CRAF R391W is a melanoma driver oncogene.

Approximately 75% of melanomas have known driver oncogenic mutations in BRAF, NRAS, GNA11 or GNAQ, while the mutations providing constitutive oncogenic signaling in the remaining melanomas are not known. We established a melanoma cell line from a tumor with none of the common driver mutations. This cell line demonstrated a signaling profile similar to BRAF-mutants, but lacked sensitivity to the BRAF inhibitor vemurafenib. RNA-seq mutation data implicated CRAF R391W as the alternative driver mutation of this melanoma. CRAF R391W was homozygous and over expressed. These melanoma cells were highly sensitive to CRAF, but not BRAF knockdown. In reconstitution experiments, CRAF R391W, but not CRAF WT, transformed NIH3T3 cells in soft-agar colony formation assays, increased kinase activity in vitro, induced MAP kinase signaling and conferred vemurafenib resistance. MAP kinase inducing activity was dependent on CRAF dimerization. Thus, CRAF is a bona fide alternative oncogene for BRAF/NRAS/GNAQ/GNA11 wild type melanomas

JUN dependency in distinct early and late BRAF inhibition adaptation states of melanoma.

A prominent mechanism of acquired resistance to BRAF inhibitors in BRAF (V600) -mutant melanoma is associated with the upregulation of receptor tyrosine kinases. Evidences suggested that this resistance mechanism is part of a more complex cellular adaptation process. Using an integrative strategy, we found this mechanism to invoke extensive transcriptomic, (phospho-) proteomic and phenotypic alterations that accompany a cellular transition to a de-differentiated, mesenchymal and invasive state. Even short-term BRAF-inhibitor exposure leads to an early adaptive, differentiation state change-characterized by a slow-cycling, persistent state. The early persistent state is distinct from the late proliferative, resistant state. However, both differentiation states share common signaling alterations including JUN upregulation. Motivated by the similarities, we found that co-targeting of BRAF and JUN is synergistic in killing fully resistant cells; and when used up-front, co-targeting substantially impairs the formation of the persistent subpopulation. We confirmed that JUN upregulation is a common response to BRAF inhibitor treatment in clinically treated patient tumors. Our findings demonstrate that events shared between early- and late-adaptation states provide candidate up-front co-treatment targets

RECEPTION DOSTOEVSKY’S "FAMILY ISSUE" IN THE WORKS OF AMERICAN WRITERS

As result, the comparative analysis of creativity of Russian and American authors revealed their similarity of the world view expressed in gravity to the theme of "accident family" and the essential difference in the interpretation of the theme.Thus, the issue of "accident family" of F. Dostoevsky was actualized in the literature of American South with express in the loss of human feeling, a tendency to separate existence, the spiritual loneliness to contribute to the creation of similar typological models of family systems in art works by American authors.The theory of Dostoevsky was based on the Orthodox axiology and the negation of isolation and included the idea of God's love leading to spiritual unity and immortality.The writers of the American South learnt to image of danger separate human existence, solved the problem of the collapse of the modern family within the existential system of values, assuming the individual support of external forces in the face of God did not call for consistent and represent individual courage and stoicism in a decaying reality.As result, the comparative analysis of creativity of Russian and American authors revealed their similarity of the world view expressed in gravity to the theme of "accident family" and the essential difference in the interpretation of the theme.Thus, the issue of "accident family" of F. Dostoevsky was actualized in the literature of American South with express in the loss of human feeling, a tendency to separate existence, the spiritual loneliness to contribute to the creation of similar typological models of family systems in art works by American authors.The theory of Dostoevsky was based on the Orthodox axiology and the negation of isolation and included the idea of God's love leading to spiritual unity and immortality.The writers of the American South learnt to image of danger separate human existence, solved the problem of the collapse of the modern family within the existential system of values, assuming the individual support of external forces in the face of God did not call for consistent and represent individual courage and stoicism in a decaying reality

"FAMILY ISSUE" IN THE RECEPTION RUSSIAN-ANGLO- AMERICAN SLAVIC STUDIES

Family is one of the nuclear concepts of human culture and mentality of any nation. The word "family" belongs to the main category of words giving an idea of a single ethnic culture and an intercultural space as a whole.The concept of "family" associatively related concepts ("home", "father", "mother", "parents") and accumulated the most important idea of the material and spiritual culture, which are transmitted from generation to generation.American society, in the period of the Civil War, Reconstruction and the Great Depression and Russia at the time after abolition of serfdom was similar to interest in the institute of the family as the traditional values to be protected.The gap was not human at all, namely kinship perceived in the American South was extremely painful. The value unit of the South is known not to be the individual itself and the family, or “southern community”.As in the XIX century and in the twentieth century the family in its traditional understanding proclaimed the enduring value of the Southern Society, "legacy" of the past, which would survive in difficult times for the southerners by its inherent quality stability and rootedness in the past.Family is one of the nuclear concepts of human culture and mentality of any nation. The word "family" belongs to the main category of words giving an idea of a single ethnic culture and an intercultural space as a whole.The concept of "family" associatively related concepts ("home", "father", "mother", "parents") and accumulated the most important idea of the material and spiritual culture, which are transmitted from generation to generation.American society, in the period of the Civil War, Reconstruction and the Great Depression and Russia at the time after abolition of serfdom was similar to interest in the institute of the family as the traditional values to be protected.The gap was not human at all, namely kinship perceived in the American South was extremely painful. The value unit of the South is known not to be the individual itself and the family, or “southern community”.As in the XIX century and in the twentieth century the family in its traditional understanding proclaimed the enduring value of the Southern Society, "legacy" of the past, which would survive in difficult times for the southerners by its inherent quality stability and rootedness in the past

