Metastatis of cancer cells

Rak je bolest kod koje se tjelesne stanice nekotrolirano razmnožavaju zbog poremećenih normalnih regulacijskih mehanizama. Maligni tumori infiltriraju se u okolna tkiva prodirući među zdrave stanice i mogu se kroz krv i limfne žile proširiti na udaljene dijelove tijela. Proces kojim maligne stanice migriraju s mjesta nastanka primarnog tumora u druge dijelove tijela naziva se metastaziranje. Metastaziranje obuhvaća invaziju, intravazaciju, transport, ekstravazaciju i metastatsku kolonizaciju. Ključni korak za preživljavanje tumora je angiogeneza, odnosno formiranje novih krvnih žila iz već postojećih. Svaki pojedini korak omogućen je brojnim genetskim i epigenetskim promjenama tumorskih stanica, kao i specifičnim interakcijama sa stromalnim stanicama pripadajućeg organa. Kako bi došlo do metastaziranja, potrebno je pronaći odgovarajuću mikrookolinu. Neki tumori kao svoje odredište za metastaziranje biraju prvi najbliži organ, budući da tumorske stanice na svom putu zbog veličine i raznih prepreka lako mogu zaglaviti unutar kapilara. Drugi pak metastaziraju na karakteristična, unaprijed određena mjesta, pri čemu se radi o genetski manipuliranim interakcijama između tumorskih stanica i receptora na stijenkama krvnih žila. Iako otprilike 1 od 3 osobe u nekom razdoblju svog života dobije rak, mnogi se mogu izliječiti zahvaljujući dostignućima u postavljanju dijagnoza i liječenju. Ovisno o vrsti i stadiju raka, terapija može biti namijenjena izliječenju, usporavanju rasta raka ili omogućavanju što ugodnijeg života. Dvije obećavajuće biološke terapije su genska terapija i angiogenska inhibicija. Razvijanje novih terapija koje će ciljno djelovati na produkte gena koji se eksprimiraju u određenim fazama rasta tumora omogućit će sprječavanje daljnjeg rasta i metastaziranje tumora.Cancer is a disease in which somatic cells multiplicate uncontrollably due to disfunctional regulation mechanisms. A malignant tumor is capable of invading into adjacent tissues and may be capable of spreading to distant tissues through blood and lymph vessels. The process by which tumor cells from a primary site invade and migrate to other parts of the body is called metastasis. Tumor cells undergo several major steps during metastasis: invasion, intravasation, transport, extravasation, and metastatic colonization. Metastatic colonization cannot be successful without the formation of new blood vessels from pre-existing ones in a proces called angiogenesis. Each of these events is driven by the acquisition of genetic and epigenetic alterations within tumor cells and the co-option of nonneoplastic stromal cells. Metastases selectively colonize specific organs because of a ‘match’ between the migrating tumor cell and a suitable environment. As the bloodstream is the predominant means of long-distance transport and tumor cells can easily get stuck in the vasculature, organs in close proximity are likely to be main sites of metastasis for a particular primary tumor. On the contrary, the destination of metastasized cells can be genetically influenced by interactions between receptors lining the capillaries in certain a organ and tumor cells. Basic research findings have helped develop two new most promising therapies: gene and anti-angiogenic therapy. Developing new techniques which will target protein products of genes that are associated with primary tumor growth and risk of metastasis could give us hope of managing cancer

Analysis of the antiproliferative and differentiation-inducing effects of the Schwann cells on neuroblastoma cells

