The impact of stem cells in neuro-oncology: applications, evidence, limitations and challenges

Background: Stem cells (SCs) represent a recent and attractive therapeutic option for neuro-oncology, as well as for treating degenerative, ischemic and traumatic pathologies of the central nervous system. This is mainly because of their homing capacity, which makes them capable of reaching the inaccessible SC niches of the tumor, therefore, acting as living drugs. The target of the study is a comprehensive overview of the SC-based therapies in neuro-oncology, also highlighting the current translational challenges of this type of approach. Methods: An online search of the literature was carried out on the PubMed/MEDLINE and ClinicalTrials.gov websites, restricting it to the most pertinent keywords regarding the systematization of the SCs and their therapeutic use for malignant brain tumors. A large part of the search was dedicated to clinical trials. Only preclinical and clinical data belonging to the last 5 years were shortlisted. A further sorting was implemented based on the best match and relevance. Results: The results consisted in 96 relevant articles and 31 trials. Systematization involves a distinction between human embryonic, fetal and adult, but also totipo-tent, pluripotent or multipotent SCs. Mesenchymal and neuronal SCs were the most studied for neuro-oncological illnesses. 30% and 50% of the trials were phase I and II, respectively. Conclusion: Mesenchymal and neuronal SCs are ideal candidates for SCs-based therapy of malignant brain tumors. The spectrum of their possible applications is vast and is mainly based on the homing capacity toward the tumor microenvironment. Availability, delivery route, oncogenicity and ethical issues are the main translational challenges concerning the use of SCs in neuro-oncology. (www.actabiomedica.it)

Advanced pharmacological therapies for neurofibromatosis type 1-related tumors

Neurofibromatosis Type 1 (NF1) is an autosomal dominant tumor-predisposition disorder that is caused by a heterozygous loss of function variant in the NF1 gene, which encodes a protein called neurofi-bromin. The absence of neurofibromin causes increased activity in the Rat sarcoma protein (RAS) signalling pathway, which results in an increased growth and cell proliferation. As a result, both oncological and non-oncological comorbidities contribute to a high morbidity and mortality in these patients. Optic pathways gliomas, plexiform neurofibromas and malignant peripheral nerve sheath tumor (MPNST) are the most fre-quent NF1-associated tumors. The treatment of these complications is often challenging, since surgery may not be feasible due to the location, size, and infiltrative nature of these tumors, and standard chemotherapy or radiotherapy are burdened by significant toxicity and risk for secondary malignancies. For these reasons, following the novel discoveries of the pathophysiological mechanisms that lead to cell proliferation and tumori-genesis in NF1 patients, emerging drugs targeting specific signalling pathways (i.e. the MEK/ERK cascade), have been developed with promising results. (www.actabiomedica.it)

Innovative therapies for malignant brain tumors: the road to a tailored cure

Background: Immune tolerance, immune escape, neoangiogenesis, phenotypic changes, and glioma stem cells are all responsible for the resistance of malignant brain tumors to current therapies and persistent recurrence. The present study provides a panoramic view of innovative therapies for malignant brain tumors, especially glioblastoma, aimed at achieving a tailored approach. Methods: PubMed/Medline and ClinicalTri-als.gov were the main sources of an extensive literature review in which “Regenerative Medicine,” “Cell-Based Therapy,” “Chemotherapy,” “Vaccine,” “Cell Engineering,” “Immunotherapy, Active,” “Immunotherapy, Adoptive,” “Stem Cells,” “Gene Therapy,” “Target Therapy,” “Brain Cancer,” “Glioblastoma,” and “Malignant Brain Tumor” were the search terms. Only articles in English published in the last 5 years were included. A further selection was made according to the quality of the studies and level of evidence. Results: Cell-based and targeted therapies represent the newest frontiers of brain cancer treatment. Active and adoptive im-munotherapies, stem cell therapies, and gene therapies represent a tremendous evolution in recent years due to many preclinical and clinical studies. Clinical trials have validated the effectiveness of antibody-based immunotherapies, including an in-depth study of bevacizumab, in combination with standard of care. Pre-clinical data highlights the role of vaccines, stem cells, and gene therapies to prevent recurrence. Conclusion: Monoclonal antibodies strengthen the first-line therapy for high grade gliomas. Vaccines, engineered cells, stem cells, and gene and targeted therapies are good candidates for second-line treatment of both newly diagnosed and recurrent gliomas. Further data are necessary to validate this tailored approach at the bedside. (www.actabiomedica.it)

Photometry of comet 9P/Tempel 1 during the 2004/2005 approach and the Deep Impact module impact

