Diss. (sammanfattning) Stockholm : Karol. inst., 2006. / Härtill 5 uppsatser.

Thesis (Ph. D.)--University of Washington, 1996. / Vita. Includes bibliographical references.

Thesis (M.Sc.), Memorial University of Newfoundland, Faculty of Medicine, 2000. / Restricted until June 2001. Typescript. Bibliography: leaves 109-129.

abstract: Motor-respiratory coordination is the synchronization of movement and breathing during exercise. The relation between movement and breathing can be described using relative phase, a measure of the location in the movement cycle relative to the location in the breathing cycle. Stability in that relative phase relation has been identified as important for aerobic efficiency. However, performance can be overly attracted to stable relative phases, preventing the performance or learning of more complex patterns. Little research exists on relative phase dynamics in motor-respiratory coordination, although those observations underscore the importance of learning more. In contrast, there is an extensive literature on relative phase dynamics in interlimb coordination. The accuracy and stability of different relative phases, transitions between patterns, and asymmetries between components are well understood. Theoretically, motor-respiratory and interlimb coordination may share dynamical properties that operate in their different physiological substrates. An existing model of relative phase dynamics in interlimb coordination, the Haken, Kelso, Bunz model, was used to gain an understanding of relative phase dynamics in the less-researched motor-respiratory coordination. Experiments 1 and 2 were designed to examine the interaction of frequency asymmetries between movement and breathing with relative phase and frequency, respectively. In Experiment 3, relative phase stability and transitions in motor-respiratory coordination were explored. Perceptual constraints on differences in stability were investigated in Experiment 4. Across experiments, contributions relevant to questions of coordinative variability were made using a dynamical method called cross recurrence quantification analysis. Results showed much consistency with predictions from an asymmetric extension of the Haken, Kelso, Bunz model and theoretical interpretation in the interlimb coordination literature, including phase wandering, intermittency, and an interdependence of perception and action. There were, however, notable exceptions that indicated stability can decrease with more natural frequency asymmetries and the connection of cross recurrence measures to categories of variability needs further clarification. The complex relative phase dynamics displayed in this study suggest that movement and breathing are softly-assembled by functional constraints and indicate that motor-respiratory coordination is a self-organized system. / Dissertation/Thesis / Ph.D. Psychology 2010

In the US, the incidence and mortality rates of prostate cancer (PCa) are higher among African American men compared to European American men. Obesity is an important risk factor of PCa. Obesity is known to alter the gene expression profiles in prostate tumors. This study evaluates the impact of obesity and the expression of obesity-related genes on the progression of PCa in African American men. The primary outcome of interest is biochemical recurrence (BCR) of PCa. There were 48 African American prostate cancer patients in the study. The tissue samples included 42 normal tissues, 40 Prostate Intraepithelial Neoplasia (PIN) and 45 tumor tissues (127 tissue samples in total). We assembled 99 obesity-related genes and determined the levels of their expression in the three types of tissue samples using Nanostring Technologies. An ANOVA test was used to compare the means for gene expression among normal, PIN and tumor tissue samples. Unconditional logistic regression models were used to calculate odds ratios (ORs) and their respective 95% confidence intervals (95% CIs) to determine the association between obesity and BCR as well as gene expression and BCR. Results were regarded as statistically significant if p-values were less than 0.05. A Kaplan Meier Curve was constructed to depict the survival time and time to event (BCR) among obese and non-obese African American prostate cancer patients. Patients were followed up from the date of first surgery to the date of biochemical recurrence or date of last follow-up. Statistical analysis was done with SAS 9.4 software. Forty-three obesity-related genes were statistically significantly associated with biochemical recurrence. There was no association between obesity and biochemical recurrence (BCR) in obese African American men compared to non-obese African American men (OR= 2.03, 95% CI = 0.22 - 18.77, p-value= 0.53). Twenty genes showed an upward trend in gene expression among normal, PIN and tumor tissue samples including ADIPOR1, AKRIC4, ALOX12, ALOX15, CRYBB2, EIF5A, ERG, GNPDA2, HNF1B, HSD3B1, KLK4, LEP, MC4R, MTCH2, PCSK1, PIK3CB, SLC2A2, STAT1, SULT1A1, YY1. The probability of survival (not having BCR) is lower in obese African American men compared to non-obese African American men as indicted in the Kaplan Meier curve. In other words, the probability of developing BCR is higher in obese African American men compared to non-obese African American men. We did not find a significant association between obesity and biochemical recurrence. However, we elucidated some obesity-related genes that could explain PCa carcinogenesis. Further studies are needed to determine functional significance of these selected obesity-related genes and the role they play in encouraging PCa progression in African American men.

