FGF2 and ET1 promote human fetal striatal neuroblasts survival in hypoxic conditions

Fetal striatal transplantation emerged as a new strategy to promote reparative responses in Huntington’s disease (HD) patients1. Mechanisms that support neuroblasts survival and replenishment of damaged cells within the HD brain in hypoxia remain to be elucidated. This study investigated how human fetal striatal neuroblasts (HSP cells) respond to hypoxia, using the hypoxia-mimetic agent cobalt chloride (CoCl2)2. We analyzed CoCl2 effect on hypoxia-related proteins, such as HIF-1α and VEGF, and on a neuroprotective factor, such as Seladin-1. Moreover, we evaluated FGF2 (50 ng/ml) and ET1 (100 nM) proliferative/survival effects in HSP cells in normoxic and hypoxic conditions. These growth factors could be important mediators under pathological conditions for striatal neuroblasts function and response to hypoxia. Dose-response experiments with increasing concentration of CoCl2 (50-750 um) showed an increase of HSP cell proliferation at 24-48h, with maximal effects observed at 400 um, while cell survival was impaired at 72h. Hypoxia increased protein expressions of HIF-1α and VEGF, whereas decreased Seladin-1 levels. FGF2 and ET1 significantly stimulated HSP cells proliferation both in normoxic and hypoxic condition, counteracting the apoptotic CoCl2 effect at 72h. FGF2 and ET1 neuroprotective effect was abolished by the selective inhibition of their receptors (FGFR1, ETA and ETB). In particular, ET1 stimulated HSP cells survival through ETA receptor in normoxic condition and through ETB receptor during hypoxia. Our results support the idea that FGF2 and ET1 promote neurogenesis and survival of HSP cells, through receptor-mediated mechanisms, when grafted into the hypoxic HD brain

Tumor Necrosis Factor α Influences Phenotypic Plasticity and Promotes Epigenetic Changes in Human Basal Forebrain Cholinergic Neuroblasts.

TNFα is the main proinflammatory cytokine implicated in the pathogenesis of neurodegenerative disorders, but it also modulates physiological functions in both the developing and adult brain. In this study, we investigated a potential direct role of TNFα in determining phenotypic changes of a recently established cellular model of human basal forebrain cholinergic neuroblasts isolated from the nucleus basalis of Meynert (hfNBMs). Exposing hfNBMs to TNFα reduced the expression of immature markers, such as nestin and β-tubulin III, and inhibited primary cilium formation. On the contrary, TNFα increased the expression of TNFα receptor TNFR2 and the mature neuron marker MAP2, also promoting neurite elongation. Moreover, TNFα affected nerve growth factor receptor expression. We also found that TNFα induced the expression of DNA-methylation enzymes and, accordingly, downregulated genes involved in neuronal development through epigenetic mechanisms, as demonstrated by methylome analysis. In summary, TNFα showed a dual role on hfNBMs phenotypic plasticity, exerting a negative influence on neurogenesis despite a positive effect on differentiation, through mechanisms that remain to be elucidated. Our results help to clarify the complexity of TNFα effects in human neurons and suggest that manipulation of TNFα signaling could provide a potential therapeutic approach against neurodegenerative disorders

Musculoskeletal pain in women from DAMA Trial: role of a physical activity intervention

Epidemiological studies showed that prevalence of musculoskeletal pain is higher in women than in men (Bracci et al. 2007; Salaffi et al. 2005) and low back pain is the most commonly reported whereas conflicting evidence exists for the association between physical activity and low back pain symptoms (Heneweer et al. 2011; Sitthipornvorakul et al. 2011). In this study, we investigated the prevalence of musculoskeletal pain and the role of a non-specific physical activity (PA) intervention in prevention/reduction of pain in the frame of the DAMA Trial. DAMA (n° ISRCTN28492718, funded by Istituto Toscano Tumori and Ministry of Health ) is a 24-month factorial randomized trial in post-menopausal women with high-Mammographic Breast Density (MBD), a risk factor for breast cancer (Masala et al. 2006), aimed to evaluate the ability of a structured intervention based on a moderate-intensity physical exercise and/or specific dietary modification, to reduce MBD. Participants were post-menopausal women, 50-69 yrs, with MBD>50%. Exclusion criteria were: current/recent HRT; current smokers; diabetes and/or other co-morbidities contraindicating dietary and PA intervention. After the baseline visit in which blood and urine samples, anthropometry, dietary and lifestyle information were collected, participants (234 women) were randomized by age- and BMI-stratified blocks, to one of the four arms: dietary intervention, PA intervention, dietary+PA intervention or control. The PA intervention included one hour/week exercise program carried out by exercise specialist, individual and group sessions to explain PA benefits, group walks and at least 1 hour/day of individual moderate PA (i.e. walking, biking, home exercise). The control arm received general advice on healthy diet and PA. To evaluate physical fitness of all participants, at baseline and follow-up (FU), specific visits were performed and a specific questionnaire on pain was self-administered to investigate body site of pain, pain intensity and duration. Baseline and FU pain questionnaires were completed by 210 women (102 randomised to PA intervention*, 108 to control arm§). At baseline pain was reported by 154 women (73%), among them 75% reported back, 29% shoulder and 29% leg pain. After the 24-month intervention a significant effect emerged for low back pain in women randomised to PA intervention, in term of reduced prevalence of women with pain and prevention of new cases (p=0.02 in PA arm, 0.30 in control arm) suggesting also a beneficial effect of non-specific PA

