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To test the hypothesis that genetic and pharmacological modulation of the classical cannabinoid type 1 (CB 1 ) and 2 (CB 2 ) receptors attenuate cancer-induced bone pain, we searched Medline, Web of Science and Scopus for relevant skeletal and non-skeletal cancer studies from inception to July 28, 2022. We identified 29 animal and 35 human studies. In mice, a meta-analysis of pooled studies showed that treatment of osteolysis-bearing males with the endocannabinoids AEA and 2-AG (mean difference [MD] - 24.83, 95% confidence interval [ 95% CI] - 34.89, - 14.76, p < 0.00001) or the synthetic cannabinoid (CB) agonists ACPA, WIN55,212-2, CP55,940 (CB 1/2 -non-selective) and AM1241 (CB 2 -selective) (MD - 28.73, 95% CI - 45.43, - 12.02, p = 0.0008) are associated with significant reduction in paw withdrawal frequency. Consistently, the synthetic agonists AM1241 and JWH015 (CB 2 -selective) increased paw withdrawal threshold (MD 0.89, 95% CI 0.79, 0.99, p < 0.00001), and ACEA (CB 1 -selective), AM1241 and JWH015 (CB 2 -selective) reduced spontaneous flinches (MD - 4.85, 95% CI - 6.74, - 2.96, p < 0. 00001) in osteolysis-bearing male mice. In rats, significant increase in paw withdrawal threshold is associated with the administration of ACEA and WIN55,212-2 (CB 1/2 -non-selective), JWH015 and AM1241 (CB 2 -selective) in osteolysis-bearing females (MD 8.18, 95% CI 6.14, 10.21, p < 0.00001), and treatment with AM1241 (CB 2 -selective) increased paw withdrawal thermal latency in males (mean difference [MD]: 3.94, 95% CI 2.13, 5.75, p < 0.0001), confirming the analgesic capabilities of CB 1/2 ligands in rodents. In human, treatment of cancer patients with medical cannabis (standardized MD - 0.19, 95% CI - 0.35, - 0.02, p = 0.03) and the plant-derived delta-9-THC (20 mg) (MD 3.29, CI 2.24, 4.33, p < 0.00001) or its synthetic derivative NIB (4 mg) (MD 2.55, 95% CI 1.58, 3.51, p < 0.00001) are associated with reduction in pain intensity. Bioinformatics validation of KEGG, GO and MPO pathway, function and process enrichment analysis of mouse, rat and human data revealed that CB 1 and CB 2 receptors are enriched in a cocktail of nociceptive and sensory perception, inflammatory, immune-modulatory, and cancer pathways. Thus, we cautiously conclude that pharmacological modulators of CB 1/2 receptors show promise in the treatment of cancer-induced bone pain, however further assessment of their effects on bone pain in genetically engineered animal models and cancer patients is warranted., (© 2024. The Author(s).)

Parkinson's disease is a neurodegenerative disorder characterized by different motor, vegetative, behavioral, and cognitive impairments, with worsening quality of life. Virtual reality devices have given promising results in neurorehabilitation as they can provide multisensory stimulation in a realistic environment. This study aims to test the efficacy of virtual reality training by using Computer Assisted Rehabilitation Environment in cognitive impairment in a sample of PD. 31 patients affected by PD were enrolled. All PD patients underwent 24 sessions of Computer Assisted Rehabilitation Environment training. The participants were assessed at baseline (T0) and after two months (T1). Our results suggested that Computer Assisted Rehabilitation Environment training may be effective in the cognitive and emotional domains, particularly by improving executive function, anxiety, and depressive symptoms. These changes have helped to improve self-efficacy and coping strategies. These results indicate greater cognitive and physical effort to overcome stressors. Our results show that Computer Assisted Rehabilitation Environment training was beneficial in improving cognitive functions. Longer duration training may be especially beneficial for patients with mild cognitive impairment. Our findings open the door to tailored personalized treatments based on the patient's motor and cognitive profiles., (© 2023. The Author(s).)