Critical inputs to evaluate fault behavior models include the frequency of large earthquakes on plate boundary faults, amount of displacement, style of deformation in these events, and how these earthquakes are associated with adjacent sites and broader segments. Paleoseismic data provide these inputs and allow the characterization of hazard posed by individual faults. This dissertation presents results from paleoseismic studies at Hazel Dell and Frazier Mountain that provide new earthquake chronologies and slip estimates for the San Andreas Fault (SAF). These data provide new insights into the recurrence and style of coseismic deformation for surface rupturing earthquakes on the SAF. The Hazel Dell site provides the first definitive paleoseismic evidence of two pre-1906, 19th century earthquakes on the Santa Cruz Mountains section of the SAF. I correlate these paleoseismic findings with the historic record of ground shaking associated with earthquakes in that period and combine the style of deformation in the last 3 events at the site with results from nearby paleoseismic sites to estimate earthquake rupture lengths and magnitudes for these early historic events. These findings increase the frequency of historic surface rupturing earthquakes on the northern SAF three-fold. At the Frazier Mountain site, on the southern SAF, I mapped deformation across a releasing step on the fault for the last five surface rupturing earthquakes to estimate deformation per-event. I compare the geometry and amount of vertical relief generated across the step-over by retrodeforming 3D surfaces interpolated from paleoseismic data step-wise for stratigraphic units deformed by each of those earthquakes. I find that structural relief is similar in four of the last five events, so slip on the fault must be within the same range for these earthquakes to generate approximately equivalent structural relief across the step-over. These results suggest displacement on the fault is comparable at the Frazier Mountain site for the last 4 events, including deformation resulting from 4-5 m lateral displacements in the historic M 7.9 1857 earthquake. This dissertation includes previously published and unpublished coauthored material. Supplemental file Plate A includes additional trench logs for the Hazel Dell site, presented in Chapters II and III.

