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Abstract: Sonic hedgehog and Noggin are morphogenetic factors involved in neural induction and ventralization of the neural tube, but recent findings suggest that they could participate in regeneration and functional recovery after injury. Here, in order to verify if these mechanisms could occur in the spinal cord and involve synaptic plasticity, we measured the expression levels of Sonic hedgehog, Noggin, Choline Acetyltransferase, Synapsin-I and Glutamate receptor subunits (GluR1, GluR2, GluR4), in a motoneuron-depleted mouse spinal cord lesion model obtained by intramuscular injection of Cholera toxin-B saporin. The lesion caused differential expression changes of the analyzed proteins. Moreover, motor performance was found correlated with Sonic hedgehog and Noggin expression in lesioned animals. The results also suggest that Sonic hedgehog could collaborate in modulating synaptic plasticity. Together, these findings confirm that the injured mammalian spinal cord has intrinsic potential for repair and that some proteins classically involved in development, such as Sonic hedgehog and Noggin could have important roles in regeneration and functional restoration, by mechanisms including synaptic plasticity. [Copyright &y& Elsevier]

Abstract: Adult mammals could spontaneously achieve a partial sensory-motor recovery after spinal cord injury, by mechanisms including synaptic plasticity. We previously showed that this recovery is associated to the expression of synapsin-I, and that sonic hedgehog and Notch-1 could be also involved in plasticity. The role of brain-derived neurotrophic factor and glutamate receptors in regulating synaptic efficacy has been explored in the last decade but, although these mechanisms are now well-defined in the brain, the molecular mechanisms underlying the so called “spinal learning” are still less clear. Here, we measured the expression levels of choline acetyltransferase, synapsin-I, sonic hedgehog, Notch-1, glutamate receptor subunits (GluR1, GluR2, GluR4, NMDAR1) and brain-derived neurotrophic factor, in a motoneuron-depleted mouse spinal lesion model obtained by intramuscular injection of cholera toxin-B saporin. The lesion caused the down-regulation of the majority of analysed proteins. Moreover, we found that in lesioned but not in control spinal tissue, synapsin-I expression is associated to that of both brain-derived neurotrophic factor and sonic hedgehog, whereas GluR2 expression is linked to that of Shh. These results suggest that brain-derived neurotrophic factor and sonic hedgehog could collaborate in modulating synaptic plasticity after the removal of motoneurons, by a mechanism involving both pre- and post-synaptic processes. Interestingly, the involvement of sonic hedgehog showed here is novel, and offers new routes to address spinal cord plasticity and repair. [Copyright &y& Elsevier]

Human skin fibroblasts were exposed to 0.2 T static magnetic field generated by a magnetic resonance tomograph. After 1 h exposure, cell morphology was modified in association with a concomitant decrease in the expression of some sugar residues of glycoconjugates. Study of cell proliferation and mitogenic signal transduction showed a decrease of thymidine incorporation and of second messenger formation. However, cell viability, assessed by colony forming assay, was unaffected. These results demonstrate that the static magnetic field generated by routinely used magnetic resonance tomograph induces alterations on human skin fibroblasts. [Copyright &y& Elsevier]

The effects of heparin on angiogenesis are controversial, with some studies claiming stimulatory and other studies claiming inhibitory effects. Since heparin in human plasma is complexed with basic peptides and proteins, we studied the angiogenic effect of complexes resulting by mixing poly-l-lysine (a basic heparin-binding polypeptide) and heparin. Angiogenesis was investigate by chorioallantoic membrane assay. In specimens treated with PBS (negative control), or poly-l-lysine, no significant vascular reaction was detectable. Heparin induced only moderate angiogenic response. However, neutral complexes purified from a mixture of poly-l-lysine and heparin (20/1, w/w) induced a very strong angiogenic response. These results demonstrate that the angiogenic effect of heparin was associated with neutralization of electric charge when the polysaccharide was complexed with a basic peptide. [Copyright &y& Elsevier]

Simple Summary: Body composition assessment in athletes is closely related to sports performance. In sports where alternating aerobic and anaerobic metabolism is required, muscle mass can affect the achievable result. Therefore, the assessment of muscle mass is a field of interest in the sports sciences. Bioimpedance analysis is a method for assessing body composition. Currently, bioimpedance evaluates muscle mass through predictive equations that could provide estimation errors. These errors could be reduced by an evaluation of the raw bioelectrical parameters. Therefore, in this study, we propose a new parameter for assessing the muscle mass in athletes. The evaluation of muscle mass in athletes correlates with sports performance directly. Bioimpedance vector analysis is a growing method of assessing body composition in athletes because it is independent of predictive formulas containing variables such as body weight, ethnicity, age, and sex. The study aims to propose a new parameter (Levi's Muscle Index, LMI) that evaluates muscle mass through raw bioelectrical data. A total of 664 male footballers underwent bioimpedance assessment during the regular season. LMI was correlated with body cell mass (BCM) and phase angle (PA) to establish efficacy. The footballers were 24.5 ± 5.8 years old, 180.7 ± 5.9 cm tall and weighed 76.3 ± 7.1 kg. The relationships were: LMI-BMI: r = 0.908, r2 = 0.824, p < 0.001; LMI-PA: r = 0.704, r2 = 0.495, p = 0.009 and PA-BCM: r = 0.491, r2 = 0.241, p < 0.001. The results obtained confirm that LMI could be considered a new parameter that provides reliable information to evaluate the muscle mass of athletes. Furthermore, the higher LMI-BCM relationship than PA-BCM demonstrates specificity for muscle mass evaluation in athletes regardless of body weight, ethnicity, age, and sex. [ABSTRACT FROM AUTHOR]

• The intestinal epithelial barrier is critical to maintain health. • Aging affects all the components of the intestinal barrier. • The intestinal barrier is a potential strategic target to improve health during aging. The intestinal epithelial barrier protects the mucosa of the gastrointestinal (GI)-tract and plays a key role in maintaining the host homeostasis. It encompasses several elements that include the intestinal epithelium and biochemical and immunological products, such as the mucus layer, antimicrobial peptides (AMPs) and secretory immunologlobulin A (sIgA). These components are interlinked with the large microbial community inhabiting the gut to form a highly sophisticated biological system that plays an important role on many aspects of human health both locally and systemically. Like any other organ and tissue, the intestinal epithelial barrier is affected by the ageing process. New insights have surfaced showing that critical functions, including intestinal stem cell regeneration and regulation of the intestinal crypt homeostasis, barrier integrity, production of regulatory cytokines, and epithelial innate immunity to pathogenic antigens change across life. Here we review the age-associated changes of the various components of the intestinal epithelial barrier and we highlight the necessity to elucidate further the mechanisms underlying these changes. Expanding our knowledge in this area is a goal of high medical relevance and it will help to define intervention strategies to ameliorate the quality of life of the ever-expanding elderly population. [ABSTRACT FROM AUTHOR]

