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Our goal was to investigate the potential use and efficacy of regorafenib for IPEC in an animal model of colorectal derived peritoneal metastases. Twenty four male rats were included. Carcinogenesis was induced in all rats through intraperitoneal injection of cancer.Cells at T0. At T1(Day 28) they were randomly allocated 1:1:1:1 into 4 groups and underwent median laparotomy and the corresponding intervention. Specifically, Group A: no other intervention; Group B: cytoreductive surgery; Group C: intraperitoneal chemotherapy with regorafenib; and Group D: cytoreductive surgery and intraperitoneal chemotherapy with regorafenib. At T2 (Day 56) rats were euthanized and laparotomy was performed for further investigation. The primary outcome was the experimental Peritoneal Cancer Index (ePCI) at T2. Secondary outcomes include relative change of body weight between T1 and T2, weight of the ascites, anastomotic leak/peritonitis and death.The ePCI was significantly lower in Group D as opposed to all other groups. Comparing Group C versus Group A we found a trend towards lesser tumor progression, but no significant difference. Growth of rats in Group D was significantly least affected compared to all other groups. Animals undergoing CRS in Group B developed less ascites than Group A and C. Less ascites was found in Group D compared to Group A and C.Intraperitoneal chemotherapy with regorafenib combined with cytoreductive surgery may impair metastases' progression.Regorafenib, Chemotherapy, Cytoreductive surgery, Colorectal cancer, Intraperitoneal injection.In questo studio, ci proponiamo di indagare l’uso potenziale e l’efficacia di regorafenib per IPEC in un modello animale di metastasi peritoneali derivate dal colon-retto.Sono stati utilizzati 24 ratti maschi. La cancerogenesi è stata indotta in tutti i ratti mediante l’iniezione intraperitoneale di cellule tumorali a T0. Al T1 (giorno 28) sono stati assegnati in modo casuale 1:1:1:1 in 4 gruppi e sono stati sottoposti a laparotomia mediana e all’intervento corrispondente. Nello specifico, Gruppo A: nessun altro intervento; Gruppo B: chirurgia citoriduttiva; Gruppo C: chemioterapia intraperitoneale con regorafenib (BAY 73-4506); e Gruppo D: chirurgia citoriduttiva e chemioterapia intraperitoneale con regorafenib. Al T2 (giorno 56) i ratti sono stati soppressi ed è stata eseguita una laparotomia mediana per ulteriori indagini. L’esito primario era l’indice sperimentale di cancro peritoneale (ePCI) a T2. Gli esiti secondari includono la variazione relativa del peso corporeo tra T1 e T2, il peso dell’ascite, la perdita anastomotica/peritonite e la morte.L’ePCI era significativamente più basso nel Gruppo D rispetto a tutti gli altri gruppi. Confrontando il Gruppo C con il Gruppo A abbiamo trovato una tendenza verso una minore progressione del tumore, ma nessuna differenza significativa. È stata calcolata la variazione di peso relativa da T1 a T2. La crescita dei ratti nel gruppo D è stata significativamente la meno colpita rispetto a tutti gli altri gruppi. L’animale sottoposto a CRS nel gruppo B ha sviluppato meno liquido ascitico rispetto al gruppo A e C. Meno ascite è stata trovata nel gruppo D rispetto al gruppo A e C. La chemioterapia intraperitoneale con regorafenib ha agito in sinergia con la chirurgia citoriduttiva nel gruppo D che ha ottenuto risultati migliori in termini di ePCI rispetto al gruppo B.La chemioterapia intraperitoneale con regorafenib è fattibile e combinata con la chirurgia citoriduttiva può compromettere la progressione delle metastasi.

Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) represent two major chronic diseases that affect a large percentage of the population and share common pathogenetic mechanisms, including oxidative stress and inflammation. Considering their common mechanistic aspects, and given the current lack of effective therapies for AD, accumulating research has focused on the therapeutic potential of antidiabetic drugs in the treatment or prevention of AD.This review examines the latest preclinical and clinical evidence on the potential of antidiabetic drugs as candidates for AD treatment. Numerous approved drugs for T2DM, including insulin, metformin, glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium glucose cotransporter 2 inhibitors (SGLT2i), are in the spotlight and may constitute novel approaches for AD treatment.Among other pharmacologic agents, GLP-1 RA and SGLT2i have so far exhibited promising results as novel treatment approaches for AD, while current research has centered on deciphering their action on the central nervous system (CNS). Further investigation is crucial to reveal the most effective pharmacological agents and their optimal combinations, maximize their beneficial effects on neurons, and find ways to increase their distribution to the CNS.

