Androgen Receptor Drives Cellular Senescence

The accepted androgen receptor (AR) role is to promote proliferation and survival of prostate epithelium and thus prostate cancer progression. While growth-inhibitory, tumor-suppressive AR effects have also been documented, the underlying mechanisms are poorly understood. Here, we for the first time link AR anti-cancer action with cell senescence in vitro and in vivo. First, AR-driven senescence was p53-independent. Instead, AR induced p21, which subsequently reduced ΔN isoform of p63. Second, AR activation increased reactive oxygen species (ROS) and thereby suppressed Rb phosphorylation. Both pathways were critical for senescence as was proven by p21 and Rb knock-down and by quenching ROS with N-Acetyl cysteine and p63 silencing also mimicked AR-induced senescence. The two pathways engaged in a cross-talk, likely via PML tumor suppressor, whose localization to senescence-associated chromatin foci was increased by AR activation. All these pathways contributed to growth arrest, which resolved in senescence due to concomitant lack of p53 and high mTOR activity. This is the first demonstration of senescence response caused by a nuclear hormone receptor

CD28null CD4 T-cell expansions in autoimmune disease suggest a link with cytomegalovirus infection

Immunosenescence is thought to contribute to the increase of autoimmune diseases in older people. Immunosenescence is often associated with the presence of an expanded population of CD4 T cells lacking expression of CD28 (CD28null). These highly cytotoxic CD4 T cells were isolated from disease-affected tissues in patients with rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, or other chronic inflammatory diseases and their numbers appeared to be linked to disease severity. However, we recently demonstrated that the common herpes virus, cytomegalovirus (CMV), not ageing, is the major driver of this subset of cytotoxic T cells. In this review, we discuss how CMV might potentiate and exacerbate autoimmune disease through the expansion of CD28null CD4 T cells

A HISTOLOGICAL COMPARISON OF MYELINATED NERVE FIBERS BETWEEN THE EXTERNAL AND EXTREME CAPSULES IN HUMAN BRAIN

Introduction: To recognize the myelinated nerve fibers of the external and extreme capsules in human brain. Materials and Methods: 10 adult and normal brains (20 hemispheres) from both sexes were studied using 15 mm serial secions in all three cardinal planes after fixation and processing. These sections were stained by Klüver – Barrera and Heidenhin – Woelcke methods. Results: Some fibers from different parts of the cortex through corona radiata entered the dorsal border of the external capsule, These fibers moved ventraly and ventrocaudaly toward the ventral border of the external capsule, and most of them entered the cerebral peduncles trans -, sub-, or retrolenticularly. Some fibers passed through dorsal part of putamen and connected the external capsule with posterior limb of the internal capsule. Some fibers passed between rostrum of corpus callosum and venteral part of the external capsule. Some fibers traced from the external capsule to posterior bundle of the anterior commissure; some of them entered the commissure but others terminated in nucleus basalis (Meynert) neurons. Some fibers passed through rostral part of the external and extreme capsules.Most of the fibers of the extreme capsule interconnected the temporal and frontoparietal operculi with the insular gyri, or with each other. A group of the extreme capsule fibers connected the adjacent insular gyri with each other. Some fibers exchanged between the extreme capsule and the claustrum. There were fibers which went between the external and extreme capsules through the dorsal claustrum. Conclusion: It is concluded that the external capsule contains all three groups of fibers, but it is mainly projectional; on the other hand, the extreme capsule is mainly associational. Thus, in our opinion, these two capsules should be classified in different groups

Three-dimensional decellularized amnion membrane scaffold as a novel tool for cancer research; cell behavior, drug resistance and cancer stem cell content

Background: Cancer is the second leading cause of human death. Therefore, comprehensive research and the appropriate tools are needed in this field. Animal models and cell culture studies are the most important preclinical tools in cancer research. In 2D cell culture models, cells are forced to grow in a 2D environment, which differs from their natural physiology. Recently, 3D cell culture models were developed to fill the gap between 2D cell culture and animal models. Materials and methods: Human amniotic membranes were obtained, decellularized, characterized and used as a natural 3D scaffold to investigate cancer cell behavior in 2D compared to 3D conditions. Time-lapse imaging of cells was used, and cell proliferation, velocity and migration were evaluated. Cisplatin was applied in 2D and 3D conditions, followed by evaluation of viability, apoptosis and cancer stem cell proteins by flow cytometry and western blot analysis. Results: The results showed that in the decellularized amnion membrane (DAM) scaffold most cells did not spread and remain rounded and then penetrated into the scaffold with no cytotoxicity. Significant differences in migration, velocity, morphology and proliferation of cancer cells were observed between the 3D DAM scaffold and 2D model. Furthermore, the cells in the 3D DAM scaffold showed much more resistance to apoptosis and higher CSC content. Conclusion: In conclusion, considering the effect of the 3D DAM scaffold in cell behavior, apoptosis resistance and CSC content as well as the short processing time for decellularizing the AM, it appears that the 3D DAM scaffold offers an appropriate tool for in vitro cancer research. © 2019 Elsevier B.V

Localization of experimental glioma grafts by means of iodinated monoclonal antibodies and radionuclide imaging.

Purified McAbs (14AC1) of IgG2a isotype raised against an experimental rat glioma (79 FR-G-41) were labeled with Na131I and used for in vivo imaging of glioma grafts by external body seintigraphy. Normal mouse131I-IgG was applied as control for non-specific uptake of proteins in the tumor. Nude mice bearing glioma grafts were injected i.v. with 15 μg of the131I-McAb or131I-IgG with an activity of approximately 150 μCi. Scands obtained 30 min, 24, 48, 72, and 96 h after injecting the intact131I-14AC1 antibody demonstrated enrichment of radioactivity in the tumors. The tumors were clearly visible 48 h after injection of131I-labeled antibody. The time course experiments showed that the uptake of131I-14AC1 antibody in the glioma grafts was the result of specific antigen binding. Intact antibody provided adequate tumor visualization in the scientigrams without background subtraction. Therefore, this technique appears promising for in vivo tumor detection and may offer the possibility of improvement in the evaluation of diagnostic and therapeutic approaches to human gliomas

Optical probing of gastrocnemius in patients with peripheral artery disease characterizes myopathic biochemical alterations and correlates with stage of disease

Peripheral artery disease (PAD) is a condition caused by atherosclerotic blockages in the arteries supplying the lower limbs and is characterized by ischemia of the leg, progressive myopathy, and increased risk of limb loss. The affected leg muscles undergo significant changes of their biochemistry and metabolism including variations in the levels of many key proteins, lipids, and nucleotides. The mechanisms behind these changes are poorly understood. The objective of this study was to correlate the severity of the PAD disease stage and associated hemodynamic limitation (determined by the ankle brachial index, ABI) in the legs of the patients with alterations in the biochemistry of chronically ischemic leg muscle as determined by ATR-Fourier transform infrared microspectroscopy. Muscle (gastrocnemius) biopsies were collected from 13 subjects including four control patients (ABI≥0.9), five claudicating patients (0.4 ≤ AB