RASopathic comedone-like or cystic lesions induced by vemurafenib: a model of skin lesions similar but not identical to those induced by dioxins MADISH.

BACKGROUND: Patients treated with vemurafenib for metastatic melanoma often develop skin lesions similar to those observed after exposure to dioxin-like compounds. We previously called these lesions MADISH (metabolizing acquired dioxin-induced skin hamartoma) when analysing a case of acute dioxin poisoning. OBJECTIVE: We performed a clinical trial aimed at comparing the skin lesions observed under vemurafenib treatment with MADISH in order to bring to light a possible crosstalk between vemurafenib and dioxin pathways. METHODS: In this case series study, we explored the histological aspect of skin lesions in 10 cases treated with vemurafenib for malignant melanoma. We also analysed the ability of vemurafenib and tyrosine kinase inhibitors to induce dioxin-AhR pathway. RESULTS: All patients had skin lesions diagnosed as 'non-inflammatory acneiform eruption' by dermatologists. These were predominantly facial with notable retroauricular involvement and clinically compatible with chloracne/MADISH when assessed by dioxin expert. Histological analysis showed mostly comedone-like lesions and dermal cysts containing epithelial wall with basal or lateral epithelial projections and lamellar keratinization and alterations of remaining sebaceous glands. The expression of CYP1A1, a gene highly induced following dioxin exposure, was not observed in these lesions. Vemurafenib and the tyrosine kinase inhibitors erlotinib and gefitinib did not induce CYP1A1 activity. DISCUSSION: Although the skin lesions under vemurafenib treatment were morphologically similar to MADISH, the absence of CYP1A1 expression in dermal cysts of patients and the absence of CYP1A1 activation by vemurafenib led us consider that these skin lesions were different from true MADISH and not mediated by a crosstalk of AhR signalling, but rather to a hyperactivation of PI3K-Akt pathway as a consequence of vemurafenib treatment. A strong expression of CYP1A1 in the epithelial wall of dermal cysts must be required, parallel to the morphology of the lesions, to make the diagnosis of MADISH, the hallmark of an exposure to dioxin-like/chloracnegen compounds.

Genetic and morphological variability of the European mudminnow Umbra krameri (Teleostei, Umbridae) in Serbia and in Bosnia and Herzegovina, a basis for future conservation activities.

As a basis for future conservation activities, the genetic and external body morphology variability of the European mudminnow Umbra krameri, a highly endangered fish species in Serbia and in Bosnia and Herzegovina, was determined for existing populations with the use of molecular markers (mitochondrial and microsatellite DNA) and geometric morphometric methods. Mitochondrial DNA cytochrome b gene analysis revealed two previously undescribed haplotypes: Da1 (the Lugomir population from the Danube River basin) and Sa1 (the Bakreni Batar and the Gromizelj populations from the Sava River system), with a corresponding genetic distance of 0·7%. Paired values of FST and DAS distances for microsatellite marker data show that the difference between the Danube and the Sava populations is seven to nine times higher than the difference between the populations within the Sava River system. Geometric morphometric analyses also support a clear separation of the Lugomir population from the Bakreni Batar and the Gromizelj populations. The analysis of the body shape variation, however, indicates a significant difference between the two genetically indistinguishable Sava populations. The observed genetic and phenetic relationships of the analysed mudminnow populations most probably represent a consequence of historical, geographical and ecological factors. These results will offer guidelines for future protection, conservation and sustainable management of this species in the region.

New distribution data and population structure of the European mudminnow Umbra krameri in Serbia and Bosnia and Herzegovina.

Seventy-six individuals of the European mudminnow Umbra krameri from two recent populations from Serbia (Bakreni Batar and Lugomir) and one from Bosnia and Herzegovina (Gromizelj) were analysed for habitat preferences and population structure. The population from Lugomir is a newly recorded population in Serbia. Besides this new record, it is noteworthy that all three studied locations are outside the currently known species distribution range limits.

Preparation of Recombinant Centromeric Nucleosomes and Formation of Complexes with Nonhistone Centromere Proteins.

Centromeres are present on each chromosome to direct proper segregation during cell division. The understanding of how the histone H3 variant, CENP-A, epigenetically marks the location of the centromere on the chromosome has been advanced, in part, through the study of histone complexes, nucleosomes, and nucleosomal complexes with nonhistone centromere proteins. In this chapter, we describe the preparation of recombinant versions of these complexes. The methodology is firmly rooted in classic nucleosome reconstitution methods, but we highlight the aspects of the preparations that diverge from those used for the methods established with canonical histones. We also provide a method for producing PCR-amplified nucleosomal DNA sequences in milligram quantities that is particularly useful for studies where multiple sequences and/or chemical modifications are desired. Lastly, we describe our approach to assemble and analyze a complex between the recombinant human CENP-A nucleosome and one of its binding partners, CENP-C.

[Joubert's syndrome]. / Joubertov sindrom.

In 1969 a new syndrome was described by Joubert et al. It is a very rare syndrome as only about 30 cases have been reported, and none in Yugoslavia. The main clinical characteristics are as ballows. - Disturbed respiratory rhythm alternating periods of hyperapnea and apnea) which tend to disappear as the child grows; - Abnormal eyemovements (jerky, rotatory, pendular); - Mental retardation (usually severe and which deteriorates with the age); and - Ataxia (sometimes also severe). The main neuropathological finding is dysplasia of the vermis cerebelli. Typical CT - findings consist of a very large cisterna magna communicating with the fourth ventricle. The prognosis of the syndrome is poor: half of the patients die within the first three years. Early recognition of the syndrome is important in view of prognosis and genetic counselling. The authors report a first case of Joubert's syndrome in Yuhoslavia, and review the relevant literature on this subject.

[Results of a multiphase oncology population screening program in the community of Becej 1986-1987. I. The Hemoccult Program]. / Rezultati multifaznog onkoloskog populacionog skrininga u opstini Becej 1986-1987. godine. I. Hemokult-program.

In the framework of a multiphase oncologic population screening-program performed in persons above 40 years of age according to the census in the community of Becej during 1986-1987, Hemoccult screening program, together with the fluorographic action involved 16.895 (83.80%) persons out of 20.160 predicted ones which was far less than the involvement of persons through the distribution and gathering of the screening material by a specialized nurse. In 907 (5.37%) Hemoccult positive persons out of which 121 (13.34%) persons rejected to cooperate or did not respond to the invitation for further investigation 16 malignant neoplasms in the lower part of the colon (anus 1, rectum 11, sigma 4) were detected as well as 53 polyposes of the rectum and the anus. Besides, 4 malignant neoplasms of the skin were found and 29 benign tumours (27 adenomas of the prostate gland, 1 fibrolipoma glutei and 1 cysta renis). Apart from these diseases 569 other previously not treated pathologic states were found, i.e. new pathologic states were detected in 85.37% of Hemoccult-positive persons. Previously known pathologic states were confirmed in 22.52% of Hemoccult-positive persons. Diagnostic was performed by the rigid rectoscope and in Hemoccult-positive persons with the negative rectoscopis finding radiologic and fiberoscopic investigations were carried out in the less scope due to the deficiency of financial resources. The number of detected malignant neoplasms of the colon surpassed the three-fold value of the average Vojvodina incidence of these localizations of malignant neoplasms at this age.(ABSTRACT TRUNCATED AT 250 WORDS)

[Results of multiphasic oncology screening of the population in the community of Beej 1986-1987. II. Questionnaire screening]. / Rezultati multifaznog onkoloskog populacionog skrininga u opstini Becej 1986-1987. godine. II. Anketni skrining.

In the framework of the multiphase oncologic population screening in the community of Becej in the period from 1986-1987, the inquiry screening comprised 16,895 persons, whereby the following results were obtained: two malignant breast neoplasms, one uterine corpus neoplasm, one carcinoma of the larynx, and out of the non-target locations, not included in the specific questionnaire, there was one carcinoma of the lower lip and one malignant neoplasm of the salivary gland. Besides, 10 benign breast neoplasms and 12 benign uterine neoplasms were also detected. These specific results lagged behind the expected ones on the basis of the known average incidence and mortality in locations of Vojvodina included by this questionnaire. The elucidation of all possible causes leading to this disaccordance, was the task of specific studies intended for the improvement of this questionnaire as a method for the early detection of malignant and premalignant lesions. Other numerous mass pathological states were detected during the screening of either the characteristic signs of specific malignant neoplasm locations, or of risk factors of particular importance for the appearances of these malignant neoplasms. These health problems with clarified epidemiological dimensions in the population studied, necessitated planned solution according to the accepted doctrinary principals (protocols). Data on these diseases gave new dimensions to the inquiry (and the overall multiphase) oncologic population screening. The target-health educational effect of this inquiry which reached every man over 40 years of age in the population studied should not be neglected, either.