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Clinical Oncology

DECEMBER 30, 2019

[Cell death]

KOPPER László, TÍMÁR József

[Cell proliferation and cell death (mainly apoptosis) have programs forming a network to maintain the functional integrity of the organism. Apoptosis has an external and internal units with ligands, signalling pathways and targets. Besides, some other participants (e.g. p53) are involved in the regulation of cell death. Although, apoptosis is a multitargeted process, there is no useful therapy, if it is needed, to correct accumulation of unwanted cells.]

Clinical Oncology

FEBRUARY 20, 2019

[P53 – the suppressor]

KOPPER László

[Our basic nature requere cells quantity and quality to perform differenciate activity. p53 has the responsibility for quick out those cells who carries molecular failures in DNA avoiding transfer mutations into doughter cells. If the DNA-repair insuffi cient p53s with on apoptosis. Whe p53 is mutated the phenotypes are different in a wide range due to the heterogenity of the DNA damages, and also the expression pattern of a suppressor protein. With the increasing amout the damaged DNA the genomic instability elevates D the risk to development of tumors. It is linict mutated gene could be a promosing tr, 10t for therapy. So far the attempts have little value for the clinic.]

Clinical Oncology

DECEMBER 10, 2016

[Defi ciency of DNA-repair]

KOPPER László

[The cell uses the DNA to keep those information, which are vital to function properly. It is essential to maintain the integrity of the DNA, the stability of the genome. Since DNA damages, caused by external or internal factors, are continuously produced, DNA-repair mechanisms should be ready to identify and eliminate the damages. Either the repair system is successful and the cell can continue its duty, or, if the damages are unrepaired, the programed cell death (apoptosis) is activated according to the rule, that it is prohibited to transfer genomic/epigenomic damages into the daughter cells. It is true that the severness of the damages are not the same. The most important is the identifi cation and repair of those damages which can make genomic instability increasing the risk of cancer development. This may happen when the repair system is insuffi cient, sometimes due to inherited mutations (e.g. BRCA1 mutations can increase the risk of breast cancer, ovarian cancer etc.). Among the damages the DNA double strand breaks are rather common, and also, that the breaks are intended to be repaired in most cases. However, if such repair fails, the cell, here the cancer cell, due to the overhelming damages will dye. This phenomenon is the synthetic lethality. An example: „cooperation” of inherited BRCA1 mutation and PARP-inhibition, can lead to clinical response using PARP inhibitors, as oliparib. New agents and clinical trials intend to take advantage from synthetic lethality.]

Hypertension and nephrology

DECEMBER 30, 2012

[Molecular mechanisms leading to renal fibrosis: the origin of myofibroblasts]

HIMER Leonóra, SZIKSZ Erna, KOVÁCS S. Krisztián, ÓNODY Anna, Reusz Anna, REUSZ György, FEKETE Andrea, TULASSAY Tivadar, VANNAY Ádám

[There are about a quarter of million patients who need chronic renal replacement therapy in Europe, and the estimated number of patients with chronic kidney disease is about tenfold higher. Interestingly, regardless of the initiating cause the mechanism of fibrosis is similar to each other in the different chronic kidney diseases. In general, the damaged glomerular or tubular cells release danger signals and produce chemotactic stimuli, which trigger the rapid recruitment of leukocytes. The infiltrating immune cells and the damaged renal cells then produce high levels of proinflammatory cytokines, growth factors, chemokines and adhesion molecules which contribute to glomerular/tubular injury, accumulation of further leukocytes and myofibroblasts, which are the effector cells of renal fibrosis. However the origin of myofibroblasts is still controversial. Recent hypotheses suggest that they are originated from different renal cells, such as epithelial and endothelial cells, pericytes or bone marrow derived fibrocytes. The myofibroblasts thus generated serve as key cellular mediators of renal fibrosis. Myofibroblasts have migratory capacity, are resistant to apoptosis, produce several growth factors and cytokines and according to our present knowledge these cells are the main source of collagen-I and -III rich extracellular matrix in the fibrous tissue. Organ fibrosis is characterized with excessive deposition of extracellular matrix leading to glomerular sclerosis and renal tubulointerstitial fibrosis. The excessive deposition of fibrous tissue replaces healthy kidney tissue; nephrons disappear and kidney function declines gradually. In this article the knowledge is summarized on the molecular changes leading to the generation of renal myofibroblasts.]

