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Article: What do we know about the Balkan endemic nephropathy and the uroepithelial tumors?

Polenakovic, Momir / Stefanović, Vladisav

Prilozi (Makedonska akademija na naukite i umetnostite. Oddelenie za medicinski nauki)

2014 Volume 35, Issue 1, Page(s) 11–15

Abstract: Balkan endemic nephropathy (BEN), a familial chronic tubulo interstitial disease with a slow progression to terminal renal failure, affects people living in the alluvial plains along the tributaries of the Danube River. One of its most peculiar ... ...

Abstract	Balkan endemic nephropathy (BEN), a familial chronic tubulo interstitial disease with a slow progression to terminal renal failure, affects people living in the alluvial plains along the tributaries of the Danube River. One of its most peculiar characteristics is a strong association with upper urothelial cancer. An increased incidence of upper urinary tract (UUT) transitional cell cancer (TCC) was discovered among the inhabitants of endemic settlements and in families affected by BEN. In areas where BEN is endemic, the incidence of upper tract TCC is significantly higher, even 100 times, than in non-endemic regions. Until now, several hypotheses have been introduced about the etiopathogenesis of BEN. Only the toxic effect aristolochia clematidis has been confirmed as a factor in the occurrence of the disease. We don't have specific biomarkers for an early diagnosis of BEN and UUT-TCC. With application of modern molecular and genetic methods in investigation of etiopathogenesis and diagnosis of BEN and UUT-TCC we should expect improvement in the study of BEN.
MeSH term(s)	Balkan Nephropathy/complications ; Balkan Nephropathy/epidemiology ; Balkan Peninsula/epidemiology ; Carcinoma, Transitional Cell ; Humans ; Incidence ; Kidney Failure, Chronic/complications ; Kidney Failure, Chronic/epidemiology ; Kidney Neoplasms/complications ; Kidney Neoplasms/epidemiology
Language	English
Publishing date	2014-01-15
Publishing country	North Macedonia
Document type	Journal Article ; Review
ZDB-ID	2743787-5
ISSN	1857-8985 ; 1857-9345
ISSN (online)	1857-8985
ISSN	1857-9345
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Article ; Online: Hypoxia and spermatogenesis.

Jankovic Velickovic, Ljubinka / Stefanovic, Vladisav

International urology and nephrology

2013 Volume 46, Issue 5, Page(s) 887–894

Abstract: This review mainly focuses on our understanding of spermatogenesis in physiological and pathological hypoxic condition. Real hypoxia is closely related to vascular changes and an increase in testicular temperature. Both induce a reduction in sperm count ... ...

Abstract	This review mainly focuses on our understanding of spermatogenesis in physiological and pathological hypoxic condition. Real hypoxia is closely related to vascular changes and an increase in testicular temperature. Both induce a reduction in sperm count and can be related to the increase in germ cell apoptosis. On the other hand, change in the temperature, and oxygen levels in the microenvironment have influence on spermatogonial stem cell function and differentiation. The initial connection between hypoxia and a factor critical for stem cell maintenance is alteration in Oct-4 expression, and these data may be a useful strategy for modulating stem cell function. Unilateral testicular ischemia-induced cell death can be accompanied by an increase in germ cell apoptosis in the contralateral testis. The injury of contralateral testis following unilateral testicular damage is controversial, and it can contribute to the reduction in fertility.
MeSH term(s)	Adaptation, Physiological ; Apoptosis ; Body Temperature Regulation ; Cell Differentiation ; Humans ; Hypoxia/physiopathology ; Ischemia/physiopathology ; Male ; Octamer Transcription Factor-3/metabolism ; Sperm Count ; Spermatogenesis/physiology ; Spermatozoa/physiology
Chemical Substances	Octamer Transcription Factor-3
Language	English
Publishing date	2013-11-22
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	204048-7
ISSN	1573-2584 ; 0301-1623 ; 0042-1162
ISSN (online)	1573-2584
ISSN	0301-1623 ; 0042-1162
DOI	10.1007/s11255-013-0601-1
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Zs.A 733: Show issues

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Article ; Online: Health-related quality of life in different stages of renal failure.

Avramovic, Marina / Stefanovic, Vladisav

Artificial organs

2012 Volume 36, Issue 7, Page(s) 581–589

Abstract: Measures of health-related quality of life (HRQoL) have a significant predictive value on patient survival and hospitalizations, especially in patients with chronic kidney disease (CKD). In this review, some of the major studies performed in patients ... ...

