Chronic cold exposure: A white adipose tissue browning factor

In the human body, there are two major subtypes of adipose tissue, white adipose tissue (WAT) and brown adipose tissue (BAT). Using 18F-fluorodeoxyglucose (FDG), an intravenously administered radioactive glucose analog, it was demonstrated with positron emission tomography and computed tomography that the main BAT depots were disseminated throughout the human body (around the thoracic aorta, common carotid artery, brachiocephalic brachiocephalic artery, kidney, adrenal glands, liver, pancreas; in anterior mediastinum, supraclavicular fossa, axilla and thoracic paravertebral loci, also between neck muscles). The magnitude of FDG uptake by BAT was reported to increase with exposure to low temperature (1-4), hence cold exposure being considered one of the major browning factors (the myokine and adipokine irisin as well as other browning factors are not in the scope of present Dance Round)

Cytokeratin AE1/AE3 mimicry in glioblastoma

INTRODUCTION: The diagnosis and treatment of intracranial tumors requires a multidisciplinary approach. A key moment in this process is the pathological verification of the tumor type. This process, although aided by immunohistochemistry (IHC), can often be difficult and misleading.MATERIALS AND METHODS: Ten histologically confirmed cases of glioblastoma multiforme (GBM) were reviewed for their IHC reaction with the anti-glial fibrillary acidic protein (GFAP) glial marker and the CK AE1/AE3 antibody cocktail, whose main use in neuropathology is to either prove or rule out metastatic cancer of epithelial origin, the primary location of which may not be known or even suspected.RESULTS: All ten pathologically verified cases of GBM were diagnostically positive for GFAP, with eight of them also revealing CK AE1/AE3 expression with variable intensity. Out of the CK AE1/AE3 positive cases, five (50% in total) gave a low to intermediate non-diagnostic positive reaction, while the other three cases (30% in total) gave a strong positive reaction with possible diagnostic value. Cells, across all GBM cases, that tested positive for CK AE1/AE3, regardless of the strength of the reaction, were also positive for GFAP on neighboring IHC serial slides.CONCLUSION: The presented results reveal CK AE1/AE3 expression in a great portion of GBM cases, which may be caused by three-dimensional mimicry between the CK AE1/AE3 and GFAP target molecules. This therefore necessitates the need for a careful interpretation of the results. CK AE1/AE3, however, remains a useful tool in neuropathology, regardless of the possibility of false positivity in GBM cells

The great imitator - EMA positive glioblastoma multiforme

INTRODUCTION: Glioblastoma multiforme (GBM) has always been a diagnostic challenge for pathologists. As a rare oncological entry with astrocytic differentiation, it can manifest itself in a variety of histomorphological forms, mimic other tumors and it often has varying immunohistochemical (IHC) profiles, further challenging the process of its verification.MATERIALS AND METHODS: Four pathologically verified cases of GBM, registered at the St. Marina University Hospital, Varna, Bulgaria were retrieved from the central pathological archive. The cases were tested and reviewed based on their hematoxylin and eosin (H&E) profiles and IHC reactions with GFAP used as a glial differentiation marker, Vimentin - as a positive IHC control and EMA, an epithelial marker, non-reactive in healthy brain tissue.RESULTS: As expected all GBM cases had the histomorphological hallmarks of the tumor on the H&E stain. They were diagnostically positive for GFAP and had a strong positive IHC reaction with Vimentin. Three out of the four cases also revealed a varying in intensity reaction with EMA, with one case having a weak reaction in individual cells that could not be considered diagnostic and the other two cases having a diffuse positive reaction in most of the tumor cells.CONCLUSION: In the age of immunohistochemistry, GBM continues to expand the set of IHC markers that react with it, although several of them such as Cytokeratin AE1/AE3 and EMA, as demonstrated in this study, should be non-reacting as they react with proteins normally present only in epithelial cells and absent in healthy brain tissue. This can often be misleading and, in certain cases, lead to histopathological misdiagnosis

