglycemia, as evaluated by blood glucose measurement: 260±46 and 295±55 in diabetic rats at days 5 and 15 after diabetic induction, respectively, versus 89±8 in control rats. Relaxation to TRAIL was completely abrogated in aortic rings obtained from SZT-induced diabetic rats. To the best of our knowledge, this is the first demonstration that soluble recombinant TRAIL promotes a dose-dependent myo-relaxation activity when added ex vivo to rat aortic rings, thus suggesting that it might play a physiological role in the control of vascular tone regulation. Importantly, such myorelaxating activity was completely abrogated in diabetic rats, as early as 15 days after diabetes mellitus induction by STZ injection. It should be emphasized that diabetic vascular dysfunction is a major clinical problem that predisposes patients to a variety of cardiovascular diseases. In fact, diabetic patients frequently suffer from macroscopic and microscopic vasculopathy and accelerated atherosclerosis. The loss of myo-relaxating activity is a key feature of endothelial dysfunction, which invariably precedes permanent vascular alterations. Taken together with previous data showing that TRAIL significantly counteracts the pro-adhesive activity of inflammatory cytokines on endothelial cells in vitro and displays anti-atherosclerotic activity when injected in vivo in ApoE−/−null mice, our present findings suggest that a therapeutic strategy aimed to restore the miorelaxating response to TRAIL may be suitable for improving the vascular function in diabetes mellitus

Oxidative stress: role of physical exercise and antioxidant nutraceuticals in adulthood and aging

Physical exercise is considered to be one of the beneficial factors of a proper lifestyle and is nowadays seen as an indispensable element for good health, able to lower the risk of disorders of the cardiovascular, endocrine and osteomuscular apparatus, immune system diseases and the onset of potential neoplasms. A moderate and programmed physical exercise has often been reported to be therapeutic both in the adulthood and in aging, since capable to promote fitness. Regular exercise alleviates the negative effects caused by free radicals and offers many health benefits, including reduced risk of all-cause mortality, sarcopenia in the skeletal muscle, chronic disease, and premature death in elderly people. However, physical performance is also known to induce oxidative stress, inflammation, and muscle fatigue. Many efforts have been carried out to identify micronutrients and natural compounds, also known as nutraceuticals, able to prevent or attenuate the exercise-induced oxidative stress and inflammation. The aim of this review is to discuss the benefits deriving from a constant physical activity and by the intake of antioxidant compounds to protect the body from oxidative stress. The attention will be focused mainly on three natural antioxidants, which are quercetin, resveratrol and curcumin. Their properties and activity will be described, as well as their benefits on physical activity and on aging, which is expected to increase through the years and can get favorable benefits from a constant exercise activity

Mesenchymal stem cells-derived vascular smooth muscle cells release abundant levels of osteoprotegerin

Although several studies have shown that the serum levels of osteoprotegerin (OPG) are significantly elevated in patients affected with atherosclerotic lesions in coronary and peripheral arteries, the cellular source and the role of OPG in the physiopathology of atherosclerosis are not completely defined. Therefore, we aimed to investigate the potential contribution of mesenchymal stem cells in the production/release of OPG. OPG was detectable by immunohistochemistry in aortic and coronary atherosclerotic plaques, within or in proximity of intimal vascular smooth muscle cells (SMC). In addition, bone marrow mesenchymal stem cell (MSC)-derived vascular SMC as well as primary aortic SMC released in the culture supernatant significantly higher levels of OPG with respect to MSC-derived endothelial cells (EC) or primary aortic EC. On the other hand, in vitro exposure to full-length human recombinant OPG significantly increased the proliferation rate of aortic SMC cultures, as monitored by bromodeoxyuridine incorporation. Taken together, these data suggest that OPG acts as an autocrine/paracrine growth factor for vascular SMC, which might contribute to the progression of atherosclerotic lesions