All allergic responses to food indicate the failure of immunological tolerance, but it is unclear why cow's milk and egg (CME) allergies resolve more readily than reactivity to peanuts (PN). We sought to identify differences between PN and CME allergies through constitutive immune status and responses to cognate and non-cognate food antigens. Children with confirmed allergy to CME (n = 6) and PN (n = 18) and non-allergic (NA) (n = 8) controls were studied. Constitutive secretion of cytokines was tested in plasma and unstimulated mononuclear cell (PBMNC) cultures. Blood dendritic cell (DC) subsets were analyzed alongside changes in phenotypes and soluble molecules in allergen-stimulated MNC cultures with or without cytokine neutralization. We observed that in allergic children, constitutively high plasma levels IL-1β, IL-2, IL-4, IL-5 and IL-10 but less IL-12p70 than in non-allergic children was accompanied by the spontaneous secretion of sCD23, IL-1β, IL-2, IL-4, IL-5, IL-10, IL-12p70, IFN-γ and TNF-α in MNC cultures. Furthermore, blood DC subset counts differed in food allergy. Antigen-presenting cell phenotypic abnormalities were accompanied by higher B and T cell percentages with more Bcl-2 within CD69+ subsets. Cells were generally refractory to antigenic stimulation in vitro, but IL-4 neutralization led to CD152 downregulation by CD4+ T cells from PN allergic children responding to PN allergens. Canonical discriminant analyses segregated non-allergic and allergic children by their cytokine secretion patterns, revealing differences and areas of overlap between PN and CME allergies. Despite an absence of recent allergen exposure, indication of in vivo activation, in vitro responses independent of challenging antigen and the presence of unusual costimulatory molecules suggest dysregulated immunity in food allergy. Most importantly, higher Bcl-2 content within key effector cells implies survival advantage with the potential to mount abnormal responses that may give rise to the manifestations of allergy. Here, we put forward the hypothesis that the lack of apoptosis of key immune cell types might be central to the development of food allergic reactions. [ABSTRACT FROM AUTHOR]

The study of the relationships between the different structures of the human locomotor system still to date raises great interest. In fact, the human body networks and in particular the myofascial system "myofascial system network" underlie posture and movement and new knowledge could be useful and applied to many fields such as medicine and prosthetics. The hypothesis of this study was to verify the possibility of creating a structural network representing the human locomotor system as well as to study and describe the relationship between the different structures considered. The graph theory was applied to a network of 2339 body parts (nodes) and 7310 links, representing the locomotor system. The open source platform software Cytoscape was used for data entry (nodes and links) as well as for debugging. In addition, the "Network Analyzer" plugin was used for the descriptive statistics of the network obtained. In order to achieve a better rendering, the results of the network parameters gained were then imported into Gephi (www.Gephi.org). At the end of this procedure, we obtained a image of a human being in an orthostatic position with a precise distribution of the nodes and links. By simulating the common amputations at the level of the foot and leg (as for necrotic complications of diabetes) the balance between the parts and the whole structure of the graph are profoundly modified. [ABSTRACT FROM AUTHOR]

Objective. The impairment of glycemic control can induce limited joint mobility even in young type 1 diabetic (T1DM) patients. The aims of this study were to verify the presence of ankle joint mobility (AJM) deficits in young T1DM subjects and define a mathematical model of diabetes mellitus long-term effects on AJM. Methods. AJM was evaluated using an inclinometer in 37 patients and 53 healthy, sex- BMI- and age-matched controls. To set up the mathematical model, we assumed that reduced metabolic control affects AJM according to a lognormal function: requiring some time for development of a reduction of joint mobility, which then persists for a long period, before fading out over time (if glycemic control has been recovered). A non-linear optimization determined the model parameters to achieve the best fit for a series of patients. Results. Both plantar and dorsiflexion AJM was significantly lower in diabetic subjects than in controls (plantarflexion: 28.5°±7.5 vs 35.2°±6.5; dorsiflexion: 93.9°±16.0 vs 104.7±12.8; p<0.01). The defined model approximates the experimental data with good accuracy; after optimization, the lognormal curve obtained is in line with empirical estimates: lack of glycemic control needs to persist for at least a few months before producing a significant effect, that lasts up until one year. The fitting procedure indicated the optimal solution is p = (37; 30; 3:5; 6:7; 137); thus, the optimal _im(t) corresponds to the curve reported. Conclusion. AJM was significantly reduced in young T1DM patients. The mathematical model represents the experimental data accurately. [ABSTRACT FROM AUTHOR]

Intestinal macrophages expressing the fraktalkine receptor (CX 3 CR1 + ) represent a cell population that plays a variety of roles ranging from maintaining intestinal immune homeostasis at steady state to controlling antigen access by extending transepithelial dendrites (TEDs) to capture luminal microbes and shuttle them across the epithelium to initiate immune responses. However, recent evidence shows that very early during infection, pathogen-capturing CX 3 CR1 + macrophages migrate to the lumen of the small intestine, therefore preventing pathogens from traversing the epithelium. Here we discuss the complexity of the at-times seemingly opposing roles played by these cells and propose that CX 3 CR1-mediated pathogen exclusion is part of a defensive strategy against infections that includes multiple effector mechanisms acting synergistically at the intestinal mucosa. [ABSTRACT FROM AUTHOR]

Discusses research which described the origin of a subpopulation of neocortical interneurons from the developing striatum in the neocortex. How the neocortex develops; Previous view of neocortical neurons' origin; Production of most forebrain neurons; Generation of neocortical neurons by striatal progenitors; Debate about status of cortico-striatal junction; Nature of cells involved; How cells are guided into cortex; Molecular regulators of migration unknown.

The article focuses on studying the blood-brain barrier (BBB) and the crucial role of astrocytes in its formation and function, highlighting their influence on the expression and correct distribution of tight junction proteins like claudin 5 in brain endothelial cells.

With the recent advances in medicine, human life expectancy is increasing; however, the extra years of life are not necessarily spent in good health or free from disability, resulting in a significantly higher incidence of age-associated pathologies. Among these disorders, neurodegenerative diseases have a significant impact. To this end, the presence of the protective blood–brain barrier (BBB) represents a formidable obstacle to the delivery of therapeutics. Thus, this makes it imperative to define strategies to bypass the BBB in order to successfully target the brain with the appropriate drugs. It has been demonstrated that targeting the BBB by ultrasound (US) can transiently make this anatomical barrier permeable and in so doing, allow the delivery of therapeutics. Thus, our aim was to carry out an in depth in vitro molecular and morphological study on the effects of US treatment on the BBB. The rat brain endothelial (RBE4) cell line was challenged with exposure to 12 MHz diagnostic US treatment for 10, 20, and 30 min. Cell viability assays, Western blotting analysis on the endoplasmic reticulum (ER), and oxidative stress marker evaluation were then performed, along with cytological and immunofluorescence staining, in order to evaluate the effects of US on the intercellular spaces and tight junction distribution of the brain endothelial cells. We observed that the US treatment exerted no toxic effects on either RBE4 cell viability or the upregulation/dislocation of the ER and oxidative stress marker (GRP78 and cytochrome C, respectively). Further, we observed that the application of US induced an increase in the intercellular spaces, as shown by Papanicolaou staining, mainly due to the altered distribution of the tight junction protein zonula occludens-1 (ZO-1). This latter US-dependent effect was transient and disappeared 20 min after the removal of the stimulus. In conclusion, our results show that US induces a transient alteration of the BBB, without altering the intracellular signaling pathways such as the ER and oxidative stress that could potentially be toxic for endothelial cells. These results suggested that US treatment could represent a potential strategy for improving drug delivery to the brain. [ABSTRACT FROM AUTHOR]