Waldenström Macroglobulinemia (WM) is a B-cell lymphoproliferative disorder characterized mainly by uncontrolled accrual of M- immunoglobulin, secreted by malignant lymphoplasmatic cells. Mast cells interacting with malignant B-cells play an important role at the manifestation of the disease. Utilizing a previous xenotransplantation mouse model, this study evaluates long-term implant viability and quantifies distinct bone marrow mast cell populations along with their dynamics in non-WM and WM human bone implants. Non-WM bone implants were obtained from the femoral head of adult humans undergoing hip arthroplasty or hemiarthroplasty, whereas WM human bone implants originated from bone biopsies obtained from the posterior iliac crest of patients with active WM. All bone particles were implanted intramuscularly in twenty-four NOD/SCID mice. Following 3, 4 or 8 months postoperatively, xenografts were removed and studied using special histological techniques to identify mature and immature mast cells. Xenografts survived up to 8 months after implantation presenting normal cytoarchitecture (non-WM) or high-grade neoplastic infiltration and microresorption (WM bone biopsies). Statistical analysis of mast cell populations showed significant elevation regarding time progression and bone marrow microenvironment, thus suggesting the possible influence of malignant cells to the mast cell population in WM. This study presents the extended survival of intramuscular implantation of human adult bone xenografts into NOD/SCID mice and provides additional information on the interaction between mast cells and malignant B-cells.

Dentate gyrus (DG) of the mammalian hippocampus gives rise to new neurons and astrocytes all through adulthood. Canine hippocampus presents many similarities in fetal development, anatomy, and physiology with human hippocampus, establishing canines as excellent animal models for the study of adult neurogenesis. In the present study, BrdU-dated cells of the structurally and functionally dissociated dorsal (dDG) and ventral (vDG) adult canine DG were comparatively examined over a period of 30 days. Each part's neurogenic potential, radial glia-like neural stem cells (NSCs) proliferation and differentiation, migration, and maturation of their progenies were evaluated at 2, 5, 14, and 30 days post BrdU administration, with the use of selected markers (glial fibrillary acidic protein, doublecortin, calretinin and calbindin). Co-staining of BrdU+ cells with NeuN or S100B permitted the parallel study of the ongoing neurogenesis and gliogenesis. Our findings reveal the comparatively higher populations of residing granule cells, proliferating NSCs and BrdU+ neurons in the dDG, whereas newborn neurons of the vDG showed a prolonged differentiation, migration, and maturation. Newborn astrocytes were found all along the dorso-ventral axis, counting however for only 11% of newborn cell population. Comparative evaluation of adult canine and rat neurogenesis revealed significant differences in the distribution of resident and newborn granule cells along the dorso-ventral axis, division pattern of adult NSCs, maturation time plan of newborn neurons, and ongoing gliogenesis. Concluding, spatial and temporal features of adult canine neurogenesis are similar to that of other gyrencephalic species, including humans, and justify the comparative examination of adult neurogenesis across mammalian species.

