Em animais, a prevalência do câncer tem aumentado de forma significativa com o passar dos anos. As neoplasias mamárias representam o tipo mais frequente de câncer em cadelas, chegando a 52% da população de fêmeas, e entre os animais afetados, 50% das neoplasias se apresentam sob a forma maligna. O desenvolvimento e caracterização de modelos animais para o estudo de neoplasias humanas é de extrema relevância para a melhoria no diagnóstico e tratamento do câncer. Os tumores sólidos apresentam uma hierarquia entre as células que determina o desenvolvimento e o comportamento da neoplasia. Recentemente, tem-se estudado um pequeno grupo de células que apresentam diversas características das células-tronco normais encontradas nos tecidos. Estas células, denominadas Células Iniciadoras de Tumor (CITs), são descritas como sendo as principais responsáveis pelas falhas na quimioterapia e no aparecimento de recidivas tumorais, devido ao grande potencial de renovação e diferenciação que elas possuem. Desta maneira, nosso objetivo foi caracterizar linhagens celulares provenientes de neoplasia de glândula mamária de cadelas que pudessem ser utilizadas futuramente na pesquisa básica e aplicada em oncologia comparada. Além das alterações citogenéticas e imunocitoquímicas, verificamos que os cultivos celulares apresentaram quantidades distintas de populações positivas e negativas quanto à expressão de CD24 e CD44 bem como da atividade de aldeído-desidrogenase, porém, todos exibiram potencial tumorigênico in vitro através do ensaio de formação de tumoresferas / The prevalence of cancer in animals has increased significantly over the years. Mammary tumors are the most common cancer in dogs, reaching 52% of female population, and among affected animals, 50% of tumors are presented in the malignant form. The development and characterization of animal models for the study of human cancers is extremely important for improving the diagnosis and treatment of cancer. Solid tumors have a hierarchy of cells that determines the development and behavior of cancer. Recently, there has been studied a small group of cells with different characteristics from those normal stem cells found in tissues. These cells, known as tumor initiating cells (TICs), are described as being primarily responsible for the failures in chemotherapy and the appearance of recurrences, because of their potential for renewal and differentiation. Thus, our objective was to characterize cell lines derived from mammary gland neoplasia of dogs that could be further used for basic and applied research in comparative oncology. In addition to the cytogenetic and immunocytochemical changes, we found that cell cultures had different amounts of positive and negative populations of CD24 and CD44 expression and aldehyde dehydrogenase activity, however, all exhibited tumorigenic potential in vitro through tumorspheres formation

Em animais, a prevalência do câncer tem aumentado de forma significativa com o passar dos anos. As neoplasias mamárias representam o tipo mais frequente de câncer em cadelas, chegando a 52% da população de fêmeas, e entre os animais afetados, 50% das neoplasias se apresentam sob a forma maligna. O desenvolvimento e caracterização de modelos animais para o estudo de neoplasias humanas é de extrema relevância para a melhoria no diagnóstico e tratamento do câncer. Os tumores sólidos apresentam uma hierarquia entre as células que determina o desenvolvimento e o comportamento da neoplasia. Recentemente, tem-se estudado um pequeno grupo de células que apresentam diversas características das células-tronco normais encontradas nos tecidos. Estas células, denominadas Células Iniciadoras de Tumor (CITs), são descritas como sendo as principais responsáveis pelas falhas na quimioterapia e no aparecimento de recidivas tumorais, devido ao grande potencial de renovação e diferenciação que elas possuem. Desta maneira, nosso objetivo foi caracterizar linhagens celulares provenientes de neoplasia de glândula mamária de cadelas que pudessem ser utilizadas futuramente na pesquisa básica e aplicada em oncologia comparada. Além das alterações citogenéticas e imunocitoquímicas, verificamos que os cultivos celulares apresentaram quantidades distintas de populações positivas e negativas quanto à expressão de CD24 e CD44 bem como da atividade de aldeído-desidrogenase, porém, todos exibiram potencial tumorigênico in vitro através do ensaio de formação de tumoresferas / The prevalence of cancer in animals has increased significantly over the years. Mammary tumors are the most common cancer in dogs, reaching 52% of female population, and among affected animals, 50% of tumors are presented in the malignant form. The development and characterization of animal models for the study of human cancers is extremely important for improving the diagnosis and treatment of cancer. Solid tumors have a hierarchy of cells that determines the development and behavior of cancer. Recently, there has been studied a small group of cells with different characteristics from those normal stem cells found in tissues. These cells, known as tumor initiating cells (TICs), are described as being primarily responsible for the failures in chemotherapy and the appearance of recurrences, because of their potential for renewal and differentiation. Thus, our objective was to characterize cell lines derived from mammary gland neoplasia of dogs that could be further used for basic and applied research in comparative oncology. In addition to the cytogenetic and immunocytochemical changes, we found that cell cultures had different amounts of positive and negative populations of CD24 and CD44 expression and aldehyde dehydrogenase activity, however, all exhibited tumorigenic potential in vitro through tumorspheres formation

<p>Övervikt och fetma anses vara ett globalt folkhälsoproblem, vars omfattning tycks ha ökat de senaste årtiondena. Förklaringen till det anses ofta vara en västerländsk livsstil bestående av kaloririk kost och bristande fysisk aktivitet. Att lyckas med en livsstilsförändring tycks därmed viktigt, men svårt. Syftet med studien var att identifiera framgångsfaktorer som bidragit till initierande och vidmakthållande av en livsstilsförändring. Enskilda intervjuer, med tre kvinnor och tre män, genomfördes därför med individer som vidmakthållit en livsstilsförändring i minst två år. Studien visade att gemensamma framgångsfaktorer för initiering och vidmakthållande var en vändpunkt som resulterat i motiv och mål, samt omgivande förutsättningar. Specifikt för initieringen var bestämdhet viktigt, medan vidmakthållandet gynnades av strategier och upplevd belöning. Respondenterna hade överlag många gemensamma framgångsfaktorer, och inga tydliga skillnader mellan könen kunde urskiljas.</p>

Övervikt och fetma anses vara ett globalt folkhälsoproblem, vars omfattning tycks ha ökat de senaste årtiondena. Förklaringen till det anses ofta vara en västerländsk livsstil bestående av kaloririk kost och bristande fysisk aktivitet. Att lyckas med en livsstilsförändring tycks därmed viktigt, men svårt. Syftet med studien var att identifiera framgångsfaktorer som bidragit till initierande och vidmakthållande av en livsstilsförändring. Enskilda intervjuer, med tre kvinnor och tre män, genomfördes därför med individer som vidmakthållit en livsstilsförändring i minst två år. Studien visade att gemensamma framgångsfaktorer för initiering och vidmakthållande var en vändpunkt som resulterat i motiv och mål, samt omgivande förutsättningar. Specifikt för initieringen var bestämdhet viktigt, medan vidmakthållandet gynnades av strategier och upplevd belöning. Respondenterna hade överlag många gemensamma framgångsfaktorer, och inga tydliga skillnader mellan könen kunde urskiljas.

In an attempt to identify agents that specifically target neuroblastoma (NB) tumour-initiating cells (TIC) we performed drug screens using libraries of bioactive compounds. Cardiac glycosides (CGs) were the largest class of drugs identified with antitumour activity. At high CG doses inhibitory effects on the Na+/K+-ATPase induce cardiotoxicity; therefore, CG analogues were designed in an attempt to separate the effects on NB cells from cardiotoxicity. We identified RIDK34 as our lead compound from a structure-activity-relationship analysis (IC50 8 nM). RIDK34 contains a unique oxime group and shows increasing potency against NB TICs. The Na+/K+-ATPase is a target for the apoptotic activity of digoxin and RIDK34, whereby a signaling cascade involving Src and ERK may induce apoptosis. Furthermore, we predict that signaling activation does not require inactivation of the Na+/K+-ATPase and subsequent deregulation of [Na+]i and [K+]I gradients. Thus CGs and particularly RIDK34 may be expected to display diminished cardiotoxicity and greater therapeutic potential.

In an attempt to identify agents that specifically target neuroblastoma (NB) tumour-initiating cells (TIC) we performed drug screens using libraries of bioactive compounds. Cardiac glycosides (CGs) were the largest class of drugs identified with antitumour activity. At high CG doses inhibitory effects on the Na+/K+-ATPase induce cardiotoxicity; therefore, CG analogues were designed in an attempt to separate the effects on NB cells from cardiotoxicity. We identified RIDK34 as our lead compound from a structure-activity-relationship analysis (IC50 8 nM). RIDK34 contains a unique oxime group and shows increasing potency against NB TICs. The Na+/K+-ATPase is a target for the apoptotic activity of digoxin and RIDK34, whereby a signaling cascade involving Src and ERK may induce apoptosis. Furthermore, we predict that signaling activation does not require inactivation of the Na+/K+-ATPase and subsequent deregulation of [Na+]i and [K+]I gradients. Thus CGs and particularly RIDK34 may be expected to display diminished cardiotoxicity and greater therapeutic potential.

Abstract The military is the foundation of a nation¡¦s safety. To ensure the safety, prosperity and a continuous development of a country, the commanding officer of each troop in the armed forces should adopt a kind of leadership which can meet the needs of a country and its people thus fulfilling the mission of defending a country and protecting its people. The writer thoroughly observed and interviewed two commanding officers who were the subjects of this case study. The study is aimed to discuss the leadership behavior of the air-force colonels who are commanding officers. The study discusses the organization structure, the characteristics of missions and the number of people in troops, the difference between the leadership behavior between the commanding officers. The study tries to find a suitable leadership behavior which can be served as a reference for commanding officers in different troops in the future. The study has found the following phenomenon: 1. To lead a huge organization which has many people and facilities and units, the most important job is to know how to control. To lead an organization which has less people and it has a professional unit, the most important job is to plan and to know how to communicate to the subordinates. 2. There are many unnecessary meetings in the troops. The meetings are too long. Only a few items need to be discussed are relevant to the units, so it is a waste of time. 3. Due to different units, some commanding officers have too much work, some have less work. Some can not fully use his talents. Responsibility and power do not match. 4. If the unit has less people and resources, the conflict between subordinates are less. If the leader has better skill of eloquence, he can persuade his subordinates and convince them easily. 5. The leadership behavior at this stage in the military is ¡§people-centered¡¨ which produces good effects in leadership. In summary, the leadership behavior of the commanding officer can directly influence the behavior and attitude of his subordinates. The more the commanding officer cares his subordinates, the better meets the psychological needs of his subordinates. Key Words: Leadership behavior and effectiveness, 4 diagrams of leadership behavior,System and person-oriented, Initiating and consideration structure,Situational factors.

The purpose of this study was to evaluate the effects of video self-modeling and behavior skills training to teach social skills to children with Asperger’s and high functioning autism. The targeted social skills were social initiations and social responses. The video self-modeling alone condition was implemented first using a video feedforward approach. A behavior skills training (BST) procedure was implemented following the video self-modeling alone condition for each participant. BST consisted of instructions, modeling, rehearsal, and feedback. The frequency of each target behavior was scored from videotapes using 10-second frequency within interval recording. After the video self-modeling was introduced, a mean increase was demonstrated in the target behaviors for 3 of the 4 participants. However, following the video self-modeling plus behavior skills training procedures, the social skills increased further for each participant. Follow up measures showed that the social interactions for each participant remained higher than baseline, however slightly lower than levels during BST+VSM.

