Brain regenerative strategies through the transplantation of stem cells hold the potential to promote functional rescue of brain lesions caused either by trauma or neurodegenerative diseases. Most of the positive modulations fostered by stem cells are fueled by bystander effects, namely increase of neurotrophic factors levels and reduction of neuroinflammation. Nevertheless, the ultimate goal of cell therapies is to promote cell replacement. Therefore, the ability of stem cells to migrate and differentiate into neurons that later become integrated into the host neuronal network replacing the lost neurons has also been largely explored. However, as most of the preclinical studies demonstrate, there is a small functional integration of graft-derived neurons into host neuronal circuits. Thus, it is mandatory to better study the whole brain cell therapy approach in order to understand what should be better comprehended concerning graft-derived neuronal and glial cells migration and integration before we can expect these therapies to be ready as a viable solution for brain disorder treatment. Therefore, this review discusses the positive mechanisms triggered by cell transplantation into the brain, the limitations of adult brain plasticity that might interfere with the neuroregeneration process, as well as some strategies tested to overcome some of these limitations. It also considers the efforts that have been made by the regulatory authorities to lead to better standardization of preclinical and clinical studies in this field in order to reduce the heterogeneity of the obtained results.

Machado–Joseph disease or spinocerebellar ataxia type 3 is an inherited neurodegenerative disease associated with an abnormal glutamine over-repetition within the ataxin-3 protein. This mutant ataxin-3 protein affects several cellular pathways, leading to neuroinflammation and neuronal death in specific brain regions resulting in severe clinical manifestations. Presently, there is no therapy able to modify the disease progression. Nevertheless, anti-inflammatory pharmacological intervention has been associated with positive outcomes in other neurodegenerative diseases. Thus, the present work aimed at investigating whether ibuprofen treatment would alleviate Machado–Joseph disease. We found that ibuprofen-treated mouse models presented a significant reduction in the neuroinflammation markers, namely Il1b and TNFa mRNA and IKB-α protein phosphorylation levels. Moreover, these mice exhibited neuronal preservation, cerebellar atrophy reduction, smaller mutant ataxin-3 inclusions and motor performance improvement. Additionally, neural cultures of Machado–Joseph disease patients’ induced pluripotent stem cells-derived neural stem cells incubated with ibuprofen showed increased levels of neural progenitors proliferation and synaptic markers such as MSI1, NOTCH1 and SYP. These findings were further confirmed in ibuprofen-treated mice that display increased neural progenitor numbers (Ki67 positive) in the subventricular zone. Furthermore, interestingly, ibuprofen treatment enhanced neurite total length and synaptic function of human neurons. Therefore, our results indicate that ibuprofen reduces neuroinflammation and induces neuroprotection, alleviating Machado–Joseph disease-associated neuropathology and motor impairments. Thus, our findings demonstrate that ibuprofen treatment has the potential to be used as a neuroprotective therapeutic approach in Machado–Joseph disease.

Management of incidentally diagnosed small testicular masses (STM) is controversial. Although there is the risk of malignancy, it might be realistic to safely seek preservation of testicles bearing benign masses. This study aims to systematically evaluate the evidence regarding prevalence of STMs, their benign or malignant histology and their management. We conducted a systematic literature search for studies reporting small or incidental testicular masses and their management by radical orchiectomy, testis sparing surgery (TSS) or ultrasound (US) surveillance. We initially screened 2126 abstracts and from these, 57 studies met the inclusion criteria. Testicular masses were detected in 1.74% of patients undergoing US examination. Regarding STMs removed by surgery, 41.12% were benign. Intraoperative frozen section examination (FSE) is a reliable tool to discriminate between benign and malignant testicular masses (average 93.05% accuracy), supporting TSS. Benign lesions were associated with smaller diameter (<1 cm 68.78% benign), were often hypoechoic and exhibited regular margins on US. Conclusions: Small testicular masses are often benign. Clinical and US patterns are not accurate enough for including patients in surveillance protocols and TSS paired with FSE is pivotal for precluding the removal of testicles bearing benign lesions. Future research might unveil new imaging tools or biomarkers to support clinical management.

The establishment of robust human brain organoids to model cerebellar diseases is essential to study new therapeutic strategies for cerebellum-associated disorders. Machado-Joseph disease (MJD) is a cerebellar hereditary neurodegenerative disease, without therapeutic options able to prevent the disease progression. In the present work, control and MJD induced-pluripotent stem cells were used to establish human brain organoids. These organoids were characterized regarding brain development, cell type composition, and MJD-associated neuropathology markers, to evaluate their value for cerebellar diseases modeling. Our data indicate that the organoids recapitulated, to some extent, aspects of brain development, such as astroglia emerging after neurons and the presence of ventricular-like zones surrounded by glia and neurons that are found only in primate brains. Moreover, the brain organoids presented markers of neural progenitors proliferation, neuronal differentiation, inhibitory and excitatory synapses, and firing neurons. The established brain organoids also exhibited markers of cerebellar neurons progenitors and mature cerebellar neurons. Finally, MJD brain organoids showed higher ventricular-like zone numbers, an indication of lower maturation, and an increased number of ataxin-3-positive aggregates, compared with control organoids. Altogether, our data indicate that the established organoids recapitulate important characteristics of human brain development and exhibit cerebellar features, constituting a resourceful tool for testing therapeutic approaches for cerebellar diseases.