"WOMEN'S TOPIC" IN PROSE AND ITS RECEPTION IN RUSSIA AND THE ANGLO-AMERICAN SLAVIC STUDIES

At the end of XX - beginning of XXI century creativity of Dostoevsky Russian writer was experienced a new surge of attention of foreign scientists to the female images and in this direction turned to intensive research studies in the US and the UK.Authors of these works considered heroines of the writer in the context of Orthodox culture, as well as studied the irrational nature of their dual nature, to allow to speak about the current trends in the West, to the interpretation of women's images of the writer as a synthesis of mythological, Christian and psychological features.It goes without saying that the "female" issue occupied an important place in the works of American writers as one of the "dimensions" of historical and cultural development of artistic consciousness and creativity.As one of the dominant themes in American literature XIX- end of the beginning of XX centuries, it provided the key to understanding the place of women in society, her role in the development of social progress, the issue of the specificity of her rights and freedoms.At the end of XX - beginning of XXI century creativity of Dostoevsky Russian writer was experienced a new surge of attention of foreign scientists to the female images and in this direction turned to intensive research studies in the US and the UK.Authors of these works considered heroines of the writer in the context of Orthodox culture, as well as studied the irrational nature of their dual nature, to allow to speak about the current trends in the West, to the interpretation of women's images of the writer as a synthesis of mythological, Christian and psychological features.It goes without saying that the "female" issue occupied an important place in the works of American writers as one of the "dimensions" of historical and cultural development of artistic consciousness and creativity.As one of the dominant themes in American literature XIX- end of the beginning of XX centuries, it provided the key to understanding the place of women in society, her role in the development of social progress, the issue of the specificity of her rights and freedoms

THE IMAGE OF THE AMERICAN "SOUTHERN" WOMEN IN LITERARY WORKS FROM THE POINT OF VIEW OF RUSSIAN AND ENGLAND-AMERICAN SLAVIC STUDIES

The term «southern culture», accepted in American literary criticism, is a complex of ideas forming a special way of perception of the world and self southerners generating idea of the uniqueness and specificity of the southern character.This term has gained a huge value for the development not only of women's literary works, but also in the development of national identity in general. The study of this concept and its genre- forming function in the women's creativity the first half of the XIX century in many ways helps to clarify the nature shaped modern American social ethics and culture concepts of "American family" and "US House", as well as deeper insight into the important phenomenon of national consciousness the so- called "American exclusiveness".The term «southern culture», accepted in American literary criticism, is a complex of ideas forming a special way of perception of the world and self southerners generating idea of the uniqueness and specificity of the southern character.This term has gained a huge value for the development not only of women's literary works, but also in the development of national identity in general. The study of this concept and its genre- forming function in the women's creativity the first half of the XIX century in many ways helps to clarify the nature shaped modern American social ethics and culture concepts of "American family" and "US House", as well as deeper insight into the important phenomenon of national consciousness the so- called "American exclusiveness"

Recurrent patterns of DNA copy number alterations in tumors reflect metabolic selection pressures.

Copy number alteration (CNA) profiling of human tumors has revealed recurrent patterns of DNA amplifications and deletions across diverse cancer types. These patterns are suggestive of conserved selection pressures during tumor evolution but cannot be fully explained by known oncogenes and tumor suppressor genes. Using a pan-cancer analysis of CNA data from patient tumors and experimental systems, here we show that principal component analysis-defined CNA signatures are predictive of glycolytic phenotypes, including 18F-fluorodeoxy-glucose (FDG) avidity of patient tumors, and increased proliferation. The primary CNA signature is enriched for p53 mutations and is associated with glycolysis through coordinate amplification of glycolytic genes and other cancer-linked metabolic enzymes. A pan-cancer and cross-species comparison of CNAs highlighted 26 consistently altered DNA regions, containing 11 enzymes in the glycolysis pathway in addition to known cancer-driving genes. Furthermore, exogenous expression of hexokinase and enolase enzymes in an experimental immortalization system altered the subsequent copy number status of the corresponding endogenous loci, supporting the hypothesis that these metabolic genes act as drivers within the conserved CNA amplification regions. Taken together, these results demonstrate that metabolic stress acts as a selective pressure underlying the recurrent CNAs observed in human tumors, and further cast genomic instability as an enabling event in tumorigenesis and metabolic evolution

МЕДСЕСТРИНСЬКИЙ ПРОЦЕС У КЛІНІЧНІЙ ФАРМАКОЛОГІЇ

The nurse's role regarding conducting physician's orders from the position of nursing process is  considered in this article. This is a new point of view for Ukraine  whereas in the USA and Canada pharmacology for nurses is taught in such a way. We looked into main topics deserved attention from nurses when they distribute or inject medications to patients.The article will be useful for both  practicing nurses and medical students, lecturers of pharmacology in medical colleges.  У статті розглянуто роль медичної сестри у виконанні лікарських призначень з позиції медсестринського процесу. В Україні ця тема нова, тоді як у США та Канаді клінічна фармакологія для медсестер викладається саме таким чином.  Розглянуто основні моменти, на які нееобхідно звертати увагу медичним сестрам, коли вони роздають або вводять лікарські засоби пацієнтам.Стаття буде корисною як практикуючим медсестрам, так і студентам та викладачам клінічної фармакології в медичних коледжах, училищах