Correlation between coagulative tumor necrosis and clinicopathologic parameters in clear cell renal cell carcinoma

ВъведениеТуморната некроза (TН) многократно е свързана с по-големия размер на туморите, по-ниска диференциация и по-висока пролиферативна активност и въпреки че патогенезата й остава до голяма степен неизвестна, се смята, че тя представлява индиректен маркер за по-агресивно биологично поведение на тумора.ЦелЦелта на проучването е да се изследва наличието на некротични участъци в метастатичен и неметастатичен светлоклетъчен карцином на бъбрека и да се анализира корелацията им с клинико-патологични параметри.Материали и методиПроучването включва данни от 43 пациенти, които са претърпели радикална нефректомия. Изследваните патологични признаци включват размер на първичния тумор, метастази в регионални лимфни възли и отдалечени метастази, TNM стадиране, диференциация според нуклеарния грейд и наличие на коагулационна туморна некроза. Степента на туморната некроза е оценена и регистрирана като отсъстваща, фокална ( 30%). Туморната некроза се дефинира като наличие на микроскопски установена коагулационна некроза, характеризираща се с хомогенни полета от дегенеративни и некротични клетки. Фокуси на хиалинизация, хеморагии и фиброза са отчетени като вторични дегенеративни промени в туморната тъкан. Корелацията между ТН и другите клинико-патологични параметри се установи чрез непараметрични анализ.РезултатиНаличие на некроза в туморния паренхим се откри при всички случаи с метастази. В случаите без метастази некроза се открива само при 6 (18%). Наличието на ТН статистически значимо корелира с наличието на метастази, голям размер на първичния тумор и лоша ядрена диференциация (р 30% of the tumor area). TN was defined as the presence of microscopic coagulative necrosis, characterized by homogeneous clusters and sheets of degenerating and dead cells. Histopathologic regressive changes, such as cystic transformation, hyalinization, and fibrosis, were not considered to represent necrosis. The relationship between TN and other clinicopathologic parameters was studied by nonparametric tests.Results: Necrosis was found in all cases with metastases. In cases without metastase, necroses were found in only 5 (16%). The presence of TN was statistically significantly associated with the presence of metastases, high T stage, large tumor size, poor differentiation (p<0.05). No statistically significant association between age or sex and the presence of TN was observed.Conclusion: It is clear that coagulative tumor necrosis is a prognostic marker that can be readily applied in combination with more traditional variables (i.e., tumor size, TNM stage, and nuclear grade) to enhance the performance of renal cell carcinoma scoring algorithms and predictive models currently in use to help assign follow-up and treatment in the clinical setting

Role of adventitia in vascular remodeling in hypertension: a trophobiological view

The vascular wall has the capacity to undergo remodeling in response to long-term changes or injuries. This is a process of structural rearrangement that involves cell growth, cell death, cell migration, cell modulation and secretion/degradation of extracellular matrix molecules. Vascular remodeling is an adaptive phenomenon, e.g. Glagov's compensatory enlargement in atherosclerosis, but it may grow into vascular diseases, such as hypertension, atherosclerosis, and coronary restenosis after angioplasty. Nowadays paradigms defining the cell biology of vascular diseases are the following: (i) the hypertensive vessel is characterized by hyperinnervation-associated medial thickening due to smooth muscle cell (SMC) hypertrophy/hyperplasia and increased extracellular matrix content, (ii) the atherosclerotic plaque is characterized by SMC/immune cells/increased extracellular matrix-containing intimal thickening, and (iii) the restenotic coronary artery is characterized by SMC/immune cells-containing neointimal thickening. The spontaneously hypertensive rats (SHR), the stroke-prone SHR (SHRSP), the genetically hypertensive (GH) rats, and other genetically hypertensive strains are widely used as a model of human essential hypertension. In this volume of Biomedical Reviews, Bell updates the knowledge about vascular wall neurotrophobiology in relation to the pathogenesis of hypertension in SHR and GH rats. Also, Kondo et al systematize the perivascular nerve-related SMC structural changes in the development of hypertension in SHR and SHRSP. The data presented in these reviews are evaluated mainly in terms of Levi-Montalcini's neurotrophic theory.Biomedical Reviews 1996; 6: 5-10

