Targeting the melanoma

Czerniak należy do najbardziej złośliwych nowotworów człowieka, a liczba zachorowań na ten typ nowotworu wzrasta na świecie w zastraszającym tempie. Komórki czerniaka charakteryzują się wyjątkową opornością na stosowane obecnie metody leczenia. Badania z ostatnich lat przyczyniły się do lepszego poznania i zrozumienia biologii nowotworu i otwarły drogę nowym terapiom celowanym. Obecnie wiele czynników znajduje się we wczesnych fazach badań klinicznych, część z nich osiągnęła już III fazę, a w sierpniu 2011 rokuFDA zaaprobowała nowy lek do walki z czerniakiem - Wemurafenib (PLX4032). Artykuł stanowi przegląd najważniejszych białek, szlaków i sieci sygnalizacyjnych zaangażowanych w rozwój i progresję czerniaka, ze szczególnym uwzględnieniem elementów będących najbardziej obiecującymi celami dla terapii antynowotworowej.Melanoma is one of the most aggressive human cancers. Its cells are inevitably resistant to conventional therapies. In recent years, better understanding of melanoma biology, has led to the development of a number of new potential therapeutic agents. Many of these compounds are being tested in early phase of clinical trials, some have already reach phase III. In August 2011 the FDA approved a new drug - Wemurafenib (PLX4032) to treatment unresectable and/or metastatic melanoma. The current article is an overview of the major proteins, signaling pathways and networks involved in the development and progression of melanoma, with particular emphasis on elements that are the most promising targets for anticancer therapy

Ultrastructure of the ventromedial hypothalamic nucleus in fasted and refed young and old rats

Many hypothalamic nuclei are involved in the regulation of food intake and energy homeostasis. An ultrastructural investigation of the hypothalamic ventromedial nucleus (VMN), a hypothetical "satiety centre" was performed to explore the morphological basis of altered feeding behaviour of old rats in an experimental model of fasting/refeeding. Young (5 months old, n = 12) and old (24 months old, n = 12) male Wistar rats were fasted for 48 hours, then refed for 24 hours and sampled thereafter. Brain tissue was fixed by perfusion, histological and ultrathin sections were obtained by routine methods. Although food intake was similar in control young and old rats, during refeeding old animals consumed less chow than young ones. The EM analysis of VMN neurones of old control rats revealed, besides typical age-related residual bodies, deep indentations of the nuclear envelope and the presence of long, undulating rough endoplasmic reticulum cisternae in the cell periphery. In both young and old rats fasting for 48 hours led to the expansion of Golgi complexes and increased folds of the nuclear envelope, which is suggestive of enhanced cellular activity of the VMN neurones. These fasting-induced alterations were sustained in the VMN neurones of refed rats in both age groups. The results showed that the VMN neurones of old control rats differ at the ultrastructural level from young ones. However, starvation and subsequent refeeding cause similar alterations in the hypothalamic neurones of "satiety centre" of both young and old rats

Outpatient decolonization after recurrent skin infection with Panton-Valentine leukocidin (PVL)-producing S. aureus - The importance of treatment repetition

Background: Recurrent skin abscesses are often associated with Panton-Valentine leukocidin-producing strains of S. aureus (PVL-SA). Decolonization measures are required along with treatment of active infections to prevent re-infection and spreading. Even though most PVL-SA patients are treated as outpatients, there are few studies that assess the effectiveness of outpatient topical decolonization in PVL-SA patients. Methods: We assessed the results of topical decolonization of PVL-SA in a retrospective review of patient files and personal interviews. Successful decolonization was defined as the absence of any skin abscesses for at least 6 months after completion of the final decolonization treatment. Clinical and demographic data was assessed. An intention-to-treat protocol was used. Results: Our cohort consisted of 115 symptomatic patients, 66% from PVL-positive MSSA and 19% from PVL-positive MRSA. The remaining 16% consisted of symptomatic patients with close contact to PVL-SA positive index patients but without detection of PVL-SA. The majority of patients were female (66%). The median age was 29.87% of the patients lived in multiple person households. Our results showed a 48% reduction in symptomatic PVL-SA cases after the first decolonization treatment. The results also showed that the decrease continued with each repeated decolonization treatment and reached 89% following the 5th treatment. A built multivariable Cox proportional-hazards model showed that the absence of PVL-SA detection (OR 2.0) and living in single person households (OR 2.4) were associated with an independently increased chance of successful decolonization. Conclusion: In our cohort, topical decolonization was a successful preventive measure for reducing the risk of PVL-SA skin abscesses in the outpatient setting. Special attention should be given to patients living in multiple person households because these settings could confer a risk that decolonization will not be successful