<p>Glioblastoma (GBM) represents the most common and lethal brain tumor in adults, with glioma initiating cells (GICs) implicated to play a critical role in its progression and recurrence. However, the molecular mechanisms underlying the distinct function of GICs and non-GICs remain largely unknown. Elucidating distinct molecular features of GICs will pave the foundation for GIC directed therapies for GBM treatment. </p><p>We first demonstrated that GICs preferentially express two interleukin 6 (IL6) receptors: IL6 receptor alpha (IL6Ra) and glycoprotein 130 (gp130). Targeting IL6Ra; or IL6 ligand expression in GICs using short hairpin RNAs (shRNAs) significantly reduces growth and neurosphere formation capacity while increasing apoptosis. Block IL6 signaling in GICs attenuates Stat3 activation, and small molecule inhibitors of STAT3 potently induce GIC apoptosis. Targeting IL6Ra; or IL6 expression in GICs increases the survival of mice bearing intracranial human glioma xenografts. The promising application of anti-IL6 therapies is demonstrated by decreased subcutaneous tumor growth of human GIC-derived xenografts treated with IL6 antibody. Together, our data indicate that IL6 signaling contributes to glioma malignancy through the promotion of GIC growth and survival, and that targeting IL6 may offer benefit for glioma patients.</p><p>MicroRNAs (miRNAs) are a class of non-coding small RNA molecules which negatively regulate gene expression and are deregulated in many types of cancer. Through a candidate-based screen, we identified microRNA-33a as a master determinant whose expression controls the functional differences between GIC and non-GICs. Antagonizing miR-33a function in GICs led to reduced self-renewal and tumor progression in immune-compromised mice, whereas overexpression of miR-33a in non-GICs rendered them to display features associated with GICs. Mechanistically, miR-33a acts to confer the biological property of GICs via enhancing the activities of cAMP/PKA pathway and Notch signaling by targeting negative regulators of these two pathways. Together these findings reveal a miR-33a-centered signaling network that dictates the identity/activity of GICs and consequently serves as a therapeutic target for the treatment of GBM.</p><p>In summary, this doctoral thesis reveals two novel molecular events that characterize the distinct feature of GICs and develops preclinical strategies for the therapeutic application of GBM.</p> / Dissertation

Malignant glioma is a highly lethal and destructive disease with no proper cure. We have investigated some of the hallmarks of cancer in connection to glioma and found ways to disrupt these and prevent tumor growth. The work is done within the context of a glioma subtype distinguished by activation of PDGF signaling termed the proneural subtype. In two of the studies we have investigated mechanisms regulating the glioma cells themselves, and in the other two we have focused on the tumor stroma. In the first study, glioma-initiating cells were isolated in defined serum free culture medium from PDGF-B driven murine glioma and shown to be independent of EGF and FGF2 for self-renewal and proliferation. When cultured in serum the GICs displayed an aberrant differentiation pattern that was reversible. Specific depletion of the transduced PDGF-B caused a loss of self-renewal and tumorigenicity and induced oligodendrocyte differentiation. The transcription factor S-SOX5 has previously been shown to have a tumor suppressive effect on PDGF-B induced murine glioma, and to induce cellular senescence in PDGF-B stimulated cells in vitro. We found that S-SOX5 had a negative effect on proliferation of newly established human glioma cells cultured under stem cell conditions. We also revealed a connection between alterations causing up-regulation of SOX5 with the proneural subgroup and a tendency towards co-occurrence with PDGFRA alterations. Angiogenesis, the formation of new blood vessels from existing ones, is an important hallmark for glioma malignancy. We found that the anti-angiogenic protein HRG had a negative effect on glioma progression in PDGF-B induced experimental tumors and that HRG was able to completely prevent formation of glioblastomas. Subsequently it was shown that HRG could skew pro-tumorigenic tumor associated macrophages into an anti-tumorigenic phenotype. Stromal cells had not previously been fully investigated in gliomas. We observed a correlation between tumor malignancy and increased numbers of tumor-associated macrophages as well as pericytes in PDGF-B induced gliomas. There was also a correlation between tumor grade and vessel functionality that had not previously been shown. Our results offer further understanding of gliomagenesis and present possible future therapies.