Objective Biomimetic chitosan/gelatin (CS/Gel) scaffolds have attracted great interest in tissue engineering of several tissues. However, limited information exists regarding the potential of combining CS/Gel scaffolds with oral cells, such as dental pulp stem cells (DPSCs), to produce customized constructs targeting alveolar/orofacial bone reconstruction, which has been the aim of the present study. Methods Two scaffold types, designated as CS/Gel-0.1 and CS/Gel-1, were fabricated using 0.1 and 1% (v/v) respectively of the crosslinker glutaraldehyde (GTA). Scaffolds (n = 240) were seeded with DPSCs with/without pre-exposure to recombinant human BMP-2. In vitro assessment included DPSCs characterization (flow cytometry), evaluation of viability/proliferation (live/dead staining, metabolic-based tests), osteo/odontogenic gene expression analysis (qRT-PCR) and structural/chemical characterization (scanning electron microscopy, SEM; energy dispersive X-ray spectroscopy, EDX; X-ray powder diffraction, XRD; thermogravimetry, TG). In vivo assessment included implantation of DPSC-seeded scaffolds in immunocompromised mice, followed by histology and SEM-EDX. Statistical analysis employed one/two-way ANOVA and Tukey’s post-hoc tests (significance for p Results Both scaffolds supported cell viability/proliferation over 14 days in culture, showing extensive formation of a hydroxyapatite-rich nanocrystalline calcium phosphate phase. Differential expression patterns indicated GTA concentration to significantly affect the expression of osteo/odontogenic genes, with CS/Gel-0.1 scaffolds being more effective in upregulating DSPP, IBSP and Osterix. In vivo analysis demonstrated time-dependent production of a nanocrystalline, mineralized matrix at 6, 8 and 10 weeks, being more prominent in constructs bearing rhBMP-2 pre-treated cells. The latter showed higher amounts of osteoid and fully mineralized bone, as well as empty space reduction. Significance These results reveal a promising strategy for orofacial bone tissue engineering.

Structural and functional dissociation between the septal and the temporal part of the dentate gyrus predispose for possible differentiations in the ongoing neurogenesis process of the adult hippocampus. In this study, BrdU-dated subpopulations of the rat septal and temporal dentate gyrus (coexpressing GFAP, DCX, NeuN, calretinin, calbindin, S100, caspase-3 or fractin) were quantified comparatively at 2, 5, 7, 14, 21, and 30 days after BrdU administration in order to examine the successive time-frames of the neurogenesis process, the glial or neuronal commitment of newborn cells and the occurring apoptotic cell death. Newborn neurons' migration from the neurogenic subgranular zone to the inner granular cell layer and expression of glutamate NMDA and AMPA receptors were also studied. BrdU immunocytochemistry revealed comparatively higher numbers of BrdU(+) cells in the septal part, but stereological analysis of newborn and total granule cells showed an identical ratio in the two parts, indicating an equivalent neurogenic ability, and a common topographical pattern along each part's longitudinal and transverse axis. Similarly, both parts exhibited extremely low levels of newborn glial and apoptotic cells. However, despite the initially equal division rate and pattern of the septal and temporal proliferating cells, their later proliferative profile diverged in the two parts. Dynamic differences in the differentiation, migration and maturation process of the two BrdU-incorporating subpopulations of newborn neurons were also detected, along with differences in their survival pattern. Therefore, we propose that various factors, including developmental date birth, local DG microenvironment and distinct functionality of the two parts may be the critical regulators of the ongoing neurogenesis process, leading the septal part to a continuous, rapid, and less-disciplined genesis rate, whereas the quiescent temporal microenvironment preserves a quite steady, less-demanding neurogenesis process.

Neural precursor cells (NPCs) located in the subgranular zone (SGZ) of the dentate gyrus (DG) give rise to thousands of new cells every day, mainly hippocampal neurons, which are integrated into existing neuronal circuits. Aging and chronic degenerative disorders have been shown to impair hippocampal neurogenesis, but the consequence of inflammation is somewhat controversial. The present study demonstrates that the inflammatory environment prevailing in the brain of experimental autoimmune encephalomyelitis (EAE) mice enhances the proliferation of NPCs in SGZ of the dorsal DG and alters the proportion between radial glial cells and newborn neuroblasts. The injection protocol of the cell cycle marker bromodeoxyuridine and the immunohistochemical techniques that were employed revealed that the proliferation of NPCs is increased approximately twofold in the SGZ of the dorsal DG of EAE mice, at the acute phase of the disease. However, although EAE animals exhibited significant higher percentage of newborn radial-glia-like NPCs, the mean percentage of newborn neuroblasts rather was decreased, indicating that the robust NPCs proliferation is not followed by a proportional production of newborn neurons. Significant positive correlations were detected between the number of proliferating cells in the SGZ and the clinical score or degree of brain inflammation of diseased animals. Finally, enhanced neuroproliferation in the acute phase of EAE was not found to trigger compensatory apoptotic mechanisms. The possible causes of altered neurogenesis observed in this study emphasize the need to understand more precisely the mechanisms regulating adult neurogenesis under both normal and pathological conditions.

Mesenchymal stromal cells (MSC) have been suggested to have beneficial effects on animal models of traumatic brain injury (TBI), owing to their neurotrophic and immunomodulatory properties. Adipose tissue-derived stromal cells (ASCs) are multipotent MSC that can be harvested with minimally invasive methods, show a high proliferative capacity, low immunogenicity if allogeneic, and can be used in autologous or heterologous settings. In the present study ASCs were genetically labelled using the Sleeping Beauty transposon to express the fluorescent protein Venus. Venus+ASCs were transplanted intra-cerebroventricularly (ICV), on a rat TBI model and their survival, fate and effects on host brain responses were examined at seven days post-injury (7dPI). We provide evidence that Venus+ASCs survived, migrated into the periventricular striatum and were negative for neuronal or glial lineage differentiation markers. Venus+ASCs stimulated the proliferation of endogenous neural stem cells (NSCs) in the brain neurogenic niches, the subventricular zone (SVZ) and the hippocampal dentate gyrus (DG). It was also evident that Venus+ASCs modify the host brain's cellular microenvironment both at the injury site and at their localization area by promoting a significant reduction of the lesion area, as well as altering the post-injury, pro-inflammatory profile of microglial and astrocytic cell populations. Our data support the view that ICV transplantation of ASCs induces alterations in the host brain's cellular response to injury that may be correlated to a reversal from a detrimental to a beneficial state which is permissive for regeneration and repair.

Structural and functional dissociation between the septal and the temporal part of the dentate gyrus predispose for possible differentiations in the ongoing neurogenesis process of the adult hippocampus. In this study, BrdU-dated subpopulations of the rat septal and temporal dentate gyrus (coexpressing GFAP, DCX, NeuN, calretinin, calbindin, S100, caspase-3 or fractin) were quantified comparatively at 2, 5, 7, 14, 21, and 30 days after BrdU administration in order to examine the successive time-frames of the neurogenesis process, the glial or neuronal commitment of newborn cells and the occurring apoptotic cell death. Newborn neurons' migration from the neurogenic subgranular zone to the inner granular cell layer and expression of glutamate NMDA and AMPA receptors were also studied. BrdU immunocytochemistry revealed comparatively higher numbers of BrdU(+) cells in the septal part, but stereological analysis of newborn and total granule cells showed an identical ratio in the two parts, indicating an equivalent neurogenic ability, and a common topographical pattern along each part's longitudinal and transverse axis. Similarly, both parts exhibited extremely low levels of newborn glial and apoptotic cells. However, despite the initially equal division rate and pattern of the septal and temporal proliferating cells, their later proliferative profile diverged in the two parts. Dynamic differences in the differentiation, migration and maturation process of the two BrdU-incorporating subpopulations of newborn neurons were also detected, along with differences in their survival pattern. Therefore, we propose that various factors, including developmental date birth, local DG microenvironment and distinct functionality of the two parts may be the critical regulators of the ongoing neurogenesis process, leading the septal part to a continuous, rapid, and less-disciplined genesis rate, whereas the quiescent temporal microenvironment preserves a quite steady, less-demanding neurogenesis process.

Objective Waldenstrom's macroglobulinemia (WM) is a low-grade lymphoplasmacytoid lymphoma characterized by production of monoclonal immunoglobulin M (IgM). The present study was undertaken with the aim of developing a novel nonobese diabetic/severe combined immunodeficient (NOD/SCID) mouse model of WM. Materials and Methods Pairs of bone particles derived from adult humans were successfully implanted intramuscularly in NOD/SCID mice. Each mouse was implanted with a bone fragment taken from a neoplastic disease-free individual in the one hind limb and with a different biopsy taken from a WM patient in the other. Results All mice implanted with the bone marrow core biopsies had increased levels of serum IgM 1 month following the implantation onward. Histopathologic and immunohistochemical analysis showed that in approximately half of the mice WM cells metastasized from the WM bone implant to the distantly implanted non-WM bone. Serum IgM value records of all mice correlated with histopathological observations and immunohistochemical analysis for neoplastic cell density and metastatic growth. Conclusion Results obtained in the present study suggest that IgM-producing WM cells not only retained viability in the bone marrow of the WM bone biopsy, but also metastasized to the normal bone marrow of the distant bone implant. The mouse model reported here improves on existing models of WM by recapitulating the adult human bone marrow microenvironment of abnormal WM neoplastic cells.