Introdução: O carcinoma adenoide cístico (CAC) é uma das neoplasias de glândula salivar mais comuns para o qual não se encontra quimioterapia eficaz. Um conceito emergente na terapia do câncer é atingir proteínas especificas do tumor. MDM2 (murine double minute 2) é um importante inibidor do supressor tumoral p53, e sua expressão é aumentada em CAC. O objetivo do Artigo 1 foi avaliar o efeito de um novo inibidor da interação MDM2-p53 (MI-773) no CAC in vitro e in vivo. O Artigo 2 teve como objetivo entender o papel da combinação de MI-773 com cisplatina, além de avaliar a recorrência de CAC frente a regime neoadjuvante de MI-773. Materiais e Métodos: 3 modelos de xenoenxerto derivado de paciente (XEDP, UM-PDXHACC- 5; ACCx6; ACCx9) e 5 culturas primarias de CAC (UM-HACC-1, -2A, -2B, -5, -6) foram usados para experimentos in vitro e in vivo. Ensaio de Sulforrodamina B (SRB) foi realizado para avaliar o efeito dos agentes experimentais na viabilidade celular, além de determinar valores de IC50. Western blots revelaram a expressão de p53, fosfo-p53, MDM2, p21, PUMA, BAX, Bcl-2 e Bcl-xL. Lâminas histológicas (UMPDX- HACC-5) foram avaliadas por imunohistoquímica e imunofluorescência para determinar a localização de p53. Técnica de TUNEL in situ revelou o número de células de UM-PDX-HACC-5 no processo de apoptose. Citometria de fluxo foi realizada para determinar o efeito da terapia na proporção de células-tronco tumorais (ALDHhighCD44high) e para avaliar o ciclo celular. Para os estudos in vivo, animais transplantados com tumores (UM-PDX-HACC5, ACCx6, ou ACCx9) receberam protocolo terapêutico (MI-773 – gavagem; cisplatina – injeção intraperitoneal; ou veículo controle) conforme indicado. ANOVA, seguido de testes post-hoc (Tukey), Mann-Whitney U-test ou Student’s t-test foram usados para determinar as diferenças no crescimento tumoral, peso, volume, apoptose, viabilidade celular, expressão de TUNEL e p53. Significância estatística: p<0.05. Resultados: MI-773 causa regressão do tumor em todos os modelos préclínicos de CAC. Doses diárias de 100mg/kg de MI-773 reduziram significativamente o volume tumoral quando comparado com doses intermediárias (10 ou 50 mg/kg MI-773) ou veículo controle, em todos os modelos de CAC. Alternativamente, camundongos transplantados com tumores UM-PDX-HACC-5 receberam doses semanais de MI-773 (200 mg/kg) e/ou cisplatina (5 mg/kg) por 30 dias, a fim de se avaliar o efeito da combinação das drogas. MI-773, como agente único, causou regressão tumoral, sendo mais efetivo do que a cisplatina. Cisplatina, por outro lado, mostrou limitado efeito terapêutico, estabilizando o crescimento tumoral. Notavelmente, a combinação MI-773 + cisplatina foi mais efetiva do que os agentes isoladamente, e não foi verificada retomada do tumor no período pósoperatório. Importantemente, os protocolos experimentais não comprometeram a saúde geral dos animais. Coletivamente, estes resultados in vivo demonstram que MI-773 atua como mediador na regressão tumoral de CAC e sensibiliza os tumores à cisplatina. A inibição terapêutica da interação MDM2-p53 ativa p53 e induz apoptose. MI-773 potentemente induz expressão de p53, seu alvo p21 e proteínas relacionadas à apoptose, como PUMA, BAX, Bcl-2 e Bcl-xL in vitro e in vivo. Análise do ciclo celular mostrou que a inibição terapêutica da interação MDM2-p53 por MI- 773 causa parada no ciclo celular no primeiro ponto de checagem (G1). Marcação por TUNEL revelou número significativamente maior de células em apoptose quando tumores de UM-PDX-HACC-5 foram tratados com MI-773 em comparação com controle (p<0.05) Utilizando o mesmo modelo de xenoenxerto, a técnica de imunohistoquímica mostrou que MI-773 não somente aumentou a porcentagem de células p53-positivas (p<0.001), como causou uma translocação parcial de p53 ao citoplasma. MI-773 reduz a fração de células-tronco tumorais (CTT) e previne recorrência do CAC. Tratamento com MI-773 como agente único ou combinado com cisplatina reduziu a fração de CTT (p<0.05). Notavelmente, nenhum animal tratado com regime neoadjuvante de MI-773 apresentou recorrência tumoral mesmo após 300 dias de acompanhamento. Em contraste, em 62,5% dos animais do grupo controle houve recorrência (p=0.0097). Conclusões: Em resumo, os estudos demonstram que a inibição terapêutica da interação MDM2-p53 com MI-773 é uma estratégia antitumoral eficaz, é capaz de sensibilizar tumores à cisplatina e previne recorrência neste modelo pré-clínico de CAC. Coletivamente, os dados sugerem que pacientes com carcinoma adenoide cístico podem ser beneficiados através de terapias-alvo contra MDM2. / Introduction: Adenoid cystic carcinoma (ACC) is one of the most common salivary gland malignancies for which no effective chemotherapy is available. An emerging concept in cancer therapy is to target specific tumor-related proteins. Murine double minute 2 (MDM2) is an important inhibitor of the tumor suppressor p53 and has been found overexpressed in ACC. Paper #1 aimed to evaluate the effect of a novel small molecule inhibitor of the MDM2-p53 interaction (MI-773) on ACC in vitro and in vivo. Paper #2 aimed to understand the role of combining MI-773 with cisplatin, and to evaluated ACC recurrence using a neoadjuvant regimen of MI-773. Material and Methods: 3 patient-derived xenograft (PDX) models (UM-PDX-HACC-5; ACCx6; ACCx9) and 5 low passage primary human ACC cells pools (UM-HACC-1, -2A, -2B, - 5, -6) were used for in vivo and in vitro experiments. Sulforhodamine B (SRB) assay was performed to evaluate the effect of experimental agents on ACC cell viability and to determine IC50 values. Western blots revealed the expression of p53, phosphop53, MDM2, p21, PUMA, BAX, Bcl-2 and Bcl-xL. Histological sections from UM-PDXHACC- 5 tumors were stained using immunohistochemistry and immunofluorescence techniques to determine p53 status. In situ TUNEL staining revealed the number of UM-PDX-HACC-5 cells undergoing apoptosis. Flow cytometry was carried out to determine the effect of therapy on the proportion of cancer stem cells (ALDHhighCD44high) and for cell cycle analysis. For in vivo studies, mice harboring UM-PDX-HACC5, ACCx6, or ACCx9 tumors were treated following specific therapeutic protocol (MI-773 – gavage; cisplatin – intraperitoneal injection; or vehicle control), as opportunely indicated. One-way ANOVA, followed by post-hoc tests (Tukey), Mann-Whitney U-test or Student’s t-test were used to determine significant differences in tumor growth, weight, volume, apoptosis levels, cell viability, TUNEL and p53 expression. Significance was determined at p<0.05. Results: MI-773 caused tumor regression in all ACC PDX models. Daily doses of 100 mg/kg MI- 773 significantly reduced tumor volume when compared to intermediate doses (10 or 50 mg/kg MI-773) or vehicle-treated controls in all ACC xenograft models. Alternatively, mice harboring UM-PDX-HACC-5 tumors received either weekly doses of MI-773 (200 mg/kg) and/or cisplatin (5 mg/kg) for 30 days, in order to evaluate the effect of this drug combination. MI-773 as single agent caused tumor regression, being more effective than single agent cisplatin. Cisplatin showed limited therapeutic response stabilizing tumor growth. Notably, combination of MI-773 with cisplatin was more effective than single agent therapies and no tumor rebound was observed during the follow up period. Importantly, experimental protocols did not compromise the overall health status of mice. Collectively, these in vivo results demonstrate that MI-773 mediates ACC tumor regression, and sensitizes ACC xenograft tumors to cisplatin. Therapeutic inhibition of the MDM2-p53 interaction activates p53 and induces apoptosis. MI-773 potently induced the expression of p53, its downstream target p21 and apoptosis-related proteins PUMA, BAX, Bcl-2 and Bcl-xL in vitro and in vivo. