Are class II phosphoinositide 3-kinases potential targets for anticancer therapies?

Of the three classes of true phosphoinositide (PI) 3-kinases, the class II subdivision, which consists of three isoforms, PI3K-C2alpha, PI3K-C2beta and PI3K-C2gamma, is the least well understood. There are a number of reasons for this. This class of PI 3-kinase was identified exclusively by PCR and homology cloning approaches and not on the basis of cellular function. Like class I PI 3-kinases, class II PI 3-kinases are activated by diverse receptor types. To complicate the elucidation of class II PI 3-kinase function further, their in vitro substrate specificity is intermediate between the receptor activated class I PI 3-kinases and the housekeeping class III PI 3-kinase. The class II PI 3-kinases are inhibited by the two commonly used PI 3-kinase family selective inhibitors, wortmannin and LY294002, and there are no widely available, specific inhibitors for the individual classes or isoforms. Here the current state of understanding of class II PI 3-kinase function is reviewed, followed by an appraisal as to whether there is enough evidence to suggest that pharmaceutical companies, who are currently targeting the class I PI 3-kinases in an attempt to generate anticancer agents, should also consider targeting the class II PI 3-kinases.

Class II phosphoinositide 3-kinase defines a novel signaling pathway in cell migration

The lipid products of phosphoinositide 3-kinase (PI3K) are involved in many cellular responses such as proliferation, migration, and survival. Disregulation of PI3K-activated pathways is implicated in different diseases including cancer and diabetes. Among the three classes of PI3Ks, class I is the best characterized, whereas class II has received increasing attention only recently and the precise role of these isoforms is unclear. Similarly, the role of phosphatidylinositol-3-phosphate (PtdIns-3-P) as an intracellular second messenger is only just beginning to be appreciated. Here, we show that lysophosphatidic acid (LPA) stimulates the production of PtdIns-3-P through activation of a class II PI3K (PI3K-C2β). Both PtdIns-3-P and PI3K-C2β are involved in LPA-mediated cell migration. This study is the first identification of PtdIns-3-P and PI3K-C2β as downstream effectors in LPA signaling and demonstration of an intracellular role for a class II PI3K. Defining this novel PI3K-C2β- PtdIns-3-P signaling pathway may help clarify the process of cell migration and may shed new light on PI3K-mediated intracellular events.

Mapping MHC Genes in River Buffalo

The major histocompatibility complex (MHC) contains a set of genes necessary for antigen presentation in the immune system. This gene dense and polymorphic region of the mammalian genome is of considerable interest due to the role of MHC genes in immune function and animal health. Previous cytogenetic studies have indicated that the MHC in river buffalo resides on the short arm of chromosome 2 (BBU2). A 5000-rad radiation hybrid mapping panel was recently generated to enable construction of a whole genome map of river buffalo. To this and, the aims of this project were to elucidate the general organization of the MHC on BBU2, and to compare gene order within this region to the MHC in cattle. PCR primers were selected from the bovine gene map and used with the BBURH(5000) panel to map a set of ten MHC class 11 genes in river buffalo. Analysis indicates that these genes fall into two linkage groups, consistent with organization of the MHC in cattle. This comparison of buffalo and bovine MHC gene order provides the first insight into the organization of the MHC on river buffalo chromosome 2.

Early cephalometric characteristics in Class III malocclusion

OBJECTIVE: Early identification of craniofacial morphological characteristics allows orthopedic segmented interventions to attenuate dentoskeletal discrepancies, which may be partially disguised by natural dental compensation. To investigate the morphological characteristics of Brazilian children with Class III malocclusion, in stages I and II of cervical vertebrae maturation and compare them with the characteristics of Class I control patients. METHODS: Pre-orthodontic treatment records of 20 patients with Class III malocclusion and 20 control Class I patients, matched by the same skeletal maturity index and sex, were selected. The craniofacial structures and their relationships were divided into different categories for analysis. Angular and linear measures were adopted from the analyses previously described by Downs, Jarabak, Jacobson and McNamara. The differences found between the groups of Class III patients and Class I control group, both subdivided according to the stage of cervical vertebrae maturation (I or II), were assessed by analysis of variance (ANOVA), complemented by Bonferroni's multiple mean comparisons test. RESULTS: The analysis of variance showed statistically significant differences in the different studied groups, between the mean values found for some angular (SNA, SNB, ANB) and linear variables (Co - Gn, N - Perp Pog, Go - Me, Wits, S - Go, Ar - Go). CONCLUSION: Assessed children displaying Class III malocclusion show normal anterior base of skull and maxilla, and anterior positioning of the mandible partially related to increased posterior facial height with consequent mandibular counterclockwise rotation.