Herein, authors present a retrospective, multi-center study to determine the number of accesses to Pediatric Emergency Unit (PEU) of patients within 28 days of life, admitted to (1) the Acute and Emergency Pediatric Unit, San Marco University Hospital, Catania, Italy; (2) Garibaldi Hospital for Emergency Care, Catania, Italy; (3) Cannizzaro Hospital for Emergency Care, Catania, Italy. We included neonates admitted for neurologic problems, from January 2015 to December 2020, to the 1-Acute and Emergency Access of the San Marco University Hospital, Catania, Italy [observation center 1 (OC1)]; 2-Garibaldi Hospital for Emergency Care, Catania, Italy (Observation Center 2-OC2); 3-Cannizzaro Hospital for Emergency Care, Catania, Italy (Observation Center 3-OC3). For each patient, we evaluated the severity of urgency, by studying the admission triage-coloured codes, the clinical data at admission and the discharge diagnosis. Neonates who had access to PEU were 812 in the OC1, 3720 in the OC2, and 748 in the OC3 respectively; 69 (8.4%), 138 (3.7%), and 55 (7.4%) was the proportion of neonatal accesses for neurological conditions. We observed that in the study period, the three hospitals had an important decrease of pediatric accesses to their PEU, but the proportion of neonates who had access to the OC1 for neurologic diseases, with respect to the total neonatal accesses, remained stable. We found that the most frequent neurologic disease for which newborns had access to PEU was Cyanosis, (46.1% of all neonatal accesses). Apnea was the second most frequent cause, with a number of 76 accesses (29%). In the literature there are numerous studies on the assessment of diseases that most frequently concern the pediatric patient in an emergency room, but there are very few references on neonatal accesses for urgent neurologic diseases. Therefore, appropriate training is required to avoid unnecessary tests without overlooking potentially serious conditions., (© 2022. The Author(s).)

Models of terrestrial planet formation predict that the final stages of planetary assembly-lasting tens of millions of years beyond the dispersal of young protoplanetary disks-are dominated by planetary collisions. It is through these giant impacts that planets like the young Earth grow to their final mass and achieve long-term stable orbital configurations 1 . A key prediction is that these impacts produce debris. So far, the most compelling observational evidence for post-impact debris comes from the planetary system around the nearby 23-million-year-old A-type star HD 172555. This system shows large amounts of fine dust with an unusually steep size distribution and atypical dust composition, previously attributed to either a hypervelocity impact 2,3 or a massive asteroid belt 4 . Here we report the spectrally resolved detection of a carbon monoxide gas ring co-orbiting with dusty debris around HD 172555 between about six and nine astronomical units-a region analogous to the outer terrestrial planet region of our Solar System. Taken together, the dust and carbon monoxide detections favour a giant impact between large, volatile-rich bodies. This suggests that planetary-scale collisions, analogous to the Moon-forming impact, can release large amounts of gas as well as debris, and that this gas is observable, providing a window into the composition of young planets., (© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)

Glioblastoma (GBM) is the most common and most aggressive intrinsic brain tumour in adults. Integrated transcriptomic and epigenomic analyses of glioblastoma initiating cells (GIC) in a mouse model uncovered a novel epigenetic regulation of EfnA5. In this model, Bmi1 enhances H3K27me3 at the EfnA5 locus and reinforces repression of selected target genes in a cellular context-dependent fashion. EfnA5 mediates Bmi1-dependent proliferation and invasion in vitro and tumour formation in an allograft model. Importantly, we show that this novel Polycomb feed-forward loop is also active in human GIC and we provide pre-clinical evidence of druggability of the EFNA5 signalling pathway in GBM xenografts overexpressing Bmi1.