Efficacy and safety of growth hormone treatment in children with short stature: the Italian cohort of the GeNeSIS clinical study

Purpose: We examined auxological changes in growth hormone (GH)-treated children in Italy using data from the Italian cohort of the multinational observational Genetics and Neuroendocrinology of Short Stature International Study (GeNeSIS) of pediatric patients requiring GH treatment. Methods: We studied 711 children (median baseline age 9.6 years). Diagnosis associated with short stature was as determined by the investigator. Height standard deviation score (SDS) was evaluated yearly until final or near-final height (n = 78). Adverse events were assessed in all GH-treated patients. Results: The diagnosis resulting in GH treatment was GH deficiency (GHD) in 85.5 % of patients, followed by Turner syndrome (TS 6.6 %). Median starting GH dose was higher in patients with TS (0.30 mg/kg/week) than patients with GHD (0.23 mg/kg/week). Median (interquartile range) GH treatment duration was 2.6 (0.6\u20133.7) years. Mean (95 % confidence interval) final height SDS gain was 2.00 (1.27\u20132.73) for patients with organic GHD (n = 18) and 1.19 (0.97\u20131.40) for patients with idiopathic GHD (n = 41), but lower for patients with TS, 0.37 ( 120.03 to 0.77, n = 13). Final height SDS was > 122 for 94 % of organic GHD, 88 % of idiopathic GHD and 62 % of TS patients. Mean age at GH start was lower for organic GHD patients, and treatment duration was longer than for other groups, resulting in greater mean final height gain. GH-related adverse events occurred mainly in patients diagnosed with idiopathic GHD. Conclusions: Data from the Italian cohort of GeNeSIS showed auxological changes and safety of GH therapy consistent with results from international surveillance databases

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Tumor Necrosis Factor α Influences Phenotypic Plasticity and Promotes Epigenetic Changes in Human Basal Forebrain Cholinergic Neuroblasts.

TNFα is the main proinflammatory cytokine implicated in the pathogenesis of neurodegenerative disorders, but it also modulates physiological functions in both the developing and adult brain. In this study, we investigated a potential direct role of TNFα in determining phenotypic changes of a recently established cellular model of human basal forebrain cholinergic neuroblasts isolated from the nucleus basalis of Meynert (hfNBMs). Exposing hfNBMs to TNFα reduced the expression of immature markers, such as nestin and β-tubulin III, and inhibited primary cilium formation. On the contrary, TNFα increased the expression of TNFα receptor TNFR2 and the mature neuron marker MAP2, also promoting neurite elongation. Moreover, TNFα affected nerve growth factor receptor expression. We also found that TNFα induced the expression of DNA-methylation enzymes and, accordingly, downregulated genes involved in neuronal development through epigenetic mechanisms, as demonstrated by methylome analysis. In summary, TNFα showed a dual role on hfNBMs phenotypic plasticity, exerting a negative influence on neurogenesis despite a positive effect on differentiation, through mechanisms that remain to be elucidated. Our results help to clarify the complexity of TNFα effects in human neurons and suggest that manipulation of TNFα signaling could provide a potential therapeutic approach against neurodegenerative disorders

Expression and localization of VEGF receptors in human fetal skeletal tissues

During development the vertebrate skeleton is the product of deriving cells from distinct embryonic lineages. The craniofacial skeleton is formed by migrating cranial neural crest cells, whereas the axial and limb skeletons are derived from mesodermal cells. The Vascular Endothelial Growth Factors (VEGFs) / receptors (VEGFRs) system plays an important role in angiogenesis, as well as osteogenesis, during bone development, growth, and remodeling, attracting endothelial cells and osteoclasts and stimulating osteoblast differentiation. Recent evidence has shown that during development VEGFR-3 is also expressed in neural and glial precursors of forebrain and cerebellum, as well as in the eye. In this study, we found that VEGFR-1, VEGFR-2 and VEGFR-3 are expressed in human bone both in fetal and adult life. The gene expression levels were significantly higher in fetal samples especially in mandibles. In addition, higher levels of VEGFR-3 in orofacial district were confirmed by western blotting analysis. We also observed that in fetal mandibular samples VEGFRs colocalized in several osteoblasts, osteoclasts and osteoprogenitor cells. Furthermore, some cells coexpressed VEGFR-3 and ET-1, a marker of neural crest cells. The results demonstrated different expression of VEGFRs in human mandibular and femoral bones which could be correlated to their different structure, function and development during organogenesis. VEGFR-3 might represent a specific signal for ectomesenchymal lineage differentiation during early human development