Cadmium (Cd) is a well-known occupational and environmental pollutant worldwide, and its toxicity is widely recognised. Cd is reported to increase the permeability of the blood–brain barrier (BBB) and to penetrate and accumulate in the brain. Although many lines of evidence show that Cd toxicity is induced by different mechanisms, one of the best known is the Cd-dependent production of reactive oxygen species (ROS). Zinc is a trace element known as coenzyme and cofactor for many antioxidant proteins, such as metallothioneins and superoxide dismutase enzymes. To date, very little is known about the role of Zn in preventing Cd-induced blood–brain barrier (BBB) alterations. The goal of this study was to test the Zn antioxidant capacity against Cd-dependent alterations in a rat brain endothelial cell line (RBE4), as an in vitro model for BBB. In order to mimic acute Cd poisoning, RBE4 cells were treated with CdCl2 30 µM for 24 h. The protective role of ZnCl2 (50 µM) was revealed by evaluating the cell viability, reactive oxygen species (ROS) quantification, cytochrome C distribution, and the superoxide dismutase (SOD) protein activity. Additionally, the effectiveness of Zn in counteracting the Cd-induced damage was investigated by evaluating the expression levels of proteins already known to be involved in the Cd signalling pathway, such as GRP78 (an endoplasmic reticulum (ER) stress protein), caspase3 pro- and cleaved forms, and BAX. Finally, we evaluated if Zn was able to attenuate the alterations of zonula occludens-1 (ZO-1), one of the tight-junction (TJ) proteins involved in the formation of the BBB. Our data clearly demonstrate that Zn, by protecting from the SOD activity impairment induced by Cd, is able to prevent the triggering of the Cd-dependent signalling pathway that leads to ZO-1 dislocation and downregulation, and BBB damage. [ABSTRACT FROM AUTHOR]

Aims Evaluation of how ankle joint mobility (AJM) can be useful in the identification of patients with diabetes at risk of foot ulcer (FU). Methods Plantar and dorsal flexion of foot were evaluated using an inclinometer in 87 patients (54 type 2 and 33 type 1), and 35 healthy sex- and age-matched control subjects. Patients with diabetes were followed up for diagnosis of FU over the next 8 years and subsequently, patients were subdivided into: those without a history of FU (18 type 1 and 33 type 2), those who had a history of FU detected before baseline evaluation (14 type 2) and those who had history of first ulceration detected by the 8th year of the evaluation period (7 type 2). Results Aging and diabetes caused a significant reduction in mobility of each of the movements investigated ( p < 0.001), whereas after adjusting for the confounding effect of age, diabetes specifically reduced plantar flexion ( p < 0.0001). AJM was significantly lower in those with history of previous FU compared to all the other groups ( p < 0.001). The first ulceration was detected in the same foot presenting lower AJM in 17 of the 22 subjects with diabetes with history of ulcer (77.27%). Conclusions Diabetes and aging reduce AJM although diabetes seems to reduce plantar flexion to a more specific extent. Reduced AJM is mostly associated with a previous history of FU. The evaluation of AJM is a valid and reliable ulcer risk scale that indicates which foot is at higher ulcer risk. [ABSTRACT FROM AUTHOR]

A hopeful spinal cord repairing strategy involves the activation of neural precursor cells. Unfortunately, their ability to generate neurons after injury appears limited. Another process promoting functional recovery is synaptic plasticity. We have previously studied some mechanisms of spinal plasticity involving BDNF, Shh, Notch-1, Numb, and Noggin, by using a mouse model of motoneuron depletion induced by cholera toxin-B saporin. TDP-43 is a nuclear RNA/DNA binding protein involved in amyotrophic lateral sclerosis. Interestingly, TDP-43 could be localized at the synapse and affect synaptic strength. Here, we would like to deepen the investigation of this model of spinal plasticity. After lesion, we observed a glial reaction and an activity-dependent modification of Shh, Noggin, and Numb proteins. By using multivariate regression models, we found that Shh and Noggin could affect motor performance and that these proteins could be associated with both TDP-43 and Numb. Our data suggest that TDP-43 is likely an important regulator of synaptic plasticity, probably in collaboration with other proteins involved in both neurogenesis and synaptic plasticity. Moreover, given the rapidly increasing knowledge about spinal cord plasticity, we believe that further efforts to achieve spinal cord repair by stimulating the intrinsic potential of spinal cord will produce interesting results. [ABSTRACT FROM AUTHOR]

Recent studies have attempted to repair the damaged spinal cord (SC) by stimulating neurogenesis or neuroplasticity. Sonic hedgehog (Shh), Notch-1 and Numb are involved in the stem cell functioning. Additionally, Notch-1 has a role as modulator of synaptic plasticity. However, little is known about the role of these proteins in the adult SC after removal of motoneurons. In this study, we have injected cholera toxin-B saporin into the gastrocnemius muscle to induce a depletion of motoneurons within the lumbar SC of adult mice, and analysed the expression of choline acetyltransferase (ChAT), Synapsin-I, Shh, Notch-1 and Numb proteins. The functional outcome of the lesion was monitored by grid walk and rotarod tasks. The neurotoxin lesion determined a motoneuron depletion and a transient decrease of ChAT, Synapsin-I, Shh and Numb levels in the lumbar SC. ChAT was associated with Synapsin-I expression and motor performance at 1 week but not 1 month after lesion, suggesting that the recovery of locomotion could depend on synaptic plasticity, at least in an early phase. Shh and Notch-1 were associated with Synapsin-I levels, suggesting a role in modulating synaptic plasticity. Numb expression also appeared reduced after lesion and linked to motor performance. Moreover, unlike other lesion models, we observed glial reaction but no evidence of cell proliferation within the depleted SC. Given the mentioned roles of Shh, Notch-1 and Numb, we believe that an in vivo manipulation of their signalling after lesion could represent a suitable way to improve functional recovery by modulating synaptic plasticity and/or neurogenesis. [ABSTRACT FROM AUTHOR]