Estudo cefalométrico das alturas faciais anterior e posterior, em crianças brasileiras, portadoras de má oclusão Classe I de Angle, na fase de dentadura mista

Realizou-se um estudo das alturas faciais anterior e posterior em 79 crianças brasileiras, sendo 46 do gênero feminino e 33 do masculino, com idades de 8 a 11 anos, portadoras de má oclusão Classe I de Angle, na fase de dentadura mista, não submetidas a tratamento ortodôntico. Esta investigação utilizou duas radiografias cefalométricas em norma lateral, de cada criança, com intervalo de 8 a 16 meses entre uma radiografia e outra, para comparação dos dados cefalométricos. Foram estudadas as proporções faciais anteriores, ou seja, a relação entre as dimensões N-Me (AFT), N-ENA (AFS), ENA-Me (AFI) e o relacionamento entre as dimensões Ar-GO (AFP) e a distância entre o plano palatino ao mento (AFA) , isto é, o Índice da Altura Facial (IAF). Os resultados obtidos, possibilitaram constatar que as tendências de crescimento foram equilibradas em todas as situações estudadas; a dimensão altura facial inferior, contribuiu de forma mais significativa, nas alterações observadas na altura facial total; as proporções faciais anteriores se mantiveram em torno de 42% para a altura facial superior e 58% para a altura facial inferior; o índice da altura facial ou se manteve constante em torno de 0,66 ou apresentou uma tendência a aumentar com a idade; não ocorreu dimorfismo sexual com relação às proporções faciais e índice da altura facial.

Role of natural killer cells in antitumor resistance

Natural killer cells constitute a population of lymphocytes able to non-specifically destroy virus-infected and some kinds of tumor cells. Since this lytic activity was shown by non-immunized animals the phenomenon is denominated natural killer (NK) activity and contrasts with specific cytotoxicity performed by cytolytic T lymphocytes (CTLs) because it does not depends on MHC-restricted peptides recognition. In fact, the main feature of most functional receptors of NK cells (NKRs) is their ability to be inhibited by different kinds of class I MHC antigens. In the middle of the 1950's, Burnet & Thomas forged the concept of tumor immunosurveillance and NK cells can be considered one of the main figures in this phenomenon both for effector and regulatory functions. In the present review the early studies on the biology of NK cells were revisited and both their antitumor activity and dependence on the activation by cytokines are discussed.

Oral myofunctional and electromyographic evaluation of the anterior suprahyoid muscles and tongue thrust in patients with class II/1 malocclusion submitted to first premolar extraction

Objective: The aim of this study was to assess the existence of myofunctional alterations before and after first premolar extraction in Class II/1 malocclusion patients that could endanger the long-term dental arch stability. Materials and Methods: The study was performed by means of morphological, functional and electromyographic analyses in 17 Class II/1 malocclusion patients (group T) and 17 Class I malocclusion patients (group C), both groups with 12-30-year age range (mean age: 20.93 ± 4.94 years). Results: Data analyzed statistically by Student's t-test showed a significant decrease in the maxillary and mandibular dental arch perimeters after orthodontic treatment (p<0.05). The Kruskal-Wallis test analyzed data from tongue posture at rest and during swallowing, not showing significant differences after treatment (groups Tb and Ta) (p>0.05). However, group T differed significantly from group C (p<0.05). The electromyographic data showed that the anterior right and left suprahyoid muscles acted synergistically in both groups, while having a lower myoelectric activity in group T during swallowing. Conclusions: Myofunctional alterations observed after the orthodontic treatment in Class II/1 malocclusion seemed to jeopardize the long-term orthodontic stability, making recurrence possible. Further research should be conducted to compare electromyographic data before and after orthodontic treatment in order to corroborate the results of the present investigation.

