Oxytocin: A Multi-Functional Biomolecule with Potential Actions in Dysfunctional Conditions; From Animal Studies and Beyond.

Oxytocin is a hormone secreted from definite neuroendocrine neurons located in specific nuclei in the hypothalamus (mainly from paraventricular and supraoptic nuclei), and its main known function is the contraction of uterine and/or mammary gland cells responsible for parturition and breastfeeding. Among the actions of the peripherally secreted oxytocin is the prevention of different degenerative disorders. These actions have been proven in cell culture and in animal models or have been tested in humans based on hypotheses from previous studies. This review presents the knowledge gained from the previous studies, displays the results from oxytocin intervention and/or treatment and proposes that the well described actions of oxytocin might be connected to other numerous, diverse actions of the biomolecule.

Atomic Force Microscope Nanoindentation Analysis of Diffuse Astrocytic Tumor Elasticity: Relation with Tumor Histopathology.

This study aims to investigate the influence of isocitrate dehydrogenase gene family (IDH) mutations, World Health Organization (WHO) grade, and mechanical preconditioning on glioma and adjacent brain elasticity through standard monotonic and repetitive atomic force microscope (AFM) nanoindentation. The elastic modulus was measured ex vivo on fresh tissue specimens acquired during craniotomy from the tumor and the peritumoral white matter of 16 diffuse glioma patients. Linear mixed-effects models examined the impact of tumor traits and preconditioning on tissue elasticity. Tissues from IDH-mutant cases were stiffer than those from IDH-wildtype ones among anaplastic astrocytoma patients (p = 0.0496) but of similar elasticity to IDH-wildtype cases for diffuse astrocytoma patients (p = 0.480). The tumor was found to be non-significantly softer than white matter in anaplastic astrocytomas (p = 0.070), but of similar elasticity to adjacent brain in diffuse astrocytomas (p = 0.492) and glioblastomas (p = 0.593). During repetitive indentation, both tumor (p = 0.002) and white matter (p = 0.003) showed initial stiffening followed by softening. Stiffening was fully reversed in white matter (p = 0.942) and partially reversed in tumor (p = 0.015). Tissue elasticity comprises a phenotypic characteristic closely related to glioma histopathology. Heterogeneity between patients should be further explored.

In vivo biodistribution study of TAT-L-Sco2 fusion protein, developed as protein therapeutic for mitochondrial disorders attributed to SCO2 mutations.

The rapid progress achieved in the development of many biopharmaceuticals had a tremendous impact on the therapy of many metabolic/genetic disorders. This type of fruitful approach, called protein replacement therapy (PRT), aimed to either replace the deficient or malfunctional protein in human tissues that act either in plasma membrane or via a specific cell surface receptor. However, there are also many metabolic/genetic disorders attributed to either deficient or malfunctional proteins acting intracellularly. The recent developments of Protein Transduction Domain (PTD) technology offer new opportunities by allowing the intracellular delivery of recombinant proteins of a given therapeutic interest into different subcellular sites and organelles, such as mitochondria and other entities. Towards this pathway, we applied successfully PTD Technology as a protein therapeutic approach, in vitro, in SCO2 deficient primary fibroblasts, derived from patient with mutations in human SCO2 gene, responsible for fatal, infantile cardioencephalomyopathy and cytochrome c oxidase deficiency. In this work, we radiolabeled the recombinant TAT-L-Sco2 fusion protein with technetium-99 m to assess its in vivo biodistribution and fate, by increasing the sensitivity of detection of even low levels of the transduced recombinant protein. The biodistribution pattern of [99mTc]Tc-TAT-L-Sco2 in mice demonstrated fast blood clearance, significant hepatobiliary and renal clearance. In addition, western blot analysis detected the recombinant TAT-L-Sco2 protein in the isolated mitochondria of several mouse tissues, including heart, muscle and brain. These results pave the way to further consider this PTD-mediated Protein Therapy Approach as a potentially alternative treatment of genetic/metabolic disorders.