Abstract	Measures of health-related quality of life (HRQoL) have a significant predictive value on patient survival and hospitalizations, especially in patients with chronic kidney disease (CKD). In this review, some of the major studies performed in patients with different stages of renal failure are presented. The most used instrument for measuring HRQoL is the Short form health survey questionnaire (SF-36). Patients with predialysis CKD had higher SF-36 scores than a large cohort of hemodialysis (HD) or peritoneal dialysis (PD) patients, but lower scores than those reported for the adult population. Kidney transplantation offers better HRQoL than dialysis. Hemoglobin level predicted both physical and mental domain scores of the SF-36. HRQoL of HD and PD patients were compared in only a few studies, mostly because these studies are difficult to interpret. PD patients generally have lower comorbidity scores at the onset of end-stage renal disease (ESRD), independent of other factors influencing modality selection. Comorbid medical conditions are common in patients with ESRD, and are an important contributing factor to clinical outcomes and quality of life. Depression occurs in about 20-30% of dialysis patients. This is important because of the negative impact depression has on quality of life, but also because depression is now established as a factor that can significantly affect morbidity and mortality in ESRD patients. Sexual life satisfaction showed marked deterioration in all age groups. Patients aged over 65 scored significantly better than younger patients on dialysis stress scales, and were generally more satisfied with life. Longitudinal studies are needed to define periods at risk for decline in HRQoL during progression of CKD.
MeSH term(s)	Humans ; Kidney/pathology ; Kidney Failure, Chronic/complications ; Kidney Failure, Chronic/epidemiology ; Kidney Failure, Chronic/pathology ; Kidney Failure, Chronic/therapy ; Kidney Transplantation ; Peritoneal Dialysis ; Renal Dialysis ; Sickness Impact Profile ; Treatment Outcome
Language	English
Publishing date	2012-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	441812-8
ISSN	1525-1594 ; 0160-564X
ISSN (online)	1525-1594
ISSN	0160-564X
DOI	10.1111/j.1525-1594.2011.01429.x
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Zs.A 1463: Show issues

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Article: Balkan nephropathy.

Stefanovic, Vladisav / Toncheva, Draga / Polenakovic, Momir

Clinical nephrology

2015 Volume 83, Issue 7 Suppl 1, Page(s) 64–69

Abstract: Balkan endemic nephropathy (BN), frequently associated to upper urothelial cancer, is a familial chronic tubulointerstitial disease with insidious onset and slow progression to end-stage renal disease. After 60 years of research, its cause remains the ... ...

Abstract	Balkan endemic nephropathy (BN), frequently associated to upper urothelial cancer, is a familial chronic tubulointerstitial disease with insidious onset and slow progression to end-stage renal disease. After 60 years of research, its cause remains the major unanswered question. Etiology assumes polygenic susceptibility to the disease in interaction with multiple environmental factors. Chronic intoxication with Aristolochia is the major environmental risk factor for this disease. The mycotoxin hypothesis considers that BN is produced by ochratoxin A. The Pliocene lignite hypothesis assumes that the disease is caused by long-term exposure to organic toxins leached from coal nearby the endemic villages. Exome sequencing of 22,000 genes revealed that mutant genes (CELA1, HSPG2, and KCNK5) in BN patients encode proteins involved in basement membrane/extracellular matrix and vascular tone, which are tightly connected to the process of angiogenesis. SEC61G, IL17RA, and HDAC11 proved to be differently methylated throughout all patient-control pairs. The acetylation of histone lysine residues was detected and found increased at specific sites of H3 and total H4 histones isolated from urothelial cells of patients with BN. The results of molecular biological research will allow the discovery of genetic markers of BN and associated urothelial cancer, permitting early detection of BN-predisposing mutations and identification of susceptible individuals who might be at risk of exposure to environmental agents. The research of gene-gene and gene-environment interactions could lead to further studies to determine the precise risk for BN.
MeSH term(s)	Balkan Nephropathy/complications ; Balkan Nephropathy/epidemiology ; Balkan Nephropathy/genetics ; Genetic Markers ; Global Health ; Humans ; Incidence ; Kidney Failure, Chronic/epidemiology ; Kidney Failure, Chronic/etiology ; Risk Factors
Chemical Substances	Genetic Markers
Language	English
Publishing date	2015-02-28
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	185101-9
ISSN	0301-0430
ISSN	0301-0430
DOI	10.5414/cnp83s064
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Article: Endemic nephropathy and upper urothelial carcinoma--new insights in molecular biology.

Jankovic Velickovic, Ljubinka / Dolicanin, Zana / Stefanovic, Vladisav

Prilozi (Makedonska akademija na naukite i umetnostite. Oddelenie za medicinski nauki)

2014 Volume 35, Issue 1, Page(s) 57–64

Abstract: Upper Tract Urothelial Carcinoma (UTUC) is an uncommon disease which occurs more frequently in some regions of Balkan countries than in other areas in the world. Investigation of UTUC in the South Morava River basin and its tributaries where BEN is ... ...

Abstract	Upper Tract Urothelial Carcinoma (UTUC) is an uncommon disease which occurs more frequently in some regions of Balkan countries than in other areas in the world. Investigation of UTUC in the South Morava River basin and its tributaries where BEN is endemic revealed increased frequency not only of tumour of the renal pelvis and ureter but also of urinary bladder tumours. A comparative morphological and immunohistochemical study of UTUC in the BEN region and control rural and city populations free of BEN, identify growth pattern as the best morphological characteristic which differentiated BEN and control tumours, i.e. solid growth for BEN tumours and papillary for control tumours. Overexpression of tumour suppressor p53 as well as decreased expression of E-CD was detected in BEN tumours. Other cells cycle related molecular markers--Cyclin D1, p16, and HER-2 showed no difference in expression between groups, as well as the proliferative marker Ki-67. Investigation of apoptosis-related markers identifies Bax as a specific marker of BEN-associated UTUC. Decrease of the pro-apoptotic protein Bax together with alteration of Survivin may be indicative of specific disturbances of an intrinsic apoptotic pathway in UTUC arising in endemic areas.
MeSH term(s)	Apoptosis ; Balkan Nephropathy/diagnosis ; Balkan Nephropathy/epidemiology ; Balkan Nephropathy/metabolism ; Biomarkers, Tumor/metabolism ; Carcinoma, Transitional Cell/diagnosis ; Carcinoma, Transitional Cell/epidemiology ; Carcinoma, Transitional Cell/metabolism ; Humans ; Molecular Biology/methods ; Urologic Neoplasms/diagnosis ; Urologic Neoplasms/epidemiology ; Urologic Neoplasms/metabolism
Chemical Substances	Biomarkers, Tumor
Language	English
Publishing date	2014-01-15
Publishing country	North Macedonia
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2743787-5
ISSN	1857-8985 ; 1857-9345
ISSN (online)	1857-8985
ISSN	1857-9345
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Article ; Online: Fifty years of research in Balkan endemic nephropathy: where are we now?

Stefanović, Vladisav / Polenaković, Momir

Nephron. Clinical practice

2009 Volume 112, Issue 2, Page(s) c51–6

Abstract: Despite broad investigations into the possible role of genetic factors, environmental agents and immune mechanisms, the etiology of Balkan endemic nephropathy (BEN) is only partially understood. An increased incidence of upper urothelial cancer in ... ...

Abstract	Despite broad investigations into the possible role of genetic factors, environmental agents and immune mechanisms, the etiology of Balkan endemic nephropathy (BEN) is only partially understood. An increased incidence of upper urothelial cancer in patients with BEN and in populations from endemic settlements has been demonstrated. Genetic studies have landed support for genetic predisposition to BEN. The similarity of the morphological and clinical pattern of BEN and Chinese herbs nephropathy has raised the possibility of a common etiologic agent, aristolochic acid (AA), described in 1969 by Ivić and confirmed by a recent study of AA-DNA adducts. Ochratoxin A (OTA) is studied extensively as the etiologic agent of BEN. Weathering of low-rank coals nearby the endemic villages produces water-soluble polycyclic aromatic hydrocarbons and aromatic amines, similar to metabolic products of acetaminophen, which has a causal relationship with analgesic nephropathy. AA is confirmed as the etiologic agent of BEN; however, it may not be the sole risk factor. More research is needed on the patterns of BEN over time and between different endemic places. Therefore, it is important to test etiological hypotheses in different endemic foci, preferably as a multicentric research. An international approach to solving the etiology of BEN is needed in the coming years. The geographic correlation and presence of AA-DNA adducts in both BEN and associated urothelial cancer support the hypothesis that these diseases share a common etiology.
MeSH term(s)	Balkan Nephropathy/diagnosis ; Balkan Nephropathy/epidemiology ; Coal ; Environmental Exposure/statistics & numerical data ; Environmental Pollution/statistics & numerical data ; Humans ; Incidence ; Polycyclic Compounds
Chemical Substances	Coal ; Polycyclic Compounds
Language	English
Publishing date	2009
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	207121-6
ISSN	1660-2110 ; 1423-0186 ; 2235-3186 ; 1660-8151 ; 0028-2766
ISSN (online)	1660-2110 ; 1423-0186 ; 2235-3186
ISSN	1660-8151 ; 0028-2766
DOI	10.1159/000213081
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Article ; Online: Dental tissue--new source for stem cells.