Severe infections of Panton-Valentine leukocidin positive Staphylococcus aureus in children

Infections caused by Panton-Valentine leukocidin-positive Staphylococcus aureus (PVL-SA) mostly present as recurrent skin abscesses and furunculosis. However, life-threatening infections (eg, necrotizing pneumonia, necrotizing fasciitis, and osteomyelitis) caused by PVL-SA have also been reported.We assessed the clinical phenotype, frequency, clinical implications (surgery, length of treatment in hospitals/intensive care units, and antibiotic treatments), and potential preventability of severe PVL-SA infections in children.Total, 75 children treated for PVL-SA infections in our in- and outpatient units from 2012 to 2017 were included in this retrospective study.Ten out of 75 children contracted severe infections (PVL-methicillin resistant S aureus n = 4) including necrotizing pneumonia (n = 4), necrotizing fasciitis (n = 2), pyomyositis (n = 2; including 1 patient who also had pneumonia), mastoiditis with cerebellitis (n = 1), preorbital cellulitis (n = 1), and recurrent deep furunculosis in an immunosuppressed patient (n = 1). Specific complications of PVL-SA infections were venous thrombosis (n = 2), sepsis (n = 5), respiratory failure (n = 5), and acute respiratory distress syndrome (n = 3). The median duration of hospital stay was 14 days (range 5-52 days). In 6 out of 10 patients a history suggestive for PVL-SA colonization in the patient or close family members before hospital admission was identified.PVL-SA causes severe to life-threatening infections requiring lengthy treatments in hospital in a substantial percentage of symptomatic PVL-SA colonized children. More than 50% of severe infections might be prevented by prompt testing for PVL-SA in individuals with a history of abscesses or furunculosis, followed by decolonization measures

The Sirtuin Family Members SIRT1, SIRT3 and SIRT6: Their Role In Vascular Biology and Atherogenesis

The sirtuins, silent mating-type information regulation 2 (SIRTs), are a family of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases with important roles in regulating energy metabolism and senescence. Activation of SIRTs appears to have beneficial effects on lipid metabolism and antioxidants, prompting investigation of the roles of these proteins in atherogenesis. Although clinical data are currently limited, the availability and safety of SIRT activators such as metformin and resveratrol provide an excellent opportunity to conduct research to better understand the role of SIRTs in human atherosclerosis. Encouraging observations from preclinical studies necessitate rigorous large, prospective, randomized clinical trials to determine the roles of SIRT activators on the progression of atherosclerosis and ultimately on cardiac outcomes, such as myocardial infarction and mortality