Structure of a novel class II phospholipase D: Catalytic cleft is modified by a disulphide bridge

Phospholipases D (PLDs) are principally responsible for the local and systemic effects of Loxosceles envenomation including dermonecrosis and hemolysis. Despite their clinical relevance in loxoscelism, to date, only the SMase I from Loxosceles laeta, a class I member, has been structurally characterized. The crystal structure of a class II member from Loxosceles intermedia venom has been determined at 1.7. Å resolution. Structural comparison to the class I member showed that the presence of an additional disulphide bridge which links the catalytic loop to the flexible loop significantly changes the volume and shape of the catalytic cleft. An examination of the crystal structures of PLD homologues in the presence of low molecular weight compounds at their active sites suggests the existence of a ligand-dependent rotamer conformation of the highly conserved residue Trp230 (equivalent to Trp192 in the glycerophosphodiester phosphodiesterase from Thermus thermophofilus, PDB code: 1VD6) indicating its role in substrate binding in both enzymes. Sequence and structural analyses suggest that the reduced sphingomyelinase activity observed in some class IIb PLDs is probably due to point mutations which lead to a different substrate preference. © 2011 Elsevier Inc.

A high-resolution radiation hybrid map of the river buffalo major histocompatibility complex and comparison with BoLA

The major histocompatibility complex (MHC) in mammals codes for antigen-presenting proteins. For this reason, the MHC is of great importance for immune function and animal health. Previous studies revealed this gene-dense and polymorphic region in river buffalo to be on the short arm of chromosome 2, which is homologous to cattle chromosome 23. Using cattle-derived STS markers and a river buffalo radiation hybrid (RH) panel (BBURH5000), we generated a high-resolution RH map of the river buffalo MHC region. The buffalo MHC RH map (cR5000) was aligned with the cattle MHC RH map (cR 12000) to compare gene order. The buffalo MHC had similar organization to the cattle MHC, with class II genes distributed in two segments, class IIa and class IIb. Class IIa was closely associated with the class I and class III regions, and class IIb was a separate cluster. A total of 53 markers were distributed into two linkage groups based on a two-point LOD score threshold of ≥8. The first linkage group included 32 markers from class IIa, class I and class III. The second linkage group included 21 markers from class IIb. Bacterial artificial chromosome clones for seven loci were mapped by fluorescence in situ hybridization on metaphase chromosomes using single- and double-color hybridizations. The order of cytogenetically mapped markers in the region corroborated the physical order of markers obtained from the RH map and served as anchor points to align and orient the linkage groups. © 2012 The Authors, Animal Genetics © 2012 Stichting International Foundation for Animal Genetics.

Características morfológicas dentoesqueléticas das más oclusões de classe I, classe II e classe II subdivisão

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Ruídos articulares em pacientes parcialmente desdentados (classe I ou II de Kennedy), antes e após a reposição dental com prótese parcial removível: avaliação através da eletrovibratografia

Pós-graduação em Odontologia - FOA

Influência dos sistemas de retenção e da inclinação do rebordo residual em casos de próteses conjugadas Classe I mandibular: análise da distribuição das tensões pelo método da fotoelasticidade

Pós-graduação em Odontologia - FOA

Análise histopatológica comparativa de polpas humanas após confecção de cavidades de classe I com turbina de alta velocidade ou laser de Er:YAG

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Angulação dos caninos em indivíduos portadores de má oclusão de Classe I e de Classe III: análise comparativa através de um novo método utilizando imagens digitalizadas