The confinement and lockdown imposed by the COVID-19 pandemic have produced restrictions in the lifestyle of Italian citizens with variations in their psychological well-being. The aim of the study was to identify changes and relationship with socio-demographic parameters. An online survey was administered to 1383 subjects (1007 females and 307 males) working in the University of Florence, Italy. Three validated questionnaires were used for the survey: the Global Physical Activity Questionnaire, the Med Diet Score and the Psychological General Well-Being Index-A. All the subjects were asked to complete the questionnaires twice, in order to attain a picture of the habits before and a later time point during confinement. Our results show that work-related physical activity was decreased, along with an increase in sedentary behaviour (from 07:22±03:20 to 08:49±03:41 h:min; p<0.001, ES = 0.38), whereas recreational physical activity was increased (vigorous exercise varied from 568.5 ± 838.6 to 833.7 ± 1263.0 METs; p<0.002, ES = 0.25). Eating habits changed according to the place where meals were eaten, with an increased habit for breakfast and snacks and a slight increase in alcohol consumption. Psychological well-being decreased (Index from 21.4±3.9 to 18.0±5.3; p<0.001, ES = 0.723), especially in terms of vitality and positive thinking. The socio-demographic variables affecting these variations were mostly represented by age, gender and working conditions: young age and self-employment conditions can be considered factors for the changes in daily habits induced by confinement that may affect psychological well-being. [ABSTRACT FROM AUTHOR]

The purpose of this paper is to characterize the skin deterministic damage due to the effect of proton beam irradiation in mice occurred during a long-term observational experiment. This study was initially defined to evaluate the insurgence of myelopathy irradiating spinal cords with the distal part of a Spread-out Bragg peak (SOBP). To the best of our knowledge, no study has been conducted highlighting high grades of skin injury at the dose used in this paper. Nevertheless these effects occurred. In this regard, the experimental evidence of significant insurgence of skin injury induced by protons using a SOBP configuration will be shown. Skin damages were classified into six scores (from 0 to 5) according to the severity of the injuries and correlated to ED50 (i.e. the radiation dose at which 50% of animals show a specific score) at 40 days post-irradiation (d.p.i.). The effects of radiation on the overall animal wellbeing have been also monitored and the severity of radiation-induced skin injuries was observed and quantified up to 40 d.p.i. [ABSTRACT FROM AUTHOR]

Plastic changes have been reported in the SOD1‐G93A mouse model of amyotrophic lateral sclerosis, a disorder characterized by progressive motoneuronal loss; however, whether these changes related with the onset and development of motor impairments is still unclear. Here, the functional and anatomical changes taking place in SOD1‐G93A mice and their time course were investigated during ongoing motoneuronal degeneration. Starting from about 4 postnatal weeks, SOD1‐G93A and wild‐type (WT) mice were evaluated in the rotarod test, to be sacrificed at about 12–13 or 19 weeks of age, and their lumbar spinal cords were processed for histo‐ and immunohistochemistry. Compared to age‐matched WT controls, 12 weeks‐old SOD1‐G93A mice exhibited relatively mild or no motor impairments in the rotarod test, in spite of a dramatic (≈60%, as estimated by stereology) loss of choline acetyl‐transferase (ChAT)‐immunoreactive motoneurons which remained virtually unchanged in SOD1‐G93A mice surviving up to 19 weeks. Notably, the functional sparing in SOD1‐G93A mice at 12 weeks was paralleled by a marked ≈50% increase in motoneuron volume and a near‐normal density of acetylcholinesterase‐positive process arborization, which was significantly increased when analyzed as ratio to the decreased number of ChAT‐positive motoneurons. By contrast, at 19 weeks, when motor deficits had become dramatically evident, both measures were found reverted to about 50–60% of control values. Thus, at specific stages during the progression of the disease, robust compensatory events take place in surviving motoneurons of SOD1‐G93A mice, which sustain motor performance, and whose full understanding may highlight a valuable therapeutic opportunity window. [ABSTRACT FROM AUTHOR]

Despite the relevant research efforts, the causes of amyotrophic lateral sclerosis (ALS) are still unknown and no effective cure is available. Many authors suggest that ALS is a multi-system disease caused by a network failure instead of a cell-autonomous pathology restricted to motoneurons. Although motoneuronal loss is the critical hallmark of ALS given their specific vulnerability, other cell populations, including muscle and glial cells, are involved in disease onset and progression, but unraveling their specific role and crosstalk requires further investigation. In particular, little is known about the plastic changes of the degenerating motor system. These spontaneous compensatory processes are unable to halt the disease progression, but their elucidation and possible use as a therapeutic target represents an important aim of ALS research. Genetic animal models of disease represent useful tools to validate proven hypotheses or to test potential therapies, and the conception of novel hypotheses about ALS causes or the study of pathogenic mechanisms may be advantaged by the use of relatively simple in vivo models recapitulating specific aspects of the disease, thus avoiding the inclusion of too many confounding factors in an experimental setting. Here, we used a neurotoxic model of spinal motoneuron depletion induced by injection of cholera toxin-B saporin in the gastrocnemius muscle to investigate the possible occurrence of compensatory changes in both the muscle and spinal cord. The results showed that, following the lesion, the skeletal muscle became atrophic and displayed electromyographic activity similar to that observed in ALS patients. Moreover, the changes in muscle fiber morphology were different from that observed in ALS models, thus suggesting that some muscular effects of disease may be primary effects instead of being simply caused by denervation. Notably, we found plastic changes in the surviving motoneurons that can produce a functional restoration probably similar to the compensatory changes occurring in disease. These changes could be at least partially driven by glutamatergic signaling, and astrocytes contacting the surviving motoneurons may support this process. [ABSTRACT FROM AUTHOR]

Michelangelo's marble sculpture of David is one of the most admired works of art in the world. It is the most iconic symbol of the Florentine Renaissance, and a representation of the idealized human form in its perfection and proportion. The statue was examined in 2004 by two anatomists who observed the apparent absence of a single muscle. Our re-examination of the statue, from our perspective as clinical geneticists, shows unexpected and hitherto unpublished details of variations and disproportions within the overall context of exceptional harmony and beauty. This apparent contradiction raises the question as to what is considered to be morphologically "normal" and what "is not". [ABSTRACT FROM AUTHOR]

Lower extremity ulcers represent the most ominous, feared, and costly complications of diabetes mellitus. The aim of this review is to highlight the role of daily life physical activities (PAs) and continuous movement monitoring (CMM) in the prevention of foot ulcers. Peripheral neuropathy and peripheral vascular disease are the main causes of foot ulceration and contribute, in turn, to the development of additional risk factors such as foot deformities and/or joint and muscular alterations. Moreover, a deficit of balance, posture abnormalities, followed by gait alterations, increases the risk of ulceration. PA can play a key role in the management of patients with diabetes and in the prevention of ulcers; however, even if it has been reported that some of these risk factors significantly improve after a few weeks of exercise therapy (ET), the real preventive role of ET has not yet been demonstrated. These uncertain results can occur due to some limitations in the management of the same relationship between PA and diabetic foot prevention. Technological advances during the last years enable timely management of overall daily PA. The use of these modern technologies and devices allows CMM assessment and description of daily PA even in the long term. The data collected from these devices can be used to properly manage patients' PA and thus contribute to the prevention of foot ulcers. [ABSTRACT FROM AUTHOR]

