The Cellular Dysfunction of the Brain-Blood Barrier from Endothelial Cells to Astrocytes: The Pathway towards Neurotransmitter Impairment in Schizophrenia.

Schizophrenia (SCZ) is an articulated psychiatric syndrome characterized by a combination of genetic, epigenetic, and environmental factors. Our intention is to present a pathogenetic model combining SCZ alterations and the main cellular actors of the blood-brain barrier (BBB): endothelial cells (ECs), pericytes, and astrocytes. The homeostasis of the BBB is preserved by the neurovascular unit which is constituted by ECs, astrocytes and microglia, neurons, and the extracellular matrix. The role of the BBB is strictly linked to its ability to preserve the biochemical integrity of brain parenchyma integrity. In SCZ, there is an increased BBB permeability, demonstrated by elevated levels of albumin and immunoglobulins in the cerebrospinal fluid, and this is the result of an intrinsic endothelial impairment. Increased BBB permeability would lead to enhanced concentrations of neurotoxic and neuroactive molecules in the brain. The pathogenetic involvement of astrocytes in SCZ reverberates its consequences on BBB, together with the impact on its permeability and selectivity represented by the EC and pericyte damage occurring in the psychotic picture. Understanding the strict interaction between ECs and astrocytes, and its consequent impact on cognition, is diriment not only for comprehension of neurotransmitter dyshomeostasis in SCZ, but also for focusing on other potential therapeutic targets.

The Cerebellum's Role in Affective Disorders: The Onset of Its Social Dimension.

Major Depressive Disorder (MDD) and Bipolar Disorder (BD) are the most frequent mental disorders whose indeterminate etiopathogenesis spurs to explore new aetiologic scenarios. In light of the neuropsychiatric symptoms characterizing Cerebellar Cognitive Affective Syndrome (CCAS), the objective of this narrative review is to analyze the involvement of the cerebellum (Cbm) in the onset of these conditions. It aims at detecting the repercussions of the Cbm activities on mood disorders based on its functional subdivision in vestibulocerebellum (vCbm), pontocerebellum (pCbm) and spinocerebellum (sCbm). Despite the Cbm having been, for decades, associated with somato-motor functions, the described intercellular pathways, without forgiving the molecular impairment and the alteration in the volumetric relationships, make the Cbm a new important therapeutic target for MDD and BD. Given that numerous studies have showed its activation during mnestic activities and socio-emotional events, this review highlights in the Cbm, in which the altered external space perception (vCbm) is strictly linked to the cognitive-limbic Cbm (pCbm and sCbm), a crucial role in the MDD and BD pathogenesis. Finally, by the analysis of the cerebellar activity, this study aims at underlying not only the Cbm involvement in affective disorders, but also its role in social relationship building.

Tumor Progression from a Fibroblast Activation Protein Perspective: Novel Diagnostic and Therapeutic Scenarios for Colorectal Cancer.

In 2020, the Global Cancer Observatory estimated the incidence of colorectal cancer (CRC) at around 10.7% coupled with a mortality rate of 9.5%. The explanation for these values lies in the tumor microenvironment consisting of the extracellular matrix and cancer-associated fibroblasts (CAFs). Fibroblast activation protein (FAP) offers a promising target for cancer therapy since its functions contribute to tumor progression. Immunohistochemistry examination of FAP, fibronectin ED-B, and CXCR4 in primary tumors and their respective synchronous and/or metachronous metastases along with semiquantitative analysis have been carried out on histological samples of 50 patients diagnosed with metastatic CRC. The intensity of FAP, articulated by both "Intensity %" and "Intensity score", is lower in the first metastasis compared to the primary tumor with a statistically significant correlation. No significant correlations have been observed regarding fibronectin ED-B and CXCR4. Tumors that produce FAP have an ambivalent relationship with this protein. At first, they exploit FAP, but later they reduce its expressiveness. Although our study has not directly included FAP-Inhibitor (FAPI) PET/CT, the considerable expression of FAP reveals its potential as a diagnostic and therapeutic tool worthy of further investigation. This dynamic relationship between cancer and FAP has substantial diagnostic and therapeutic implications.