Mechanical properties of human glioma.

Brain gliomas represent some of the most aggressive tumors encountered by modern medicine and, despite major efforts to optimize early diagnosis and treatment, the prognosis remains poor. Due to the complex structure of the brain and the unique mechanical properties of the extracellular matrix, gliomas invade and expand into the brain parenchyma, along white matter tracts and within perivascular spaces, usually sparing normal vessels. Different methods have been developed to study the mechanical properties of gliomas in a wide range of scales, from cells and the microscale to tissues and the macroscale. In this review, the current view on glioma mechanics is presented and the methods used to determine glioma mechanical properties are outlined. Their principles and current state of affairs are discussed.

Establishment of an animal model for Waldenström's macroglobulinemia.

OBJECTIVE: Waldenström'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.

A metastatic human prostate cancer model using intraprostatic implantation of tumor produced by PC-3 neolacZ transfected cells.

The purpose of this study was to develop a model that investigates the biology of prostate cancer (PCA) that is metastatic to the bone, while closely approximates the clinical presentation of this disease. Human prostate cancer PC-3 cells were transfected with the neolacZ retrovirus. Then, eight-week-old SCID mice were injected subcutaneously with a single dose of PC-3 neolacZ cells. When the mice developed tumors at the injection site, they were sacrificed to harvest tumor fragments. One tumor fragment from a single PC-3 neolacZ injected animal was implanted into the prostates of five SCID mice. The SCID mice had all been previously grafted with adult human bone. Mice were sacrificed and tumor growth and metastasis to murine tissues as well as to the human bone graft were sought. The histologic samples were stained with X-Gal. In three mice tumors metastasized to the skeletal system. One animal showed limited X-Gal staining of the cells surrounding the human bone implant. In two mice tumors metastasized to liver and kidney and one metastasized to the lung. In this study we established a spontaneous bone metastasis model of human PCA cells with the combination of lacZ expression and orthotopic implantation of the PC-3 implanted tumor fragments. This model offers potential advantages in monitoring the metastatic pattern and behavior of prostate cancer and may be used to selectively study its interaction with human bone.

Anatomic organization of the ascending branch of the milk-ejection reflex in sheep: primary afferent neurons.

The present study examines the anatomic characteristics of the primary afferent neurons that innervate the nipples and pseudonipples of ewes and the nipples of lambs. For this purpose, horseradish-peroxidase coupled to wheat germ agglutinin (WGA-HRP) was injected intradermally into the whole extent, the tip, or the base of the nipples and pseudonipples, as well as into a region of the posterior surface of the udder. After survival periods of 72-96 hours, dorsal root ganglia (DRG), segments of the spinal cord and medulla oblongata were sectioned and reacted histochemically with tetramethylbenzidine to reveal the transganglionically transported tracer. Injections of WGA-HRP in the nipples and pseudonipples of the ewe resulted in labeled cells in the second to fifth ipsilateral lumbar spinal ganglia (L(2)-L(5)) and third and fourth (L(3) and L(4)) lumbar spinal ganglia, respectively. Labeled cells after WGA-HRP injections in the nipples of the lamb were found in the ipsilateral L(3)-L(5) spinal ganglia. Central projections of the DRG-labeled cells were found in the medial part of laminae I-III of the ipsilateral L(3) and L(4) spinal segments (ewe and lamb) and in the ipsilateral dorsal column nuclei (ewe). Central projections of the DRG-labeled cells after injections in the pseudonipples of the ewe were located in the medial part of laminae I-III of the ipsilateral L(3) spinal segment. The results of this study demonstrate that, whereas the innervation of the nipples of the ewe originates from four successive lumbar spinal ganglia (L(2)-L(5)), the innervation of the nipples of the lamb and the pseudonipples of the ewe originates from three (L(3)-L(5)) and two (L(3) and L(4)) successive ganglia, respectively.