Variations in the branching pattern of the aortic arch are clinically relevant because of the direct influence that their presence can have on the success of cardio-vascular procedures, neck or thorax surgery, trauma management or intensive care. In most cases these anatomical variations are asymptomatic and considered clinically benign, but some particular aortic branching patterns have been associated with surgical complications or with vascular diseases in non-surgical patients. The main objective of this work was to study the frequency of variation of the aortic arch branching pattern in a wide and varied population on the basis of literature reports. The aortic arch branching pattern of 20,030 cases reported by 40 anatomical or radiological studies were analyzed. 84,52% of the studied population had a three branches pattern and 14,65% had a two branches pattern. The four primary arteries were seen arising directly from the aortic arch in 0,81% of the cases and only 0,02% had them all arising from a common trunk. [ABSTRACT FROM AUTHOR]

The vertical jump is frequently used for the functional evaluation of athletes and non-sporting subjects. The jump height is often used as an indicator of lower limbs strength. The aim of this study was to verify the presence of a relationship between the maximum height reached and muscle parameters expressed during the vertical jump. In 22 healthy males practicing recreational physical activity (age, mean ± standard deviation: 22.5±1.2 years; body mass: 72.8±13.2 kg; body height: 177.1±7.0 cm) and in 15 female volley players (age: 16.5±0.4 years; body mass: 64.4± 8.4 kg; body height: 175.5±7.9 cm), Jump Height (cm), Muscle Strength (N/kg) and Power (W/kg) were recorded during the jump tests. In the healthy males group, jump height was correlated with muscle power: r = 0.33, p>0.05; a higher correlation resulted between muscle strength and power: r = 0.62, p<0.01. In the female volleyball players group, only the muscle strength and power showed a correlation: r = 0.54, p<0.05. It is therefore possible to confirm that the jump height reached during a vertical jump does not provide clear information on the strength of the lower limbs. At the same time, an improvement in muscular strength of the lower limbs does not guarantee an increase in jump height. Several parameters should be evaluated at the same time for a correct functional assessment of athletes and healthy non-sporting subjects. [ABSTRACT FROM AUTHOR]

Even if physical activity plays a key role within diabetic foot treatment its use and the results obtained from this treatment seem to be still limited. Nowadays, new and even more advanced technologies for the long term daily physical activity monitoring are available and they are radically changing some aspects of physical activity such as its amount, features and monitoring. In spite of the past, the several electronic devices that are currently available can be integrated into routine care and provide essential information for management to both the healthcare providers and patients. In particular, since the end of the last century, an increasing number of studies have applied the movement monitoring to patients at risk or with history of ulceration. The questionnaires have been progressively replaced with modern technologies such as accelerometers or complex multisensory devices able to objectively measure the physical activity performed. The data collected through the use of such devices can allow a better assessment of patient's condition and provide useful information for the definition of a more complete treatment protocol. Daily physical activity monitoring devices provide to the Diabetes Units information on the typology, quantity, distribution and intensity of the daily physical activity performed by each patient concurring to the prevention of foot ulcers that represent the most dreadful diabetes complications. The different functions and modes of operation of monitoring devices can be integrated to provide a more comprehensive and intelligent monitoring system that provide valuable information on patients' ongoing health status and the physical activity performed during daily life. These devices can manage in real time or even in remote the physical activity performed in addition to calculate that to be performed in the following hours. As a result, they contribute to improve patients' lifestyle and reduce the costs for the treatment of such complications. The aim of this review is to define and emphasize the role of a long term daily physical activity monitoring in the prevention of diabetic foot ulcers. [ABSTRACT FROM AUTHOR]

Background/Objective: It is known that patients with diabetes can develop limited joint mobility (LJM) and that this can depend on the metabolic control maintained and the duration of the disease. The aims of this study were to verify the presence of ankle joint mobility (AJM) deficits in both plantar and dorsiflexion in young type 1 diabetic patients (T1D) considering also the possible role of sport practiced as a further factor, able to modify AJM. Methods: AJM was evaluated by an inclinometer in 82 T1D patients (M/F: 48/34), mean age 12.9 ± 2.6 years, body mass index (BMI) 19.7 ± 3.6 kg/m2, duration of diabetes 5.6 ± 3.3 years, mean HbA1c 7.5 ± 1.0% and in 226 healthy controls (M/F: 146/80), age‐, gender‐, and BMI‐matched practicing different sports (soccer, volleyball, basketball, and dance). Results: The patients’ ankle range of motion was significantly lower than that in controls (132.7 ± 22.3° vs 126.1 ± 17.9°; P < .017). In particular, ankle plantar flexion was significantly lower in the patients group (31.6° ± 7.9° vs 28.5° ± 6.6°; P < .002). Soccer players showed lower AJM in both groups: patients (120.1 ± 15.9° vs 127.3 ± 18.1) and controls (119.4 ± 21.1° vs 142.0 ± 18.1; P < .0001) than subjects practicing other sports or who were sedentary. In both groups, patients and controls, age, sex, duration of disease, hemoglobin 1Ac, and BMI have not been shown to be correlated to the mobility assessed. Conclusions: The results of this study, in addition to confirming the negative effect of diabetes on AJM of young T1D patients, suggest that during these evaluations the sport‐related effect should be considered because it can induce significant changes of AJM. [ABSTRACT FROM AUTHOR]

Objective: Hand muscle strength assessment is widespread and can be a useful marker in the evaluation and monitoring of subjects at different ages and health conditions. This study aimed at validating and determining the reliability of a new digital device for evaluation of hand pinch strength by comparing it with a well-validated hand strength assessment device, the Jamar hydraulic hand dynamometer. Methods: In 65 healthy subjects, (males / females: 29 / 36), mean age 40.3±18.0 (range: 19.3 - 76.5) years, hand pinch strength and hydraulic hand dynamometer were used to assess hand strength following a testing protocol. Only the dominant hand was tested. Evaluations were performed considering gender, hand dominance, body mass index and age, according to the standardized testing protocol. The mean of three consecutive grip tests and lateral pinch tests was recorded. Results: There was a strong correlation (p<0.0001) between the hydraulic hand dynamometer and hand pinch strength tests. Both mean strengths measured by hydraulic hand dynamometer and hand pinch strength in females were significantly lower than in males (P<0.001), the grip strength being 34.75% and the lateral pinch test 27.83% weaker than in males. Multivariate analysis indicated that the strength expressed by the hand pinch strength pinch test remained significantly associated with the results of hydraulic hand dynamometer (p<0,001), independent of age and body weight. Conclusions: hand pinch strength and hydraulic hand dynamometer have been shown to be significantly correlated with each other in subjects of different ages, sex and body mass index.The hand pinch strength device has been proven to be a reliable tool for measuring maximal isometric strength by lateral pinch test. This device can be used for quick and inexpensive numerical evaluation of muscular strength in cases as the elderly in communities, bedridden patients, and during drug therapies presumed to be strength affecting. [ABSTRACT FROM AUTHOR]