Astrocytes as Neuroimmunocytes in Alzheimer's Disease: A Biochemical Tool in the Neuron-Glia Crosstalk along the Pathogenetic Pathways.

This work aimed at assessing Alzheimer's disease (AD) pathogenesis through the investigation of the astrocytic role to transduce the load of amyloid-beta (Aß) into neuronal death. The backbone of this review is focused on the deepening of the molecular pathways eliciting the activation of astrocytes crucial phenomena in the understanding of AD as an autoimmune pathology. The complex relations among astrocytes, Aß and tau, together with the role played by the tripartite synapsis are discussed. A review of studies published from 1979 to 2023 on Scopus, PubMed and Google Scholar databases was conducted. The selected papers focused not only on the morphological and metabolic characteristics of astrocytes, but also on the latest notions about their multifunctional involvement in AD pathogenesis. Astrocytes participate in crucial pathways, including pruning and sprouting, by which the AD neurodegeneration evolves from an aggregopathy to neuroinflammation, loss of synapses and neuronal death. A1 astrocytes stimulate the production of pro-inflammatory molecules which have been correlated with the progression of AD cognitive impairment. Further research is needed to "hold back" the A1 polarization and, thus, to slow the worsening of the disease. AD clinical expression is the result of dysfunctional neuronal interactions, but this is only the end of a process involving a plurality of protagonists. One of these is the astrocyte, whose importance this work intends to put under the spotlight in the AD scenario, reflecting the multifaceted nature of this disease in the functional versatility of this glial population.

Are Renal Cell Carcinoma with Fibromyomatous Stroma (RCC-FMS) and Thyroid-like Follicular Carcinoma of the Kidney (TLFCK) Really Independent Variants?

BACKGROUND: Renal cell carcinoma with fibromyomatous stroma (RCC-FMS) is a recent provisional entity already recognised in the 2016 WHO Classification of Cancer of the Urinary Tract and Male Genital Organs 4th Edition as renal cell carcinoma with (angio)leiomyomatous stroma, histologically defined as a tumour characterised by clear cells intertwined in a conspicuous vascular stroma. In the casuistry taken into consideration, another proposed variant, thyroid-like follicular carcinoma of the kidney (TLFCK), endowed with a morphology mimicking thyroid parenchyma, was examined. The aim of this work was to parse the theoretical system, experimental data and diagnostic impact of these new entities proposed in the field of renal neoplasms. MATERIALS AND METHODS: An analysis of 120 cases of kidney tumours from the Department of Surgical, Medical, Molecular and Critical Area at the University of Pisa was run. Subsequently, all samples were reassessed by two pathologists with expertise in uropathology, whose revaluation provided a histomorphological study combined with subsequent and coherent immunohistochemical analyses of CK7, CD10, CAIX, CK34betaE12, CD117, vimentin, TTF-1 and thyroglobulin. These analyses were performed using the Ventana Benchmark Automated Staining System (Ventana Medical Systems, Tucson, AZ, USA) and Ventana reagents. RESULTS: On the one hand, the data, thus brought to light, did not show an immunohistochemical profile consistent with that proposed for RCC-FMS. However, it should be emphasised that the morphological background also unearthed a poor specificity for RCC-FMS. This was specifically due to a stromal component which was, in any case, evident, although characterised by a wide range of presentation, in clear cell renal cell carcinoma (ccRCC). This latter is, indeed, the reference background for this theorised variant. On the other hand, a thyroid-like pattern was highlighted in 11 cases, more specifically in 10 ccRCCs and in one oncocytoma, presenting itself as a type of neoplastic appearance rather than as the peculiar morphological pattern of a standalone cancer. CONCLUSIONS: In the light of these results, RCC-FMS and TLFCK appear to be more appropriately variants of already categorised neoplastic entities rather than new independent neoplasias.