Sonic Hedgehog (SHH) medulloblastomas are brain tumours that arise in the posterior fossa. Cancer-propagating cells (CPCs) provide a reservoir of cells capable of tumour regeneration and relapse post-treatment. Understanding and targeting the mechanisms by which CPCs are maintained and expanded in SHH medulloblastoma could present novel therapeutic opportunities. We identified the aryl hydrocarbon receptor (AHR) pathway as a potent tumour suppressor in a SHH medulloblastoma mouse model. Ahr-deficient tumours and CPCs grown in vitro, showed elevated activation of the TGFβ mediator, SMAD3. Pharmacological inhibition of the TGFβ/SMAD3 signalling axis was sufficient to inhibit the proliferation and promote the differentiation of Ahr-deficient CPCs. Human SHH medulloblastomas with high expression of the AHR repressor (AHRR) exhibited a significantly worse prognosis compared to AHRR low tumours in two independent patient cohorts. Together, these findings suggest that reduced AHR pathway activity promotes SHH medulloblastoma progression, consistent with a tumour suppressive role for AHR. We propose that TGFβ/SMAD3 inhibition may represent an actionable therapeutic approach for a subset of aggressive SHH medulloblastomas characterised by reduced AHR pathway activity.

In order to limit the smoking tobacco sector crisis, a new non-GMO Nicotiana tabacum L. cv. Solaris was proposed as oil seed crop. Residues of oil extraction were successfully used in swine nutrition. The aim of this study was to explore the full potential of this innovative tobacco cultivar as multitasking feedstock non interfering with the food chain. In the triennium 2016-2018, samples from whole plant, inflorescence and stem-leaf biomass were collected in three experimental sites and analysed for chemical constituents, including fibre fractions, sugars and starch, macro-minerals and total alkaloids. The KOH soluble protein content and the amino-acid profile were also investigated as well as the biochemical methane potential. All the analyses were performed according to official methods and results were compared with values reported in literature for conventional lignocellulosic crops and agro-industry residues. The average protein content, ranging from 16.01 to 18.98 g 100 g -1 dry matter respectively for stem-leaf and whole plant samples, and their amino-acid profile are consistent with values reported for standard grass plant. These findings suggest the potential use of cv. Solaris in industrial food formulations. Moreover, considering the average content of both fibre available for fermentations (72.6% of Neutral Detergent Fibre) and oils and fats (7.92 g 100 g -1 dry matter), the whole plant biomass of cv. Solaris showed good attitude to anaerobic fermentation, confirmed by the biochemical methane potential of whole plant (168 Nm 3 t -1 organic matter). Similarly, results allow to define the cv. Solaris biomass as a good quality forage apt to ensiling for its chemical composition. The low total alkaloids content of cv. Solaris, in average 0.3 g 100 g -1 dry matter, was previously reported not to affect growth performances and welfare traits of dairy heifers. These are the first results showing the multitasking potential use of cv. Solaris biomass, that could allow the recovery of tobacco cultivation know-how especially in marginal areas.

The UK Biobank is a rich national health resource that provides enormous opportunities for international researchers to examine, model, and analyze census-like multisource healthcare data. The archive presents several challenges related to aggregation and harmonization of complex data elements, feature heterogeneity and salience, and health analytics. Using 7,614 imaging, clinical, and phenotypic features of 9,914 subjects we performed deep computed phenotyping using unsupervised clustering and derived two distinct sub-cohorts. Using parametric and nonparametric tests, we determined the top 20 most salient features contributing to the cluster separation. Our approach generated decision rules to predict the presence and progression of depression or other mental illnesses by jointly representing and modeling the significant clinical and demographic variables along with the derived salient neuroimaging features. We reported consistency and reliability measures of the derived computed phenotypes and the top salient imaging biomarkers that contributed to the unsupervised clustering. This clinical decision support system identified and utilized holistically the most critical biomarkers for predicting mental health, e.g., depression. External validation of this technique on different populations may lead to reducing healthcare expenses and improving the processes of diagnosis, forecasting, and tracking of normal and pathological aging.