During Salmonella Typhimurium infection, intestinal CX3CR1+ cells can either extend transepithelial cellular processes to sample luminal bacteria or, very early after infection, migrate into the intestinal lumen to capture bacteria. However, until now, the biological relevance of the intraluminal migration of CX3CR1+ cells remained to be determined. We addressed this by using a combination of mouse strains differing in their ability to carry out CX3CR1-mediated sampling and intraluminal migration. We observed that the number of S. Typhimurium traversing the epithelium did not differ between sampling-competent/migrationcompetent C57BL/6 and sampling-deficient/migration-competent BALB/c mice. In contrast, in sampling-deficient/migrationdeficient CX3CR1-/- mice the numbers of S. Typhimurium penetrating the epithelium were significantly higher. However, in these mice the number of invading S. Typhimurium was significantly reduced after the adoptive transfer of CX3CR1+ cells directly into the intestinal lumen, consistent with intraluminal CX3CR1+ cells preventing S. Typhimurium from infecting the host. This interpretation was also supported by a higher bacterial fecal load in CX3CR1+/gfp compared with CX3CR1gfp/gfp mice following oral infection. Furthermore, by using real-time in vivo imaging we observed that CX3CR1+ cells migrated into the lumen moving through paracellular channels within the epithelium. Also, we reported that the absence of CX3CR1-mediated sampling did not affect Ab responses to a noninvasive S. Typhimurium strain that specifically targeted the CX3CR1-mediated entry route. These data showed that the rapidly deployed CX3CR1+ cell-based mechanism of immune exclusion is a defense mechanism against pathogens that complements the mucous and secretory IgA Ab-mediated system in the protection of intestinal mucosal surface. [ABSTRACT FROM AUTHOR]

Thyroid carcinoma is the most common endocrine neoplasm, with the highest mortality rate of all the endocrine cancers. Among the endocrine malignancies, ~80% are papillary thyroid carcinomas (PTCs). In the initiation and progression of this tumor, genetic alterations in the mitogen-associated protein kinase pathway, including RAS point mutations, RET/PTC oncogene rearrangements and BRAF point mutations, play an important role, particularly in deciding targeted therapy. In the present study, a small population of thyroid tumor cells, known as tumor spheres, were isolated and characterized from PTC surgical samples. These spheres can be expanded indefinitely in vitro and give rise to differentiated adherent cells when cultivated in differentiative conditions. The present study showed by reverse transcription-polymerase chain reaction and flow cytometric analysis that the undifferentiated PTC cells exhibited a characteristic antigen expression profile of adult progenitor/stem cells. The cells were more resistant to chemotherapeutics, including bortezomib, taxol, cisplatin, etoposide, doxorubicin and vincristine, than differentiated PTC cells and the majority possessed a quiescent status, as revealed by the various cell cycle characteristics and anti-apoptotic protein expression. Such advances in cancer thyroid stem cell biology may provide relevant information for future targeted therapies. [ABSTRACT FROM AUTHOR]

A better understanding of pediatric tumor biology is needed to allow the development of less toxic and more efficient therapies, as well as to provide novel reliable biomarkers for diagnosis and risk stratification. The emerging role of microRNAs in controlling key pathways implicated in tumorigenesis makes their use in diagnostics a powerful novel tool for the early detection, risk assessment and prognosis, as well as for the development of innovative anticancer therapies. This perspective would be more urgent for the clinical management of pediatric cancer. In this review, we focus on the involvement of microRNAs in the biology of the main childhood tumors, describe their clinical significance and discuss their potential use as novel therapeutic tools and targets. [ABSTRACT FROM AUTHOR]

Research is presented that examines genetic factors' influence on athletic performance, noting the polymorphisms of the angiotensin-converting enzyme (ACE), vitamin D receptor genes, and ACTN3. The study found that the Italian male gymnasts with ACTN3 RR/RX genotypes were not predisposed to power-oriented apparatus, that vitamin D receptor polymorphisms had no significant link to athletic performance, and that ACTN3 R577X and ACE insertion/deletion polymorphisms do affect physical performance.

Abstract: CD200 is a relatively ubiquitously expressed molecule that plays a role in cancer immune evasion through interaction with its receptors. High expression levels of CD200 have been described in different human malignancies. For example, CD200 has been shown to be targeted after RAS/RAF/MEK/ERK activation in melanoma. Here we present the analysis of CD200 expression in human Multiple Myeloma (MM) samples. We found that CD200-positive cells express ERK and p-ERK. Moreover, UO126, a MEK inhibitor, reduces CD200 expression. Furthermore, we observe that CD200-positive cells show reduced immunogenicity compared to normal lymphocytes and that such immunogenicity increases when UO126 is used. We therefore hypothesize that CD200 expression in MM could suppress antitumor response and that anti-CD200 treatment might be therapeutically beneficial in CD200-expressing tumors. [Copyright &y& Elsevier]

The term astrocytoma defines a quite heterogeneous group of neoplastic diseases that collectively represent the most frequent brain tumors in humans. Among them, glioblastoma multiforme represents the most malignant form and its associated prognosis is one of the poorest among tumors of the central nervous system. It has been demonstrated that a small population of tumor cells, isolated from the brain neoplastic tissue, can reproduce the parental tumor when transplanted in immunodeficient mouse. These tumor initiating cells are supposed to be involved in cancer development and progression and possess stem cell-like features; like their normal counterpart, these cells remain quiescent until they are committed to differentiation. Many studies have shown that the role of the tumor suppressor protein PTEN in cell cycle progression is fundamental for tumor dynamics: in low grade gliomas, PTEN contributes to maintain cells in G1 while the loss of its activity is frequently observed in high grade gliomas. The mechanisms underlying the above described PTEN activity have been studied in many tumors, but those involved in the maintenance of tumor initiating cells quiescence remain to be investigated in more detail. The aim of the present study is to shed light on the role of PTEN pathway on cell cycle regulation in Glioblastoma stem cells, through a cell differentiation model. Our results suggest the existence of a molecular mechanism, that involves DUB3 and WEE1 gene products in the regulation of Cdc25a, as functional effector of the PTEN/Akt pathway. [ABSTRACT FROM AUTHOR]

