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Lege Artis Medicinae

OCTOBER 21, 2020

[Atherosclerosis: an ancient process in a new interpretation]


[The progress of atherosclerosis starts in childhood and lasts until the body dies. Most cardiovascular diseases and deaths can be traced back to atherosclerotic vascular changes. The process is thousands of years old, but its complex pathophysiology becomes recognized and realised only nowadays. Based on the evidence available today, atherosclerosis is such a chronic inflammatory disease of large- and medium-sized arteries, which is characterized by lipoproteins and immune cells transformed through oxidative and other changes and subendothelial accumulation of extracellular matrix. Innate and adaptive immunity provide a complex regulating system of atherogenesis, which while directing specifically the pro-atherogenic inflammatory and atheroprotective anti-inflammatory processes intensify plaque progression or even stabilize them respectively. With our growing knowledge about the pathology of atherogenesis, we can further improve the identification of cardiovascular risk conditions and apply more personalized therapeutic strategies.]

Clinical Oncology

FEBRUARY 28, 2020

[Role of infl ammation in the carcinogenesis]

KOPPER László, TÍMÁR József

[Chronic infl ammation is an important promoter of the carcinogenesis of several cancer types and also an important contributor to mutagenicity beside the known carcinogens. Beside the continous regeneration of the affected epithelia chronic infl ammation provide a special microenvironment intra and extracellular environment which support malignant transformation and block emerging immune reactions. On the other hand, cancer is generating chronic infl ammation itself independent from its role in the carcinogenic process. It is due to cancer necrosis as well as to the production of infl ammatory cytokines. Cancer-induced infl ammatory reactions block antitumoral immune responses and continous monitoring of this process provide valuable clinical parameter of cancer progression.]

Clinical Neuroscience

SEPTEMBER 30, 2020

[Prognostic significance of invasion in glioblastoma]


[Glioblastoma is the most common malignant CNS tumor, its surgical removal is hindered by the tumors invasive nature, while current anti-tumor therapies show limited effectiveness – mean overall survival is 16-24 months. Some patients show minimal response towards standard oncotherapy, however there are no routinely available prognostic and predictive markers in clinical practice to identify the background of mentioned differences in prognosis. This research aims to identify the prognostic significance of invasion-related extracellular (ECM) components. Patient groups with different prognoses were created (OS: group A <16 months, group B > 16 months), and internationally recognized prognostic markers (IDH1 mutation and MGMT promoter hyper-methylation) were tested in the flash-frozen tumor samples. Furthermore, the mRNA levels of 46 invasion-related ECM molecules were measured. Clinical data of the patients who have been operated on at the University of Debrecen Clinical Center Department of Neurosurgery and treated at the Department of Clinical Oncology showed no significant differences except for survival data (OS and PFS), and reoperation rate. All samples were IDH wild type. MGMT promoter hypermethylation rate showed significant differences (28.6% vs 68.8%). The expressional pattern of the invasion-related ECM molecules, i.e. the invasion spectrum also showed major differences, integrin β2, cadherin-12, FLT4/VEGFR-3 and versican molecules having signficantly different mRNA levels. The accuracy of the inivasion spectrum was tested by statistical classifier, 83.3% of the samples was sorted correctly, PPV was 0.93. The difference found in the reoperation rate when comparing different prognostic groups aligns with literature data. MGMG promoter region methylation data in Hungarian samples has not been published yet, and further confirming current knowledge urges the implementation of MGMT promoter analysis in clinical practice. Studying the invasion spectrum provides extra information on tumors, as a prognostic marker it helps recognizing more aggressive tumors, and calls attention to the necessity of using anti-invasive agents in GBM therapies in the future.]

Lege Artis Medicinae

SEPTEMBER 30, 2020

[The pain-trigger role of cytokines in the nervous system – the direct analgesic effect of anti-cytokine therapy ]


[Nociceptive, neuropathic and central me­chanisms are involved in the perception, transmission and processing of chronic pain and shaping of cerebral pain image. Alar­mins – molecules alarming defence and signing the presence of pathogens and tissue damage - trigger a series of pathogenic events resulting in inflammatory pain stimuli. Proinflammatory cytokines play a determining role in the pain perception at the level of the nervous system. Continuous inflammatory stimuli while sensitizing the periferic and central neurons activate the pain-related cerebral areas and develop the complex pain image, the pain matrix. Ce­reb­ral functional connections are operating in networks and can be visualized by functional MRI. Cytokines activate the neurons directly or indirectly by other neuromediators. Cytokine receptors are expressed on no­ciceptors and even on higher-level neurons and on various non-neural cells, such as microglia and astrocytes. The most ubiquitous cytokines are the Tumour Necrosis Factor and Interleukin 6 in the nervous sys­tem. The signaling pathways are the Nuclear Factor κB and the Janus-kinase enzyme system. The proinflammatory cytokines and the Janus-kinase are therefore primary therapeutic targets. Anti-cytokine biologicals and small molecular kinase inhibitors decrease the pain and improve functional activity in rheumatoid arthritis. Decrease of pain was more pronounced than expected only from the decrease of the clinical biomarkers of inflammation. The early and ra­pid painkiller effect of targeted biological and chemical-biological response modifiers is attributed to their direct analgesic effect on the brain.]

Clinical Oncology

APRIL 10, 2019

[The role of stromal components in the behavior of malignant tumors]


[Stroma was considered for a long time as an innocent bystander without infl uence on the behavior of the cancer tissue. However, this opinion considerably changed in the last twenty years. Increasing evidences have been gathered proving that all components of the stroma is active participant in the development and progression of cancer. Although stroma can exert protective role against the early development of tumors, this changes soon as cancer cells are forcing the stromal components to support their growth. This can be accomplished by the induction of stromal stiffness, production of fuels, citokines, growth factors, new blood vessels for the progression of cancer cells. This recognition lead to the introduction of a new approach, targeting stroma in anticancer therapy. Among those attempt excellent results have been achieved by the immune and antiangiogenesis therapy, but countless other attempts are going on.]

Hypertension and nephrology

SEPTEMBER 10, 2019

[Role of IL-10 family of cytokines in kidney fibrosis]

PAP Domonkos, VERES-SZÉKELY Apor, SZEBENI Beáta, SZIKSZ Erna, KISS József Zoltán, TAKÁCS István Márton, REUSZ György, SZABÓ J. Attila, VANNAY Ádám

[Chronic renal failure is a major health problem, affecting 8 to 16% of the population. Regardless of the etiology the common hallmark of chronic renal failure is inflammation, leading to the activation of renal myofibroblasts. Chronic activation of myofibroblasts lead to abnormal accumulation of extracellular matrix, disruption of the architecture of the kidney and finally to reduced renal function. Although our knowledge is rapidly expanding about the pathomechanism of chronic renal failure, we still have no drug to treat or hinder the progression of the disease. In our present review article, we summarize the role of the cytokines of the IL-10 family in renal scarring.]

Lege Artis Medicinae

SEPTEMBER 20, 2018

[Differential diagnosis and treatment of hyponatraemia]

NÉMETH Zsófia, DEÁK György

[Hyponatraemia (serum sodium concentration < 136 mmol/l) is the most frequent electrolyte abnormality that inceases the risk of both in-hospital, and outpatient mortality. Antidiuretic hormone action or low glomerular fitration rate or low excretable osmoles or their combination are involved in its pathogenesis. Differential diagnosis is based on medical and medication histories, serum- and urine osmolality and urine sodium concentration. Measurement of fractional excretions of urea and uric acid help identifying low effective circulting volume, renal hypoperfusion. Symptomatic hyponatraemia or an acute decrease of serum sodium concentration exceeding 10 mmol/l should be treated with 3% NaCl to avoid impending threat to life. The principles of the treatment of chronic hyponatraemia are restriction of water intake and elimination of etiologic factor(s) (eg. medications - most often thiazides). In case of contracted axtracellular volume, isotonic saline should be given. In case of euvolaemia, restriciton of water intake is fundamental. In case of expanded extracellular volume, (heart failure, liver cirrhosis, nephrosis), water and NaCl intake should be restricted along with aldosteron antagonist and loop diuretic therapy. In chronic hyponatraemia, the rise of serum sodium concentration should not exceed 10 mmol/l during the first 24 hours and 8 mmol/l/day thereafter. ]

Clinical Oncology

SEPTEMBER 10, 2017

[MEK and ERK - against RAS and RAF ]


[In most cases, the targeted therapy is able to produce clinical response, but after a certain interval it turns to be ineffective due to secondary resistance against the therapy. One of the most demanding challenge in treatment of cancer is to prevent or inhibit such resistance, which could have several forms, e.g. appearance of new driver activating mutations in the treated tumor, clon(s) existed in minority with different mutations (targets) can grow and replace the temporarely sensitive tumor cells (on the basis of tumor heterogeneity); another pathway takes over the role in cancer progression, etc. Such problems are very common in the RAS-RAF-MEK-ERK pathway. These are very important proteins to collect extracellular signals in order to regular different cell functions, especially proliferation. With activating mutations make the RAS-pathway independent from the normal .regulation. To inhibit the consequence of the mutations is largely still an unsolved problem, with few exceptions (e.g. inhibition of BRAF mutations). Theoretically, the inhibition of the next steps of the pathway, MEK and ERK, may stop the pathologically activated signals, partly due to their inhibition, and party to effi ciently decrease the feedback inside the pathway. This review discusses aspects of this possibilities, especially to overcome resistance and prolong the effectiveness of therapy.]

Hypertension and nephrology

MAY 20, 2017

[New agents in the therapy of hyperkalaemia]

PATÓ Éva, DEÁK György

[Serum potassium level higher than 5,5 mmol/l denotes hyperkalemia that becomes severe above 7,5 mmol/l being a potentially life threatening condition due to ventricular arrythmias. It may develop as a consequence of high potassium intake, decreased renal excretion, and extracellular potassium shift. Its treatment is a challenge even nowadays especially in the setting of chronic kidney disease, diabetes mellitus, and heart failure where RAAS inhibion is an essential component of the therapy. Sodium polystyrene sulfonate, an ion exchange resin is applied for more than fifty years. Recently new angents, patiromer and sodium zirconium cyclosylicate (ZS-9) were introduced and available results show a safer, more tolerable and predicatble effect. Efficiency of patiromer to reduce hyperkalemia is verified in clinical trials in patients with chronic kidney disease, or diabetes mellitus, or hypertension or heart failure on RAAS inhibitor therapy.]