Street children- the curse of XXI century Russia

This work is an attempt to answer the question of why on the streets of modern Russia - country rich in money from the sale of oil and gas - lives up to several million children whose nobody wants. So huge number of street children is a serious threat to national security of the state and involves dangerous effects for the whole Russian society. Nobody can understand why the modern state, having power, technology, human potential, can not cope with this problem. What's more, government can not even count the number of minors living on the streets.'Bezprizornost’ has always been in Russia, and the present condition of the problem of street children has its roots in the distant past.The problem of ''beznadzornye' and 'bezprizornye'children in the Russian Federation, that is, generally speaking, street children, is dealed by numerous experts - sociologists, educators, psychologists, etc. They all try to find the causes and factors affecting the growth of this phenomenon in the modern state. There are opinions that the 'bezprizornost' phenomenon in the Russian Federation reached the same level as during the Civil War in 20s, when the streets filled with seven million child-vagrants. Therefore, man should find all those who are responsible for the topicality of this problem in the twenty-first century. It is necessary to check the authenticity of the numerous accusations against the inaction of the Russian authorities in the fight against the phenomenon of street children, as well as prevention of the problem. Man should also consider the situation of all children in contemporary Russia, and the protection or lack of protection by the state of their rights.Thesis has been divided into six chapters that analyze in detail the problem of street children, from clarifying concepts and history reconstruction through the origins of 'beznadzornost' and 'bezprizornost', to a review of contemporary Russian legislation and ways to combat this phenomenon and applied preventive measures. Included are: the author's interview with the Catholic nun, working with street children and children from dysfunctional families in Siberia, as well as memories of the “Starowiejskie” Handmaids associated with the activity of their work with children in Angarsk. Among these stories there are touching memories of children forced to flee from their parents and relatives into the street.In this thesis, the author tried to find the most appropriate term for all the children living on the streets of Russian cities today. This phenomenon is present in virtually all countries of the world. However, in each of them it has its own term and definition. For Russia, the most famous and widespread is the notion 'bezprizornye', which in modern times, however, can not be referenced to all the children which of some reasons, found themselves on the street. Another term currently used - 'beznadzornye', which can not be identified and equated with the term 'bezprizornye'. There is a significant difference between them, which the modern legislation defines. To put it briefly, 'beznadzornye' child is deprived of the care and control by the parents or legal guardians. However 'bezprizorny' is a 'beznadzorny' that has no place of residence and is totally devoid of shelter.In this study, therefore, the author uses the general term for street children, under which we should understand both 'bezprizornyje' and 'beznadzornyje'. These formal terms are separately used only in situations in which it is important to highlight the characteristics specific to a particular group of street children.Niniejsza praca jest próbą odpowiedzi na pytanie, dlaczego na ulicach współczesnej Rosji, państwa obfitego w pieniądze, pochodzące ze sprzedaży ropy i gazu, żyje nawet do kilku milionów nikomu nie potrzebnych dzieci. Tak ogromna liczba dzieci ulicy stanowi poważne zagrożenie dla bezpieczeństwa narodowego państwa i pociąga za sobą niebezpieczne dla całego społeczeństwa rosyjskiego skutki. Nikt nie może zrozumieć, dlaczego współczesne państwo, posiadające siłę, technologie, ludzki potencjał, nie może poradzić sobie z tym problemem. Co więcej, nie potrafi nawet policzyć żyjących na ulicach niepełnoletnich.Bezprizornost’ w Rosji istniała od zawsze, a dzisiejsza kondycja problemu dzieci ulicy ma swoje korzenie w dalekiej przeszłości.Problemem istnienia w Federacji Rosyjskiej bezprizornych i beznadzornych dzieci, czyli ogólnie mówiąc dzieci ulicy, zajmują się liczni eksperci – socjolodzy, pedagodzy, psycholodzy, itp. Wszyscy oni starają się znaleźć przyczyny oraz czynniki wpływające na wzrost tego zjawiska we współczesnym państwie. Pojawiają się opinie, że zjawisko bezprizornosti w Federacji Rosyjskiej osiągnęło poziom wojny domowej lat 20., kiedy to na ulicach, po tragicznych wydarzeniach tamtych czasów, znalazło się siedem milionów dzieci-włóczęgów. Dlatego też, należy znaleźć wszystkich tych, którzy są odpowiedzialni za aktualność tego problemu w XXI wieku. Niezbędne jest, by sprawdzić autentyczność oskarżeń licznych badaczy przeciwko braku działania władz rosyjskich w kwestii walki ze zjawiskiem dzieci ulicy, a także profilaktyki bezprizornosti i beznadzornosti. Należy także zastanowić się nad sytuacją wszystkich dzieci we współczesnej Rosji, nad ochroną lub brakiem ochrony przez państwo ich praw.Praca podzielona została na sześć rozdziałów, które w szczegółowy sposób analizują problem dzieci ulicy, poczynając od wyjaśnienia pojęć i rekonstrukcji historii, poprzez genezę bezprizornosti i beznadzornosti, i kończąc na przeglądzie współczesnego rosyjskiego ustawodawstwa oraz sposobów walki z tym zjawiskiem i stosowanej profilaktyki. Do pracy dołączony został wywiad autorki z katolicka siostrą zakonną, pracującą z dziećmi ulicy i dziećmi z rodzin dysfunkcyjnych na Syberii, a także wspomnienia Sióstr Służebniczek Starowiejskich związane z działalnością ich zgromadzenia i pracą z dziećmi w Angarsku. Wśród tych opowieści znaleźć można wzruszające historie dzieci, zmuszonych uciekać od swoich rodziców i krewnych na ulicę.W niniejszej pracy autorka starała się znaleźć najbardziej odpowiedni termin, określający wszystkie dzieci żyjące na ulicach współczesnych miast rosyjskich. Zjawisko to obecne jest praktycznie we wszystkich państwach świata. Jednak w każdym z nich ma własne określenie i definicję. Dla Rosji najbardziej znanym i rozpowszechnionym jest pojęcie bezprizornyje (bezprizorni), które w dzisiejszych czasach nie może być jednak odnoszone do wszystkich dzieci, które z tych lub innych przyczyn znalazły się na ulicy. Obecnie używa się jeszcze jednego określenia – beznadzornyje (beznadzorni), którego nie można utożsamiać i stawiać na równi z terminem bezprizornyj. Istnieje bowiem pomiędzy nimi znacząca różnica, którą określa współczesne prawodawstwo. Mówiąc pokrótce, beznadzornyj to dziecko pozbawione opieki i kontroli ze strony jego rodziców lub opiekunów prawnych. Natomiast bezprizornyj to beznadzornyj, nie posiadający miejsca zamieszkania lub pobytu – całkowicie pozbawiony dachu nad głową.W niniejszej pracy autorka posługuje się zatem ogólnym terminem dzieci ulicy, pod którym rozumieć należy zarówno bezprizornych, jak i beznadzornych. Pojęć tych odrębnie używa jedynie w momentach, w których istotne jest podkreślenie cech swoistych dla danej grupy dzieci ulicy

Effect of α3β1 and αvβ3 integrin glycosylation on interaction of melanoma cells with vitronectin

The metastatic transformation of melanocytes is associated with altered expression of adhesion molecules, including αvβ3 and α3β1 integrins. Integrin αvβ3 is a primary vitronectin (VN) receptor, while both integrin types take part in adhesion to VN when they are in complex with uPAR. Although their role in melanoma cell interaction with VN is of great interest, the influence of N-oligosaccharides attached to these glycoproteins is still unappreciated. The present study assesses the role of αvβ3 and α3β1 integrins and the influence of their glycosylation status on WM9 and WM239 metastatic melanoma cell interactions with VN. Cell adhesion to and migration on VN were selected as the studied cell behaviour parameters. Functionblocking antibodies and swainsonine (SW) treatment were used in these tests. Both cell lines interacted with VN in an integrin-mediated but cell-line-specific manner. In WM9 cells, migration was not completely inhibited by antibodies against α3β1 or αvβ3 integrins, suggesting the participation of other VN receptors. In both cell lines in coprecipitation test the formation of an integrins/uPAR complex was shown. In the presence of SW formation of the complex did not occur, suggesting the participation of glycosylation in this proccess. Additionally, the adhesion properties of WM9 cells were changed after SW treatment. Our results suggest that in these two metastatic cell lines integrin-linked N-oligosaccharides influence the VN adhesion receptor activity and function