α-N-acetylgalactosaminidase (nagalase) accumulates in the serum of cancer patients and its activity correlates with tumor burden, aggressiveness and clinical disease progression. The administration of GC protein-derived macrophage-activating factor (GcMAF) to cancer patients with elevated levels of nagalase has been associated with a decrease of serum nagalase activity and with significant clinical benefits. Here, we report the results of the administration of GcMAF to a heterogeneous cohort of patients with histologically diverse, advanced neoplasms, generally considered as "incurable" diseases. In most cases, GcMAF therapy was initiated at late stages of tumor progression. As this is an open-label, non-controlled, retrospective analysis, caution must be employed when establishing cause-effect relationships between the administration GcMAF and disease outcome. however, the response to GcMAF was generally robust and some trends emerged. All patients (n = 20) presented with elevated serum nagalase activity, well above normal values. All patients but one showed a significant decrease of serum nagalase activity upon weekly GcMAF injections. Decreased nagalase activity was associated with improved clinical conditions and no adverse side effects were reported. The observations reported here confirm and extend previous results and pave the way to further studies aimed at assessing the precise role and indications for GcMAF-based anticancer immunotherapy. [ABSTRACT FROM AUTHOR]

Previous studies by us and other groups characterized protein expression variation following long-term moderate training, whereas the effects of single bursts of exercise are less known. Making use of a proteomic approach, we investigated the effects of acute swimming exercise (ASE) on protein expression and carbonylation patterns in two hind limb muscles: the Extensor Digitorum Longus (EDL) and the Soleus, mostly composed of fast-twitch and slow-twitch fibres, respectively. Carbonylation is one of the most common oxidative modifications of proteins and a marker of oxidative stress. In fact, several studies suggest that physical activity and the consequent increase in oxygen consumption can lead to increase in reactive oxygen and nitrogen species (RONS) production, hence the interest in examining the impact of RONS on skeletal muscle proteins following ASE. Results indicate that protein expression is unaffected by ASE in both muscle types. Unexpectedly, the protein carbonylation level was reduced following ASE. In particular, the analysis found 31 and 5 spots, in Soleus and EDL muscles respectively, whose carbonylation is reduced after ASE. Lipid peroxidation levels in Soleus were markedly reduced as well. Most of the decarbonylated proteins are involved either in the regulation of muscle contractions or in the regulation of energy metabolism. A number of hypotheses may be advanced to account for such results, which will be addressed in future studies. [ABSTRACT FROM AUTHOR]

The article offers information on morphological features of rat brain vascular pericytes (RBVP) during toxic insult and their role in blood-brain barrier characterization. Topics include information on pericytes which are fibroblast like cells; information on extensive cytoplasmic elongation; and different cell types of central nervous system.

The article presents information that the mammalian target of rapamycin (mTOR) is a serine which forms different multiprotein complexes with diverse subunit compositions. It informs that mTOR is a key regulator for cell growth and metabolism and its improper activation has been linked to carcinogenesis. It mentions that the polycythaemia vera, essential thrombocythaemia and primary myelofibrosis are the BCR-ABL1-negative myeloproliferative neoplasms.

Background Mechanical stresses induce variations in tissue tensegrity leading to cell proliferation and differentiation thus contributing to tissue remodelling. Besides mechanical forces, skin remodelling may be induced by the application of plasma, a new type of energy delivery resulting in controlled heat damage. Here we demonstrate that mechanical stress induced by the application of vacuum increases the efficacy of plasma in skin regeneration treatment. Methods Vacuum alone and vacuum plus plasma at different energies were applied to rat skin and biopsies collected at different time intervals after treatments. Skin integrity, collagen arrangement, inflammation and myofibroblast differentiation were assessed by Masson's trichrome staining. Procollagen synthesis was evaluated by immunohistochemistry. Results Vacuum alone induced significant and temporary alterations in the distribution of collagen bundles, with concomitant procollagen synthesis in the dermis; no myofibroblasts and no signs of inflammation were observed. Vacuum plus plasma determined an important spatial modification of collagen bundles, more intense than vacuum or plasma alone. Significant increase of procollagen synthesis, numerous myofibroblasts but slight sign of inflammation appeared after the treatment. Conclusion Vacuum mechanically stimulated fibroblasts, producing changes in collagen arrangement and procollagen synthesis. Plasma led to the same effects through thermal damage. Application of a combined treatment consisting in vacuum plus plasma induced more remarkable effects on skin regeneration with relatively low plasma energies and no relevant side effects. [ABSTRACT FROM AUTHOR]

Background and Objective: In patients with advanced cancer, cachexia correlates with low performance status and poor quality of life. In addition, cachexia may be associated with reduced response to chemoradiotherapy and a poor prognosis in cancer patients. Nearly all forms of cachexia are closely associated with chronic inflammation and elevated levels of inflammatory and pro-inflammatory circulating factors, including C-reactive protein (CRP), which is considered a valid laboratory and clinical marker. Among the different pathways involved in the production of inflammatory cytokines and chemokines, the vitamin D- vitamin D receptor (VDR) axis plays a fundamental role. In this study, we explore the possible association between CRP and key factors pertaining to the vitamin D axis - in particular, VDR gene polymorphisms - in cancer patients with cachexia. Although certain tumor types are more commonly associated with cachexia, even within the same tumor type there are significant differences in the extent and duration of cachexia. Such variations may be due to polymorphisms of the VDR gene that could lead to cachexia-prone genotypes or to cachexia-resistant genotypes. Identification of such genotypes could be very helpful in the management of cancer patients. Methods: Forty-three cancer patients were recruited by the Nutritional Unit of the Prato Hospital. Data on age, gender, type of cancer, stage of cancer, and nutritional assessment, as well as transferrin, ferritin, albumin, and CRP levels, were collected. Genomic DNA was extracted from peripheral blood leukocytes and amplified by polymerase chain reaction. BsmI, ApaI, TaqI, and FokI polymorphisms of the VDR gene were investigated using the respective restriction enzymes. For the different VDR polymorphisms, the absence or presence of the restriction sites were designated with capital or small letters, respectively. For example, for the BsmI polymorphism, the presence of the undigested fragment identified the B allele, whereas the presence of the digested fragment identified the b allele. Results: Cancer patients with cachexia have higher CRP levels compared with non-cachectic cancer patients, independently from the genotype. In cachectic patients, the presence of specific VDR BsmI and TaqI alleles was associated with higherCRPlevels. In particular, theVDRb and T alleles were more frequent in cachectic cancer patients with elevated CRP levels than in cachectic patients with normal CRP levels. Conclusion: From these results, we hypothesize that there is an association between BsmI and TaqI VDR gene polymorphisms and the cachectic syndrome. In particular, we propose that in cancer patients, the concomitance of b and T alleles with elevated CRP levels may represent an early clinical predictor for the development of a more aggressive form of cachexia. [ABSTRACT FROM AUTHOR]