OBJETIVO: determinar as angulações mesiodistais das coroas dos caninos em indivíduos portadores de má oclusão de Classe III, comparando-os a indivíduos Classe I. MÉTODOS: foram empregadas medidas tomadas em fotografias digitalizadas de modelos de gesso e transportadas para um programa gráfico para leitura das medidas (Image Tool). Tais procedimentos foram repetidos para avaliação do erro do método casual (fórmula de Dahlberg) e para a análise da reprodutibilidade através da Correlação intraclasse. A amostra constituiu-se de 57 pacientes com dentição permanente completa e não tratados ortodonticamente, dividida em dois grupos, de acordo com a má oclusão apresentada: o grupo I foi constituído por 33 pacientes portadores de má oclusão de Classe I, sendo 16 do sexo masculino e 17 do feminino, com média de idades de 27 anos; o grupo II era representado por 24 pacientes portadores de má oclusão de Classe III, 20 do sexo masculino e 4 do feminino, com média de idades de 22 anos. RESULTADOS: o erro casual mostrou-se com uma variação de 1,54 a 1,96 graus para a angulação dos caninos. A análise estatística revelou que o método apresenta uma excelente reprodutibilidade (p<0,01). Os resultados obtidos na angulação da coroa dos caninos não mostraram diferença estatisticamente significativa entre os caninos superiores nos grupos Classe I e Classe III, embora esse dente mostrasse, em média, uma angulação 2 graus maior nos indivíduos Classe III. Entretanto, para os caninos inferiores, foi observada uma diferença estatisticamente significativa em ambos os lados (p=0,0009 e p=0,0074) entre os grupos Classe I e Classe III. Os pacientes Classe III apresentaram uma menor angulação nos caninos inferiores em comparação aos pacientes Classe I, tendendo a acompanhar a compensação natural dos incisivos, descrita rotineiramente na literatura. CONCLUSÃO: os resultados permitem concluir que as compensações dentárias, frequentemente observadas na literatura para a região de incisivos, se estendem também à angulação dos caninos, principalmente no que se refere à arcada inferior.

Avaliação clínica da sensibilidade pós-operatória em restaurações oclusais com 3 sistemas adesivos: 3 passos (Scotchbond MP Plus), 2 passos associado a dessensibilizante (Gluma Confort Bond + Dessensitizer) e de 1 passo-auto-condicionante simplificado (I Bond)

O objetivo desse estudo foi analisar clinicamente o comportamento de 60 restaurações oclusais, em relação à sensibilidade pós-operatória em cavidades oclusais em pré-molares e molares. Foram selecionados dentes considerados dentro da normalidade, após testes clínicos e radiográficos, onde cavidades de média profundidade e largura máxima de ½ da distancia entre os vértices de cúspides na área do istmo, eram requeridas. A profundidade da parede pulpar foi estabelecida em dentina pelo menos 1 mm além da junção amelodentinária. Os detalhes do preparo foram registrados por fotografia (digitalizadas), por moldagem com silicone de condensação, modelos de gesso. Esses cuidados foram tomados para que futuramente servissem como auxiliar de interpretação de resultados. As restaurações foram feitas sob isolamento absoluto, para evitarmos contaminação pela saliva e sangue. Em 20 preparos foram feitos procedimentos restauradores com sistema de 3 passos (Scotchbond MP Plus). Em outros 20 preparos foram feitos procedimentos restauradores com sistema de 2 passos associado a dessensibilizantes (Gluma Confort Bond + Dessensitizer). Em outros 20 preparos foram feitos procedimentos restauradores com sistema de 1 passo autocondicionante simplificado (I Bond). Os 60 dentes foram restaurados com a resina composta Filtek Supreme, por ser um material apropriado para dentes posteriores, por meio da técnica incremental. Após 48 horas e 7 dias os pacientes retornavam para o controle da sensibilidade pós-operatória. Inicialmente era obtido um relato do paciente, para em seguida serem realizados testes clínicos (térmico, pressão e percussão). Os dados foram tabelados e os resultados analisados. Não houve diferença na sensibilidade antes e após (48 horas e 7 dias) a colocação das restaurações para todos os grupos.