Semaphorin 3A (Sema3A), a secreted member of the Semaphorin family, increases osteoblast differentiation, stimulates bone formation and enhances fracture healing. Here, we report a previously unknown role of Sema3A in the regulation of ectopic bone formation and osteolysis related to osteosarcoma. Human recombinant (exogenous) Sema3A promoted the expression of osteoblastic phenotype in a panel of human osteosarcoma cell lines and inhibited the ability of these cells to migrate and enhance osteoclastogenesis in vitro. In vivo, administration of exogenous Sema3A in mice after paratibial inoculation of KHOS cells increased bone volume in non-inoculated and tumour-bearing legs. In contrast, Sema3A overexpression reduced the ability of KHOS cells to cause ectopic bone formation in mice and to increase bone nodule formation by engaging DKK1/β-catenin signalling. Thus, Sema3A is of potential therapeutic efficacy in osteosarcoma. However, inhibition of bone formation associated with continuous exposure to Sema3A may limit its long-term usefulness as therapeutic agent.

NFκB plays an important role in inflammation and bone remodelling. Tumour necrosis factor receptor associated factor 2 (TRAF2), a key component of NFκB signalling, has been identified as an oncogene, but its role in the regulation of breast cancer osteolytic metastasis remains unknown. Here, we report that stable overexpression of TRAF2 in parental and osteotropic sub-clones of human MDA-MB-231 (MDA-231) breast cancer cells increased cell growth and motility in vitro, whereas TRAF2 knockdown was inhibitory. In vivo, TRAF2 overexpression in the parental MDA-231-P cells enhanced tumour growth after orthotopic injection into the mammary fat pad of mice but failed to promote the metastasis of these cells to bone. In contrast, overexpression of TRAF2 in osteotropic MDA-231-BT cells increased skeletal tumour growth, enhanced osteoclast formation and worsened osteolytic bone loss after intra-tibial injection in mice. Mechanistic and functional studies in osteotropic MDA-231-BT and osteoclasts revealed that upregulation of TRAF2 increased the ability of osteotropic MDA-231-BT cells to migrate and to enhance osteoclastogenesis by a mechanism dependent, at least in part, on NFκB activation. Thus, the TRAF2/NFκB axis is implicated in the regulation of skeletal tumour burden and osteolysis associated with advanced breast cancer.

Ex vivo explant culture models are powerful tools in bone research. They allow investigation of bone and cartilage responses to specific stimuli in a controlled manner that closely mimics the in vivo processes. Because of limitations in obtaining healthy human bone samples the explant growth of animal tissue serves as a platform to study the complex physico-chemical properties of the bone. Moreover, these models enable preserving important cell-cell and cell-matrix interactions in order to better understand the behaviour of cells in their natural three-dimensional environment. Thus, the use of bone ex vivo explant cultures can frequently be of more physiological relevance than the use of two-dimensional primary cells grown in vitro. Here, we describe isolation and ex vivo growth of different animal bone explant models including metatarsals, femoral heads, calvaria, mandibular slices and trabecular cores. We also describe how these explants are utilised to study bone development, cartilage and bone metabolism, cancer-induced bone diseases, stem cell-driven bone repair and mechanoadaptation. These techniques can be directly used to understand mechanisms linked with bone physiology or bone-associated diseases.

Osteoclasts are highly specialized cells of haematopoietic lineage that are uniquely responsible for bone resorption. In the past, osteoclasts were isolated as mature cells from chicken long bones, or were generated using osteoblasts or stromal cells to induce osteoclast formation in total bone marrow from mice or rabbits. The Copernican revolution in osteoclast biology began with the identification of macrophage-colony stimulating factor (M-CSF) and receptor activator NFκB-ligand (RANKL ) as the key regulators of osteoclast formation, fusion and function. The availability of recombinant human and mouse M-CSF and RANKL has enabled researchers to reliably generate osteoclasts from primary monocyte/macrophage cells as well as from cell lines such as RAW 264.7. This article summarizes the most commonly used procedures for the isolation, generation and characterization of human, rodent and chicken osteoclasts in vitro. Lists of further reading and recommendations are included to facilitate a successful application by the reader.