Petrovic, Vladimir / Stefanovic, Vladisav

TheScientificWorldJournal

2009 Volume 9, Page(s) 1167–1177

Abstract: Stem cells have been isolated from many tissues and organs, including dental tissue. Five types of dental stem cells have been established: dental pulp stem cells, stem cells from exfoliated deciduous teeth, stem cells from apical papilla, periodontal ... ...

Abstract	Stem cells have been isolated from many tissues and organs, including dental tissue. Five types of dental stem cells have been established: dental pulp stem cells, stem cells from exfoliated deciduous teeth, stem cells from apical papilla, periodontal ligament stem cells, and dental follicle progenitor cells. The main characteristics of dental stem cells are their potential for multilineage differentiation and self-renewal capacity. Dental stem cells can differentiate into odontoblasts, adipocytes, neuronal-like cells, glial cells, osteoblasts, chondrocytes, melanocytes, myotubes, and endothelial cells. Possible application of these cells in various fields of medicine makes them good candidates for future research as a new, powerful tool for therapy. Although the possible use of these cells in therapeutic purposes and tooth tissue engineering is still in the beginning stages, the results are promising. The efforts made in the research of dental stem cells have clarified many mechanisms underlying the biological processes in which these cells are involved. This review will focus on the new findings in the field of dental stem cell research and on their potential use in the therapy of various disorders.
MeSH term(s)	Animals ; Cell Differentiation ; Dentinogenesis ; Dentition ; Humans ; Stem Cells/cytology ; Stem Cells/metabolism ; Tissue Engineering
Language	English
Publishing date	2009-10-14
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2075968-X
ISSN	1537-744X ; 1537-744X
ISSN (online)	1537-744X
ISSN	1537-744X
DOI	10.1100/tsw.2009.125
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Article ; Online: Balkan endemic nephropathy and associated urothelial cancer.

Stefanovic, Vladisav / Radovanovic, Zoran

Nature clinical practice. Urology

2008 Volume 5, Issue 2, Page(s) 105–112

Abstract: Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease described only in some rural parts of southeastern Europe. One of its most peculiar characteristics is a strong association with upper urothelial cancer (UUC). BEN-related UUC has ... ...

Abstract	Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial disease described only in some rural parts of southeastern Europe. One of its most peculiar characteristics is a strong association with upper urothelial cancer (UUC). BEN-related UUC has the same histological features as other forms of UUC in general, but is more frequently bilateral, less frequently affects the bladder and has a sex ratio close to 1. BEN and BEN-associated UUC share the same etiology. Over time, incidence of these conditions has been declining. Since BEN was first described, around half a century ago, socioeconomic changes (in housing, farming, living standards, etc.) have been profound and have obscured the factors responsible for the observed reduction in incidence. Whatever the causes of BEN, the disease might not be restricted only to southeastern Europe. Rather, the intensity of exposure to risk factors for BEN and, consequently, clustering of cases has more likely determined our knowledge of topographical distribution of an etiological entity that is much more widespread, or that might even be ubiquitous in its sporadic form.
MeSH term(s)	Balkan Nephropathy/complications ; Balkan Nephropathy/diagnosis ; Balkan Nephropathy/epidemiology ; Balkan Nephropathy/etiology ; Balkan Nephropathy/therapy ; Carcinoma, Transitional Cell/complications ; Humans ; Kidney Neoplasms/complications
Language	English
Publishing date	2008-02
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	2177665-9
ISSN	1743-4289 ; 1743-4270
ISSN (online)	1743-4289
ISSN	1743-4270
DOI	10.1038/ncpuro1019
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Zs.A 6030: Show issues

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Article ; Online: Primary mucosal melanomas: a comprehensive review.