Nerve-mast cell-nerve growth factor link: the mast cell as yin-yang modulator in inflammation and fibrosis

Inflammation and fibroproliferation are biological responses aiming at recovering from injury. Wound healing is considered a paradigm of such a homeostatic phenomenon. However, what begins as a protective response, in excess becomes a damaging process we call chronic inflammatory-fibroproliferative disease.Biomedical Reviews 1995; 4: 1-6

Adipobiology of inflammation

Besides its importance for glucose, lipid and energy metabolism, the present paradigm defines adipose tissue as thebody's largest endocrine and paracrine organ. Accumulating evidence demonstrates that adipose tissue cells synthesize and release a large number of signaling proteins collectively termed adipokines. Adipokines regulate a broad spectrum of biological processes, with inflammation being a key example. This defines a new field of study: adipobiology of inflammation. Herewe shalldance round it, supposing that the pathogenesis of inflammation-related diseases such as atherosclerosis, thyroid-associated ophthalmopathy, inflammatory bowel diseases, and breast cancer may be influenced by competing stimulatory and inhibitory effects mediated by adipokines. This concept may reveal new tools for the development of adipopharmacology of inflammatory disease.Biomedical Reviews 2005; 16: 83-88

Born on 19 November 1912: he, George Palade, a man who contributed so much to the progress of modern cell biology

In his 1971 paper George Palade wrote for Albert Claude, the founder of biological electron microscopic method: “Seldom has a field owed so much to a single man”. Herein, we articulate the same words for George Palade, the Teacher of many generations in cell biology research and education. Herein we focus on the paradigm shifts in the cell biology, namely the transition from light to transmission electron microscopy in studying cell protein secretion made by George Palade. Onward, we discuss on the transition from contractile to secretory phenotype of vascular smooth muscle cells initiated by Maria Daria Haust and developed by our research group. Taken together, we argue that one of the present challenges in cell biology is to cultivate secretocentric thinking and thus further focusing on how we could make secretory pathways work for the benefit of human’s health

Neuroadipobiology of arrhythmogenic right ventricular dysplasia. An immunohistochemical study of neurotrophins

Arrhythmogenic right ventricular dysplasia (ARVD) is an inherited disorder of cardiomyocyte-to-cardiomyocyte adhesion proteins associated with ventricular arrhythmias and sudden cardiac death. It is a characterized by progressive fibrofatty replacement of right ventricular myocardium. The presence of adipose tissue either with or without fibrous tissue, scattered among cardiomyocytes is the histological hallmark of the disease. Being in the myocardium, adipocytes trigger damage to cardiomyocytes, thus causing electrical instability of the right ventricular myocardium, but the molecular pathogenesis of such an electrical instability in ARVD is still unclear. Since (i) adipose tissue replacement of cardiomyocytes is the most essential histological finding in ARVD, (ii) nerve growth factor (NGF) exerts an arrhythmogenic effect related to sudden cardiac death, and (iii) adipose tissue produces NGF and brain-derived neurotrophic factor (BDNF), the aim of the present study is to analyze immunohistochemically ARVD-related adipocytes with special attention to the expression of NGF and related neurotrophins, BDNF and neurotrophin-3 (NT-3) and their respective TrkA, TrkB and TrkC receptors. Eight cases with ARVD were autopsy proven. The present results demonstrate that the intramyocardial adipocytes and cardiomyocytes in ARVD express NGF/TrkA and NT-3/TrkC, suggesting that they may play a substantial part in life-threatening myocardial electrical instability