Abstract: Understanding the relationship between physical exercise, reactive oxygen species and skeletal muscle modification is important in order to better identify the benefits or the damages that appropriate or inappropriate exercise can induce. Unbalanced ROS levels can lead to oxidation of cellular macromolecules and a major class of protein oxidative modification is carbonylation. The aim of this investigation was to study muscle protein expression and carbonylation patterns in trained and untrained animal models. We analyzed two muscles characterized by different metabolisms: tibialis anterior and soleus. Whilst tibialis anterior is mostly composed of fast-twitch fibers, the soleus muscle is mostly composed of slow-twitch fibers. By a proteomic approach we identified 15 protein spots whose expression is influenced by training. Among them in tibialis anterior we observed a down-regulation of several glycolitic enzymes. Concerning carbonylation, we observed the existence of a high basal level of protein carbonylation. Although this level shows some variation among individual animals, several proteins (mostly involved in energy metabolism, muscle contraction, and stress response) appear carbonylated in all animals and in both types of skeletal muscle. Moreover we identified 13 spots whose carbonylation increases after training. [Copyright &y& Elsevier]

The effects of Gc protein-derived macrophage-activating factor (GcMAF) have been studied in cancer and other conditions where angiogenesis is deregulated. In this study, we demonstrate for the first time that the mitogenic response of human peripheral blood mononuclear cells (PBMCs) to GcMAF was associated with 3′-5′-cyclic adenosine monophosphate (cAMP) formation. The effect was dose dependent, and maximal stimulation was achieved using 0.1 ng/ml. Heparin inhibited the stimulatory effect of GcMAF on PBMCs. In addition, we demonstrate that GcMAF (1 ng/ml) inhibited prostaglandin E- and human breast cancer cell-stimulated angiogenesis in chick embryo chorionallantoic membrane (CAM) assay. Finally, we tested different GcMAF preparations on CAM, and the assay proved to be a reliable, reproducible and inexpensive method to determine the relative potencies of different preparations and their stability; we observed that storage at room temperature for 15 days decreased GcMAF potency by about 50%. These data could prove useful for upcoming clinical trials on GcMAF. [ABSTRACT FROM AUTHOR]

Abstract: Several reports demonstrated that the activation of Nuclear Factor-kappa B NF-κB is essential for the pathogenesis of multiple myeloma (MM). We analyzed the nuclear localization of NF-κB in MM-cells derived from 60 different patients with MM at presentation and in relapse, as well as in three myeloma cell lines. Nuclear localization (the active form) of NF-κB was detected in only one MM-sample from a refractory patient and in two samples from relapsed patients, while all the other samples, including the MM-cell lines, almost exclusively express the cytoplasmic (inactive) form of NF-κB. In mesenchymal cells from MM-patients NF-κB was clearly present in the nucleus. In addition, the proteasome inhibitor Bortezomib, which is described to antagonize NF-κB activity, had a consistent antitumor activity against both chemoresistant and chemosensitive MM-cells, regardless the NF-κB localization, thus suggesting the existence of other molecular targets of proteasome inhibitors in MM. [Copyright &y& Elsevier]

Acute myeloid leukemia (AML) is a malignant disease characterized by abnormal proliferation of clonal precursor cells. Although different strategies have been adopted to obtain complete remission, the disease actually progresses in about 60–70% of patients. Bortezomib has been used in multiple myeloma and other lymphoid malignancies because of its antitumor activity. Here we examined the sensitivity of bone marrow cells from AML patients (34 patients: 25 newly diagnosed, 4 relapsed, 5 refractory) to bortezomib alone or in combination with TRAIL, a member of the TNF family that induces apoptosis in tumor cells while sparing normal cells. Bortezomib induced cell death in blasts from each patient sample. The cytotoxic effect was dose- and time-dependent (concentration from 0.001 to 10 μM for 24 and 48 h) and was associated with a downregulation of Bcl-xL and Mcl-1, an upregulation of TRAIL-R1, TRAIL-R2, p21, activation of executioner caspases and a loss of the mitochondrial membrane potential. Moreover, low doses of bortezomib primed TRAIL-resistant AML cells for enhanced TRAIL-mediated killing. These results suggest that a combination of proteasome inhibitors and TRAIL could be effective for treating AML patients, even patients who are refractory to conventional chemotherapy. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Purpose: Different biologically equivalent dose (BED) values associated with stereotactic radiotherapy (SRT) of patients with primary and metastatic pulmonary nodules were studied. The BED values were calculated for tumoral tissue and low α/β ratio, assuming that better local response could be obtained by using stereotactic high-BED treatment. Methods and Materials: Fifty-eight patients with T1–T3 N0 non–small-cell lung cancer and 46 patients with metastatic lung nodules were treated with SRT. The BED was calculated for α/β ratios of 3 and 10. Overall survival (OS) was assessed according to Kaplan-Meier and appraised as a function of three BED levels: low (30–50 Gy), medium (50–70 Gy), and high (70–98 Gy; α/β = 10). Results: The OS rates for all 104 patients at 12, 24, and 36 months were 73%, 48.3%, and 35.8%, respectively. Local response greater than 50% for low, medium, and high BED values was observed in 54%, 47%, and 73%, respectively. In the high-BED treated group, OS rates at 12, 24, and 36 months (80.9%, 70%, and 53.6%, respectively) were significantly improved compared with low- (69%, 46.1%, and 30.7%, respectively) and medium-BED (67%, 28%, and 21%, respectively) treated patients. Results are also discussed in terms of BED calculated on α/β 3 Gy characteristic of the microcapillary bed. No acute toxicity higher than Grade 1 was observed. Conclusions: Radioablation of pulmonary neoplastic nodules may be achieved with SRT delivered by using a high-dose fraction with high BED value. [Copyright &y& Elsevier]

Carbon-based nanomaterials are nowadays attracting lots of attention, in particular in the biomedical field, where they find a wide spectrum of applications, including, just to name a few, the drug delivery to specific tumor cells and the improvement of non-invasive imaging methods. Nanoparticles inhaled during breathing accumulate in the lung alveoli, where they interact and are covered with lung surfactants. We recently demonstrated that an apparently non-toxic concentration of engineered carbon nanodiamonds (ECNs) is able to induce oxidative/nitrosative stress, imbalance of energy metabolism, and mitochondrial dysfunction in microglial and alveolar basal epithelial cells. Therefore, the complete understanding of their "real" biosafety, along with their possible combination with other molecules mimicking the in vivo milieu, possibly allowing the modulation of their side effects becomes of utmost importance. Based on the above, the focus of the present work was to investigate whether the cellular alterations induced by an apparently non-toxic concentration of ECNs could be counteracted by their incorporation into a synthetic lung surfactant (DPPC:POPG in 7:3 molar ratio). By using two different cell lines (alveolar (A549) and microglial (BV-2)), we were able to show that the presence of lung surfactant decreased the production of ECNs-induced nitric oxide, total reactive oxygen species, and malondialdehyde, as well as counteracted reduced glutathione depletion (A549 cells only), ameliorated cell energy status (ATP and total pool of nicotinic coenzymes), and improved mitochondrial phosphorylating capacity. Overall, our results on alveolar basal epithelial and microglial cell lines clearly depict the benefits coming from the incorporation of carbon nanoparticles into a lung surfactant (mimicking its in vivo lipid composition), creating the basis for the investigation of this combination in vivo. [ABSTRACT FROM AUTHOR]