Mihajlovic, Marija / Vlajkovic, Slobodan / Jovanovic, Predrag / Stefanovic, Vladisav

International journal of clinical and experimental pathology

2012 Volume 5, Issue 8, Page(s) 739–753

Abstract: Primary mucosal melanomas arise from melanocytes located in mucosal membranes lining respiratory, gastrointestinal and urogenital tract. Although a majority of mucosal melanomas originate from the mucosa of the nasal cavity and accessory sinuses, oral ... ...

Abstract	Primary mucosal melanomas arise from melanocytes located in mucosal membranes lining respiratory, gastrointestinal and urogenital tract. Although a majority of mucosal melanomas originate from the mucosa of the nasal cavity and accessory sinuses, oral cavity, anorectum, vulva and vagina, they can arise in almost any part of mucosal membranes. Most of mucosal melanomas occur in occult sites, which together with the lack of early and specific signs contribute to late diagnosis, and poor prognosis. Because of their rareness the knowledge about their pathogenesis and risk factors is insufficient, and also there are not well established protocols for staging and treatment of mucosal melanomas. Surgery is the mainstay of treatment, with trends toward more conservative treatment since radical surgery did not show an advantage for survival. Radiotherapy can provide better local control in some locations, but did not show improvement in survival. There is no effective systemic therapy for these aggressive tumors. Compared with cutaneous and ocular melanoma, mucosal melanomas have lowest percent of five-year survival. Recently revealed molecular changes underlying mucosal melanomas offer new hope for development of more effective systemic therapy for mucosal melanomas. Herein we presented a comprehensive review of various locations of primary melanoma along mucosal membranes, their epidemiological and clinical features, and treatment options. We also gave a short comparison of some characteristics of cutaneous and mucosal melanomas.
MeSH term(s)	Combined Modality Therapy ; Female ; Genital Neoplasms, Female/pathology ; Head and Neck Neoplasms/pathology ; Humans ; Male ; Melanocytes/pathology ; Melanoma/etiology ; Melanoma/pathology ; Melanoma/therapy ; Mouth Neoplasms/pathology ; Mucous Membrane/pathology ; Paranasal Sinus Neoplasms/pathology ; Rectal Neoplasms/pathology ; Skin Neoplasms/etiology ; Skin Neoplasms/pathology ; Skin Neoplasms/therapy ; Survival Rate
Language	English
Publishing date	2012-10-01
Publishing country	United States
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2418306-4
ISSN	1936-2625 ; 1936-2625
ISSN (online)	1936-2625
ISSN	1936-2625
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Article ; Online: Craniofacial bone tissue engineering.

Petrovic, Vladimir / Zivkovic, Petar / Petrovic, Dragan / Stefanovic, Vladisav

Oral surgery, oral medicine, oral pathology and oral radiology

2012 Volume 114, Issue 3, Page(s) e1–9

Abstract: There are numerous conditions, such as trauma, cancer, congenital malformations, and progressive deforming skeletal diseases, that can compromise the function and architectonics of bones of craniofacial region. The need to develop new approaches for ... ...

Abstract	There are numerous conditions, such as trauma, cancer, congenital malformations, and progressive deforming skeletal diseases, that can compromise the function and architectonics of bones of craniofacial region. The need to develop new approaches for treatment of these disorders arises from the fact that conventional therapeutic strategies face many obstacles and limitations. The use of tissue engineering in regeneration of craniofacial bone structures is a very promising possibility and a great challenge for researchers and practitioners. Developments in stem cell biology and engineering have led to the discovery of different stem cell populations and biodegradable materials with suitable properties. This review summarizes the current achievements in tissue engineering of craniofacial bone, temporomandibular joint, and periodontal ligament.
MeSH term(s)	Biocompatible Materials/therapeutic use ; Bone Diseases/surgery ; Bone Regeneration/physiology ; Facial Bones/surgery ; Genetic Therapy ; Humans ; Periodontal Diseases/surgery ; Periodontal Ligament/surgery ; Reconstructive Surgical Procedures/methods ; Skull/surgery ; Stem Cells/physiology ; Temporomandibular Joint Disorders/surgery ; Tissue Engineering/methods ; Tissue Scaffolds
Chemical Substances	Biocompatible Materials
Language	English
Publishing date	2012-09
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2650843-6
ISSN	2212-4411 ; 2212-4403
ISSN (online)	2212-4411
ISSN	2212-4403
DOI	10.1016/j.oooo.2012.02.030
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