Cells with stem cell properties have been isolated from various areas of the postnatal mammalian brain, most recently from the postnatal mouse cerebellum. We show here that inactivation of the tumor suppressor genes Rb and p53 in these endogenous neural stem cells induced deregulated proliferation and resistance to apoptosis in vitro. Moreover, injection of these cells into mice formed medulloblastomas. Medulloblastomas are the most common malignant brain tumors of childhood, and despite recent advances in treatment they are associated with high morbidity and mortality. They are highly heterogeneous tumors characterized by a diverse genetic make-up and expression profile as well as variable prognosis. Here, we describe a novel ontogenetic pathway of medulloblastoma that significantly contributes to understanding their heterogeneity. Experimental medulloblastomas originating from neural stem cells preferentially expressed stem cell markers Nestin, Sox2 and Sox9, which were not expressed in medulloblastomas originating from granule-cell-restricted progenitors. Furthermore, the expression of these markers identified a subset of human medulloblastomas associated with a poorer clinical outcome.

Overexpression of the polycomb group gene Bmi1 promotes cell proliferation and induces leukaemia through repression of Cdkn2a (also known as ink4a/Arf) tumour suppressors. Conversely, loss of Bmi1 leads to haematological defects and severe progressive neurological abnormalities in which de-repression of the ink4a/Arf locus is critically implicated. Here, we show that Bmi1 is strongly expressed in proliferating cerebellar precursor cells in mice and humans. Using Bmi1-null mice we demonstrate a crucial role for Bmi1 in clonal expansion of granule cell precursors both in vivo and in vitro. Deregulated proliferation of these progenitor cells, by activation of the sonic hedgehog (Shh) pathway, leads to medulloblastoma development. We also demonstrate linked overexpression of BMI1 and patched (PTCH), suggestive of SHH pathway activation, in a substantial fraction of primary human medulloblastomas. Together with the rapid induction of Bmi1 expression on addition of Shh or on overexpression of the Shh target Gli1 in cerebellar granule cell cultures, these findings implicate BMI1 overexpression as an alternative or additive mechanism in the pathogenesis of medulloblastomas, and highlight a role for Bmi1-containing polycomb complexes in proliferation of cerebellar precursor cells.

p300 and CBP are large nuclear acetyltransferases exhibiting a complex multi-domain structure. Mouse embryos nullizygous for either p300 or Cbp die at midgestation, while heterozygotes are viable but in part display defects in neurulation or bone morphogenesis. To directly examine the contribution of the acetyltransferase (AT) activity to mouse development, we have abrogated this function by a knock-in approach. Remarkably, a single AT-deficient allele of p300 or Cbp leads to embryonic or neonatal lethality, indicating that the mutant alleles are dominant. Formation of the cardiovascular system, the lung and the small intestine are strongly impaired in p300 AT and to a much lesser extent in Cbp AT mutant embryos, a difference that is also reflected by the defects in gene expression. Embryonic stem cells homozygous for either the p300 AT or a p300 null mutation respond differently to BMP2 stimulation, indicating that the two alleles are not equivalent. Unexpectedly, the p300 AT-mutant cells upregulate BMP-inducible genes to levels similar or even higher than observed in wild-type cells.