Schwannove su stanice neophodne za proces sazrijevanja benignih tipova neuroblastoma, ganglioneuroma, djelujući kroz neuritogenične, anti-proliferativne i pro-apoptostske signale. Cilj ovog diplomskog rada bio je identificirati proteine koje izlučuju Schwanove stanice, a koji sudjeluju u njihovoj interakciji sa stanicama neuroblastoma, te definirati koncentraciju i kombinaciju potrebnu za inhibiciju rasta stanica neuroblastoma. Usporedbom rezultata dobivenih pomoću analize proteina i podataka dobivenih sekvenciranjem transkriptoma s podacima iz literature, izabrano je osam faktora: IGFBP6, FGF7, CNTF, PTN, NGF, BDNF, GDNF i EGFL8. Za funkcionalnu potvrdu njihova djelovanja in vitro, odgovarajući su rekombinantni proteini dodani u medij korišten za kultiviranje dviju staničnih linija neuroblastoma porijeklom iz agresivnih tumora, STA-NB-6 i STA-NB-10, te je učinak izmjeren pomoću protočne citometrije. Ovo je istraživanje identificiralo PTN, IGFBP6 i EGFL8 kao proteine koje izlučuju Schwannove stanice, koji, kada su individualno dodani staničnom mediju tijekom 17 dana, smanjuju proliferaciju i potiču diferencijaciju STA-NB-6 stanica. NGF je potvrđen kao neuritogenični faktor STA-NB-6 stanica. Kombinacija svih navedenih faktora nije imala značajni učinak na STA-NB-6 stanice. Faktori nisu imali značajan učinak na STA-NB-10 stanice. Ovaj rad daje osnovu za daljnja in vitro i buduća istraživanja in vivo, za ispitivanje učinka navedenih faktora na rast neuroblastoma metodom staničnog eksplantata.Schwann cells are essential for the maturation process of benign forms of neuroblastoma, ganglioneuroma, acting via neuritogenic, anti-proliferative and pro-apoptotic signals. The goal of this master thesis was to identify Schwann cell-secreted proteins involved in the cross-talk with neuroblastoma cells, and define the concentration and combination needed to induce a growth-impairing effect in neuroblastoma cells. Eight factors were chosen based on protein array results, RNA-sequencing data and literature research: IGFBP6, FGF7, CNTF, PTN, NGF, BDNF, GDNF and EGFL8. They were functionally validated in vitro by cultivating two neuroblastoma cell lines derived from aggressive tumors, STA-NB-6 and STA-NB-10, in presence of corresponding recombinant proteins. The effects were measured by flow cytometry. PTN, IGFBP6 and EGFL8 were identified as Schwann cell-secreted proteins that cause reduction of cell proliferation and induction of neuronal-like differentiation of STA-NB-6 cells, when individually added to culture media for 17 days. NGF was confirmed as a neuritogenic factor of STA-NB-6 cells. The combination of all factors had no significant effect on STA-NB-6 cells. The factors had no significant effect on STA-NB-10 cells. This work forms basis for further in vitro and in vivo experiments to address the effect of these factors on neuroblastoma growth in xenograft models

Metastatis of cancer cells

Rak je bolest kod koje se tjelesne stanice nekotrolirano razmnožavaju zbog poremećenih normalnih regulacijskih mehanizama. Maligni tumori infiltriraju se u okolna tkiva prodirući među zdrave stanice i mogu se kroz krv i limfne žile proširiti na udaljene dijelove tijela. Proces kojim maligne stanice migriraju s mjesta nastanka primarnog tumora u druge dijelove tijela naziva se metastaziranje. Metastaziranje obuhvaća invaziju, intravazaciju, transport, ekstravazaciju i metastatsku kolonizaciju. Ključni korak za preživljavanje tumora je angiogeneza, odnosno formiranje novih krvnih žila iz već postojećih. Svaki pojedini korak omogućen je brojnim genetskim i epigenetskim promjenama tumorskih stanica, kao i specifičnim interakcijama sa stromalnim stanicama pripadajućeg organa. Kako bi došlo do metastaziranja, potrebno je pronaći odgovarajuću mikrookolinu. Neki tumori kao svoje odredište za metastaziranje biraju prvi najbliži organ, budući da tumorske stanice na svom putu zbog veličine i raznih prepreka lako mogu zaglaviti unutar kapilara. Drugi pak metastaziraju na karakteristična, unaprijed određena mjesta, pri čemu se radi o genetski manipuliranim interakcijama između tumorskih stanica i receptora na stijenkama krvnih žila. Iako otprilike 1 od 3 osobe u nekom razdoblju svog života dobije rak, mnogi se mogu izliječiti zahvaljujući dostignućima u postavljanju dijagnoza i liječenju. Ovisno o vrsti i stadiju raka, terapija može biti namijenjena izliječenju, usporavanju rasta raka ili omogućavanju što ugodnijeg života. Dvije obećavajuće biološke terapije su genska terapija i angiogenska inhibicija. Razvijanje novih terapija koje će ciljno djelovati na produkte gena koji se eksprimiraju u određenim fazama rasta tumora omogućit će sprječavanje daljnjeg rasta i metastaziranje tumora.Cancer is a disease in which somatic cells multiplicate uncontrollably due to disfunctional regulation mechanisms. A malignant tumor is capable of invading into adjacent tissues and may be capable of spreading to distant tissues through blood and lymph vessels. The process by which tumor cells from a primary site invade and migrate to other parts of the body is called metastasis. Tumor cells undergo several major steps during metastasis: invasion, intravasation, transport, extravasation, and metastatic colonization. Metastatic colonization cannot be successful without the formation of new blood vessels from pre-existing ones in a proces called angiogenesis. Each of these events is driven by the acquisition of genetic and epigenetic alterations within tumor cells and the co-option of nonneoplastic stromal cells. Metastases selectively colonize specific organs because of a ‘match’ between the migrating tumor cell and a suitable environment. As the bloodstream is the predominant means of long-distance transport and tumor cells can easily get stuck in the vasculature, organs in close proximity are likely to be main sites of metastasis for a particular primary tumor. On the contrary, the destination of metastasized cells can be genetically influenced by interactions between receptors lining the capillaries in certain a organ and tumor cells. Basic research findings have helped develop two new most promising therapies: gene and anti-angiogenic therapy. Developing new techniques which will target protein products of genes that are associated with primary tumor growth and risk of metastasis could give us hope of managing cancer