The results of the 9P/Tempel 1 CARA (Cometary Archive for Amateur Astronomers) observing campaign is presented. The main goal was to perform an extended survey of the comet as a support to the Deep Impact (DI) Mission. CCD R, I and narrowband aperture photometries were used to monitor the $Af\rho$ quantity. The observed behaviour showed a peak of 310 cm 83 days before perihelion, but we argue that it could be distorted by the phase effect, too. The phase effect is roughly estimated around 0.0275 mag/degree, but we had no chance for direct determination because of the very similar geometry of the observed apparitions. The log-slope of $Af\rho$ was around -0.5 between about 180--100 days before the impact but evolved near the steady-state like 0 value by the impact time. The DI module impact caused an about 60%{} increase in the value of $Af\rho$ and a cloud feature in the coma profile which was observed just after the event. The expansion of the ejecta cloud was consistent with a fountain model with initial projected velocity of 0.2 km/s and $\beta$=0.73. Referring to a 25~000 km radius area centered on the nucleus, the total cross section of the ejected dust was 8.2/$A$ km$^2$ 0.06 days after the impact, and 1.2/$A$ km$^2$ 1.93 days after the impact ($A$ is the dust albedo). 5 days after the event no signs of the impact were detected nor deviations from the expected activity referring both to the average pre-impact behaviour and to the previous apparitions ones.Comment: 25 pages (including cover pages), 9 figures, 1 table, accepted by Icarus DI Special Issu

Dust Environment Model of the Interstellar Comet 2I/Borisov

2I/Borisov is the first interstellar comet discovered on 2019 August 30, and it soon showed a coma and a dust tail. This study reports the results of images obtained at the Telescopio Nazionale Galileo telescope, on La Palma - Canary Islands, in 2019 November and December. The images have been obtained with the R filter in order to apply our dust tail model. The model has been applied to the comet 67P/Churyumov-Gerasimenko and compared to the Rosetta dust measurements showing a very good agreement. It has been applied to the comet 2I/Borisov, using almost the same parameters, obtaining a dust environment similar to that of 67P/Churyumov-Gerasimenko, suggesting that the activity may be very similar. The dust tail analysis provided a dust-loss rate Qd ≍ 35 kg s-1 in 2019 November and Qd ≍ 30 kg s-1 in 2019 December

Enhancing the Trajectory Tracking Performance Capabilities of Position-Controlled Manipulators

This paper addresses the problem of enhancing the performance capabilities of position-controlled robot manipulators. The proposed strategy aims at adaptively generating the position set-points for the standard position controller of the robot, so that the desired behavior is obtained even in the presence of system uncertainty. This algorithm is computationally simple, does not require knowledge of both manipulator payload model parameters and dynamics, and is implemented in decentralized form. It can be shown that this control strategy is globally stable and that the ultimate size of the controller errors can be made arbitrarily small. The performance of the proposed control scheme is illustrated through actual hardware experiments with a COMAU Smart S2 anthropomorphic manipulator. The results show that the additional controller provides a way to enhance the performance of a standard PID regulator often in use for industrial robot manipulators, while still keeping it in operatio

Paediatric clinically isolated syndromes: report of seven cases, differential diagnosis and literature review

Purpose: Few paediatric cases of clinically isolated syndrome (CIS) have been described in literature, even though it has been increasingly recognized also in this age group. Our study retrospectively enrolled seven Italian patients (four males and three females) who met the International Paediatric Multiple Sclerosis Study Group (IPMSSG) 2012 criteria for clinically isolated syndrome over the period 2010–2014; their clinical, laboratory and imaging findings were compared with current literature and with those seen in five patients (three males and two females) with acute disseminated encephalomyelitis, who were followed in our department over the same years (mean follow-up time 2.84 ± 1.8 years). Results: In our CIS sample, male sex was prevalent, 42.8 % of patients had a multifocal presentation, MRI lesions mostly appeared confluent and with poorly defined margins, and CSF oligoclonal bands (OCBs) were identified in 28.6 %. All acute disseminated encephalomyelitis (ADEM) patients had polyfocal presentation and encephalopathy; large MRI subcortical lesions and polyclonal IgG distribution were identified. During the subsequent follow-up assessments, MRI scan revealed new lesions in three CIS patients, while in ADEM children it appeared normal. Conclusions: Paediatric CIS patients often show peculiar epidemiological, clinical and radiological features, which significantly differ from adult ones. The presence of encephalopathy and of extended MRI lesions leads to a diagnosis of ADEM, instead. In CIS patients the presence of multiple asymptomatic MRI lesions and of OCBs revealed to be the most predictive risk factors for progression to clinically definite multiple sclerosis (CDMS), so a regular long-term follow-up is recommended; in ADEM, no suitable risk factors for a relapse could be identified