The Mouse Models of Cancer Consortium of the NCI sponsored a meeting of neuropathologists and veterinary pathologists in New York City in November of 2000. A rapidly growing number of genetically engineered mice (GEM) predisposed to tumors of the nervous system have led to a concomitant need for neuropathological evaluation and validation of these models. A panel of 13 pathologists reviewed material representing most of the available published and unpublished GEM models of medulloblastoma, primitive neuroectodermal tumor, astrocytoma, oligodendroglioma, mixed glioma, and tumors of the peripheral nerve. The GEM tumors were found to have many similarities and some distinct differences with respect to human disease. After review of the biology and pathology for all models presented, participants were split into groups reflective of clinical expertise in human pathology, tumor biology, neuroimaging, or treatment/intervention. Recommendations were made detailing an extensive and complete neuropathological characterization of animals. Importance was placed on including information on strains, tumor clonality, and examination for genetic mutation or altered gene expression characteristics of the corresponding human malignancy. Specific proposals were made to incorporate GEM models in emerging neuroradiological modalities. Recommendations were also made for preclinical validation of these models in cancer therapeutics, and for incorporation of surrogate markers of tumor burden to facilitate preclinical evaluation of new therapies.

The bmi-1 gene was first isolated as an oncogene that cooperates with c-myc in the generation of mouse lymphomas. We subsequently identified Bmi-1 as a transcriptional repressor belonging to the mouse Polycomb group. The Polycomb group comprises an important, conserved set of proteins that are required to maintain stable repression of specific target genes, such as homeobox-cluster genes, during development. In mice, the absence of bmi-1 expression results in neurological defects and severe proliferative defects in lymphoid cells, whereas bmi-1 overexpression induces lymphomas. Here we show that bmi-1-deficient primary mouse embryonic fibroblasts are impaired in progression into the S phase of the cell cycle and undergo premature senescence. In these fibroblasts and in bmi-1-deficient lymphocytes, the expression of the tumour suppressors p16 and p19Arf, which are encoded by ink4a, is raised markedly. Conversely, overexpression of bmi-1 allows fibroblast immortalization, downregulates expression of p16 and p19Arf and, in combination with H-ras, leads to neoplastic transformation. Removal of ink4a dramatically reduces the lymphoid and neurological defects seen in bmi-1-deficient mice, indicating that ink4a is a critical in vivo target for Bmi-1. Our results connect transcriptional repression by Polycomb-group proteins with cell-cycle control and senescence.

Accumulation of the prion protein PrPSc, a pathological and protease-resistant isoform of the normal host protein PrPC, is a feature of prion disease such as scrapie. It is still unknown whether scrapie pathology comes about by neurotoxicity of PrPSc, acute depletion of PrPC, or some other mechanism. Here we investigate this question by grafting neural tissue overexpressing PrPC into the brain of PrP-deficient mice which are scrapie-resistant and do not propagate infectivity. After intracerebral inoculation with scrapie prions, the grafts accumulated high levels of PrPSc and infectivity and developed the severe histopathological changes characteristic of scrapie. Moreover, substantial amounts of graft-derived PrPSc migrated into the host brain. Even 16 months after inoculation no pathological changes were seen in PrP-deficient tissue, not even in the immediate vicinity of the grafts. Therefore, in addition to being resistant to scrapie infection, brain tissue devoid of PrPC is not damaged by exogenous PrPSc.

Nine Sicilian children known to be deficient in glucose-6-phosphate dehyrdrogenase (G6PD) were studied to see if there were anomalies of bactericidal activity in peripheral blood phagocytes. The type of deficiency was established. The G6PD levels in the leukocyte were found to be 26% of the controls (0.094 +/- 0.03, normal controls 0.360 +/- 0.12). The Michaelis constant for NADP and glucose-6-phosphate (G6P) was lower than the control. Conversely, the utilization of the analogous 2-deoxyglucose-6-phosphate (2dG6P) and galactose-6-phosphate (Ga16P) was higher. The thermostability of the enzyme in the deficient subjects was lower and the pH optima (8 and 9.5) were different from the controls. An identical electrophoretic pattern was found in both normal and deficient subjects. The bactericidal activity in the deficient subjects was normal. There was no difference in the results of nitroblue tetrazolium (NBT) tests in either group.