Metastatis of cancer cells

Rak je bolest kod koje se tjelesne stanice nekotrolirano razmnožavaju zbog poremećenih normalnih regulacijskih mehanizama. Maligni tumori infiltriraju se u okolna tkiva prodirući među zdrave stanice i mogu se kroz krv i limfne žile proširiti na udaljene dijelove tijela. Proces kojim maligne stanice migriraju s mjesta nastanka primarnog tumora u druge dijelove tijela naziva se metastaziranje. Metastaziranje obuhvaća invaziju, intravazaciju, transport, ekstravazaciju i metastatsku kolonizaciju. Ključni korak za preživljavanje tumora je angiogeneza, odnosno formiranje novih krvnih žila iz već postojećih. Svaki pojedini korak omogućen je brojnim genetskim i epigenetskim promjenama tumorskih stanica, kao i specifičnim interakcijama sa stromalnim stanicama pripadajućeg organa. Kako bi došlo do metastaziranja, potrebno je pronaći odgovarajuću mikrookolinu. Neki tumori kao svoje odredište za metastaziranje biraju prvi najbliži organ, budući da tumorske stanice na svom putu zbog veličine i raznih prepreka lako mogu zaglaviti unutar kapilara. Drugi pak metastaziraju na karakteristična, unaprijed određena mjesta, pri čemu se radi o genetski manipuliranim interakcijama između tumorskih stanica i receptora na stijenkama krvnih žila. Iako otprilike 1 od 3 osobe u nekom razdoblju svog života dobije rak, mnogi se mogu izliječiti zahvaljujući dostignućima u postavljanju dijagnoza i liječenju. Ovisno o vrsti i stadiju raka, terapija može biti namijenjena izliječenju, usporavanju rasta raka ili omogućavanju što ugodnijeg života. Dvije obećavajuće biološke terapije su genska terapija i angiogenska inhibicija. Razvijanje novih terapija koje će ciljno djelovati na produkte gena koji se eksprimiraju u određenim fazama rasta tumora omogućit će sprječavanje daljnjeg rasta i metastaziranje tumora.Cancer is a disease in which somatic cells multiplicate uncontrollably due to disfunctional regulation mechanisms. A malignant tumor is capable of invading into adjacent tissues and may be capable of spreading to distant tissues through blood and lymph vessels. The process by which tumor cells from a primary site invade and migrate to other parts of the body is called metastasis. Tumor cells undergo several major steps during metastasis: invasion, intravasation, transport, extravasation, and metastatic colonization. Metastatic colonization cannot be successful without the formation of new blood vessels from pre-existing ones in a proces called angiogenesis. Each of these events is driven by the acquisition of genetic and epigenetic alterations within tumor cells and the co-option of nonneoplastic stromal cells. Metastases selectively colonize specific organs because of a ‘match’ between the migrating tumor cell and a suitable environment. As the bloodstream is the predominant means of long-distance transport and tumor cells can easily get stuck in the vasculature, organs in close proximity are likely to be main sites of metastasis for a particular primary tumor. On the contrary, the destination of metastasized cells can be genetically influenced by interactions between receptors lining the capillaries in certain a organ and tumor cells. Basic research findings have helped develop two new most promising therapies: gene and anti-angiogenic therapy. Developing new techniques which will target protein products of genes that are associated with primary tumor growth and risk of metastasis could give us hope of managing cancer