Clinical Neuroscience

JULY 30, 2012

[Selective ultrastructural vulnerability in the cuprizone-induced experimental demyelination]

ÁCS Péter, KOMOLY Sámuel

[Background and purpose - It has been reported that multiple sclerosis has four different neuropathological subtypes, and two of them (type III and IV) are characterized by primary oligodendrocyte loss. However, the exact pathomechanism that lead to oligodendrocyte apoptosis in human demyelinating diseases is still elusive. The copper chelator cuprizone induces primary oligodendrocyte apoptosis and consequent demyelination in well defined areas of the mouse brain. Nevertheless, the precise subcellular events that result in oligodendrocyte cell death in the cuprizone model are still unknown. We aimed to study the ultrastructural alterations that might induce oligodendrocyte apoptosis in the cuprizone experimental demyelination model. Methods - C57BL/6 mice were given cuprizone for two, 21 and 35 days to induce demyelination to investigate early pathological events, and different stages of demyelination. In addition, mice were given cuprizone for 35 days and were allowed to recover for two or 14 days to study early and late remyelination. After the cuprizone treatment, mice were sacrificed and the corpus callosum, the superior cerebellar peduncle, the optic nerve and the sciatic nerve were studied by electron microscopy. Results - The ultrastructural analysis revealed that cuprizone induced oligodendrocyte apoptosis is accompanied by the formation of giant mitochondria in the affected cells in the corpus callosum and in the superior cerebellar peduncle. Apoptosis of the myelin producing cells was present through the whole cuprizone challenge. Severe demyelination occurred after three weeks of cuprizone administration associated with massive macrophage infiltration and astrocytosis of the demyelinated areas. Axons and neurons remained unaffected. Conclusion - The formation of giant mitochondria in myelin producing oligodendrocytes is the first pathological sign in the cuprizone experimental demyelination. Mitochondrium pathology in the cuprizone challenge might serve as a useful model to study the pathomechanism of multiple sclerosis subtypes (III and IV) characterized by primary oligodendrocyte degeneration.]

Hungarian Immunology

DECEMBER 20, 2002

[On the role of aging in etiology of autoimmunity]

SEMSEI Imre, ZEHER Margit, BAKÓ Gyula

[Several types of diseases, among others autoimmune illnesses, could be coupled with the general processes of aging. The two-edged sword of the immune defense is directed once against environmental attacks and on the other side against the self. However, one has to make a difference between normal (physiological) clearance and autoimmune diseases, although both sides of autoimmunity are influenced by the general processes of senescence. Aging of the thymus seems to be one of the key elements of the etiology of autoimmunity, although other cell types and their aging also play a substantial role in this process. The spontaneous genetic instability, the acquired genetic mutations due to aging and the age-related alterations of the information level of the body together may be important elements of the patomechanism of both the physiological autoimmunity and the autoimmune diseases. Nevertheless, physiological autoimmunity seems to be directed mostly by natural factors (such as aging and apoptosis) but primary autoimmune diseases may be caused by genetic instability that is enhanced by aging as well.]

Hungarian Immunology

MARCH 20, 2006

[The role of nerve growth (NGF) factor in the immune and inflammatory events and in autoimmune thyroid diseases]

MOLNÁR Ildikó

[Nerve growth factor (NGF) is a neurotroph cytokine, and beside its effect on the central and peripheral nervous systems NGF plays an important role in the inflammatory and autoimmune processes. There are two types of NGF receptors, the high-affinity (TrkA) and the low-affinity (p75), which activations via signal transduction could lead to the inhibition or induction of apoptosis. Suppression of apoptosis could be induced by cytokines, hormones, antioxidans and increased intracellular Ca2+-levels. In the pathogenesis of many autoimmune diseases (systemic lupus erythematosus, 1-type diabetes mellitus, multiple sclerosis) could detect elevated serum levels of NGF associated with the disease activity. Our study demonstrated increased levels of NGF in autoimmune thyroid diseases (Graves’ disease, Hashimoto’s thyroiditis) in comparison with the controls. Decreased serum levels of NGF were found in Graves’ ophthalmopathy suggesting the role of apoptosis in the development of the eye symptoms. Orbital tissues are characterized with the high expression of TrkA receptors. NGF plays an important role in the pathomechanisms of neuro-immuno-hormonal diseases and its knowledge may be helpful in the diagnosis and therapy.]

Lege Artis Medicinae

JULY 14, 2007

[ACE-INHIBITORS IN THE SECONDARY PREVENTION OF CORONARY ARTERY DISEASE]

SÁRSZEGI Zsolt

[The beneficial effects of angiotensin-converting enzyme inhibitors on biochemical and vascular markers have been proven by many experimental studies. Reduction of the angiotensin-II level has a positive effect on oxidative stress, lipid peroxidation, apoptosis, inflammatory and prothrombotic processes. Two large multicentric trials, EUROPA and HOPE, showed that perindopril and ramipril significantly reduce mortality and the risk of both fatal and non-fatal cardiovascular events in patients with atherosclerosis, thereby making them the base drugs of secondary prevention of coronary artery disease.]

Ca&Bone

JUNE 20, 2005

[Mechanotransduction, or the impact of physical activity on bone architecture]

MONDUK Péter, SZEKERES László

[It has long been known that, along with bone mineral content, bone strength is also fundamentally determined by its architecture.This architecture is shaped primarily by the forces that act on the bone, i.e., gravity and muscle traction conveyed by the tendons.Thus the bone acts as a kind of a mechanostat. The authors provide an overview of the literature on the systems that regulate mechanotransduction turning mechanical strain into bone texture. Regularly performed movements that provide a frequently changing axial load induce an extracellular fluid flow in the lacunar system of the bones.This flow induces prostaglandin synthesis in the osteocytes, which in turn inhibits the Receptor Activator of Nuclear factor κB (RANK) - RANK-Ligand (RANKL) mechanism through the secretion of osteoprotegerin by osteoblasts.This leads to osteoclast inhibition. Furthermore, leptin secretion by osteoblasts increases, which enhances osteoblast activation and inhibits the apoptosis of osteocytes and osteoblasts by both an autocrine and paracrine route. All these together act in the direction of bone formation. Based on the available evidence, the authors conclude that regular exercise results in an increased bone mass, better muscle strength and firmer balance, which leads to a decreased fracture risk.Thus, physical activity, through its beneficial effects on cardiac and bone health described above, contribute to the improvement of the quality of life.]

Hungarian Immunology

MARCH 20, 2006

[Familial autoinflammatory syndromes]

ORBÁN Ilonka, BALOGH Zsolt

[A group of rare inherited disorders, the familial autoinflammatory syndromes are characterised by attacks of seemingly unprovoked inflammation without significantly elevated autoantibody and autoreactive T cell levels. The rare diseases are present from infancy to lifelong, with periodic fever attacks and usually are accompanied by recurrent systemic inflammatory symptoms such as abdominal pain, diarrhoea, rash, arthralgia, polyarthritis, polyserositis, ocular disorders are separated by symptom-free intervals. Referred to as hereditary periodic fever syndromes appear by spontaneous crisis attacks and reveal a severe acute-phase response during the fever. In their pathogenesis there are no evidence neither of infection nor the common characteristics for autoimmune diseases: the production of high-titer auto-antibodies and antigenspecific T cell activation. The basic disease mechanism consists of the recently identified mutations in genes enconding important proteins: pyrin, cryopyrin, tumour necrosis factor (TNF) receptor and other mediators of apoptosis, inflammation and morbid citokine processing. The differential diagnosis of the diseases is not easy, their treatment is not resolved, although in same cases the biological treatment may be efficacious.]