Training of adult psychiatrists and child and adolescent psychiatrists in europe : a systematic review of training characteristics and transition from child/adolescent to adult mental health services

BACKGROUND:Profound clinical, conceptual and ideological differences between child and adult mental health service models contribute to transition-related discontinuity of care. Many of these may be related to psychiatry training. METHODS:A systematic review on General Adult Psychiatry (GAP) and Child and Adult Psychiatry (CAP) training in Europe, with a particular focus on transition as a theme in GAP and CAP training. RESULTS:Thirty-four full-papers, six abstracts and seven additional full text documents were identified. Important variations between countries were found across several domains including assessment of trainees, clinical and educational supervision, psychotherapy training and continuing medical education. Three models of training were identified: i) a generalist common training programme; ii) totally separate training programmes; iii) mixed types. Only two national training programs (UK and Ireland) were identified to have addressed transition as a topic, both involving CAP exclusively. CONCLUSION:Three models of training in GAP and CAP across Europe are identified, suggesting that the harmonization is not yet realised and a possible barrier to improving transitional care. Training in transition has only recently been considered. It is timely, topical and important to develop evidence-based training approaches on transitional care across Europe into both CAP and GAP training

Architecture and functioning of child and adolescent mental health services : a 28-country survey in Europe

The WHO Child and Adolescent Mental Health Atlas, published in 2005, reported that child and adolescent mental health services (CAMHS) in Europe differed substantially in their architecture and functioning. We assessed the characteristics of national CAMHS across the European Union (EU), including legal aspects of adolescent care. Using an online mapping survey aimed at expert(s) in each country, we obtained data for all 28 countries in the EU. The characteristics and activities of CAMHS (ie, availability of services, inpatient beds, and clinicians and organisations, and delivery of specific CAMHS services and treatments) varied considerably between countries, as did funding sources and user access. Neurodevelopmental disorders were the most frequent diagnostic group (up to 81%) for people seen at CAMHS (data available from only 13 [46%] countries). 20 (70%) countries reported having an official national child and adolescent mental health policy, covering young people until their official age of transition to adulthood. The heterogeneity in resource allocation did not seem to match epidemiological burden. Substantial improvements in the planning, monitoring, and delivery of mental health services for children and adolescents are needed

Validation of the Transition Readiness and Appropriateness Measure (TRAM) for the Managing the Link and Strengthening Transition from Child to Adult Mental Healthcare in Europe (MILESTONE) study

OBJECTIVE:Young people moving from child and adolescent mental health services (CAMHS) to adult mental health services (AMHS) are faced with significant challenges. To improve this state of affairs, there needs to be a recognition of the problem and initiatives and an urgent requirement for appropriate tools for measuring readiness and outcomes at the transfer boundary (16-18 years of age in Europe). The objective of this study was to develop and validate the Transition Readiness and Appropriateness Measure (TRAM) for assessing a young person's readiness for transition, and their outcomes at the transfer boundary. DESIGN:MILESTONE prospective study. SETTING:Eight European Union (EU) countries participating in the EU-funded MILESTONE study. PARTICIPANTS:The first phase (MILESTONE validation study) involved 100 adolescents (pre-transition), young adults (post-transition), parents/carers and both CAMHS and AMHS clinicians. The second phase (MILESTONE cohort study and nested cluster randomised trial) involved over 1000 young people. RESULTS:The development of the TRAM began with a literature review on transitioning and a review of important items regarding transition by a panel of 34 mental health experts. A list of 64 items of potential importance were identified, which together comprised the TRAM. The psychometric properties of the different versions of the TRAM were evaluated and showed that the TRAM had good reliability for all versions and low-to-moderate correlations when compared with other established instruments and a well-defined factor structure. The main results of the cohort study with the nested cluster randomised trial are not reported. CONCLUSION:The TRAM is a reliable instrument for assessing transition readiness and appropriateness. It highlighted the barriers to a successful transition and informed clinicians, identifying areas which clinicians on both sides of the transfer boundary can work on to ease the transition for the young person. TRIAL REGISTRATION NUMBER:ISRCTN83240263 (Registered 23 July 2015), NCT03013595 (Registered 6 January 2017); Pre-results

Are psychiatrists trained to address the mental health needs of young people transitioning from child to adult services? Insights from a European survey

Background: In mental health, transition refers to the pathway of young people from child and adolescent to adult services. Training of mental health psychiatrists on transition-related topics offers the opportunity to improve clinical practice and experiences of young people reaching the upper age limit of child and adolescent care. Methods: National psychiatrist's organizations or experts from 21 European countries were surveyed 1/ to describe the status of transition in adult psychiatry (AP) and child and adolescent psychiatry (CAP) postgraduate training in Europe; 2/ to explore the amount of cross-training between both specialties. This survey was a part of the MILESTONE project aiming to study and improve the transition process of young people at the service boundary. Results: Transition was a mandatory topic in the AP curriculum of 1/19 countries (5%) and in the CAP curriculum of 4/17 countries (24%). Most topics relevant for transition planning were addressed during AP training in 7/17 countries (41%) to 10/17 countries (59%), and during CAP training in 9/11 countries (82%) to 13/13 countries (100%). Depending on the training models, theoretical education in CAP was mandatory during AP training in 94% (15/16) to 100% of the countries (3/3); and in AP during CAP training in 81% (13/16) to 100% of the countries (3/3). Placements were mandatory in CAP during AP training in 67% (2/3) to 71% of the countries (12/17); and in AP during CAP training in 87% (13/15) to 100% of the countries (3/3). Discussion and Conclusion: Specific training about transition is limited during CAP and AP postgraduate training in Europe. Cross-training between both specialties offers a basis for improved communication between child and adult services but efforts should be sustained in practical training. Recommendations are provided to foster further development and meet the specific needs of young people transitioning to adult services

Training of adult psychiatrists and child and adolescent psychiatrists in europe

Background: Profound clinical, conceptual and ideological differences between child and adult mental health service models contribute to transition-related discontinuity of care. Many of these may be related to psychiatry training. Methods: A systematic review on General Adult Psychiatry (GAP) and Child and Adult Psychiatry (CAP) training in Europe, with a particular focus on transition as a theme in GAP and CAP training. Results: Thirty-four full-papers, six abstracts and seven additional full text documents were identified. Important variations between countries were found across several domains including assessment of trainees, clinical and educational supervision, psychotherapy training and continuing medical education. Three models of training were identified: i) a generalist common training programme; ii) totally separate training programmes; iii) mixed types. Only two national training programs (UK and Ireland) were identified to have addressed transition as a topic, both involving CAP exclusively. Conclusion: Three models of training in GAP and CAP across Europe are identified, suggesting that the harmonization is not yet realised and a possible barrier to improving transitional care. Training in transition has only recently been considered. It is timely, topical and important to develop evidence-based training approaches on transitional care across Europe into both CAP and GAP training

Cohort profile : demographic and clinical characteristics of the MILESTONE longitudinal cohort of young people approaching the upper age limit of their child mental health care service in Europe

Purpose: The presence of distinct child and adolescent mental health services (CAMHS) and adult mental health services (AMHS) impacts continuity of mental health treatment for young people. However, we do not know the extent of discontinuity of care in Europe nor the effects of discontinuity on the mental health of young people. Current research is limited, as the majority of existing studies are retrospective, based on small samples or used non-standardised information from medical records. The MILESTONE prospective cohort study aims to examine associations between service use, mental health and other outcomes over 24 months, using information from self, parent and clinician reports. Participants: Seven hundred sixty-three young people from 39 CAMHS in 8 European countries, their parents and CAMHS clinicians who completed interviews and online questionnaires and were followed up for 2 years after reaching the upper age limit of the CAMHS they receive treatment at. Findings to date: This cohort profile describes the baseline characteristics of the MILESTONE cohort. The mental health of young people reaching the upper age limit of their CAMHS varied greatly in type and severity: 32.8% of young people reported clinical levels of self-reported problems and 18.6% were rated to be ‘markedly ill’, ‘severely ill’ or ‘among the most extremely ill’ by their clinician. Fifty-seven per cent of young people reported psychotropic medication use in the previous half year. Future plans: Analysis of longitudinal data from the MILESTONE cohort will be used to assess relationships between the demographic and clinical characteristics of young people reaching the upper age limit of their CAMHS and the type of care the young person uses over the next 2 years, such as whether the young person transitions to AMHS. At 2 years follow-up, the mental health outcomes of young people following different care pathways will be compared. Trial registration number: NCT03013595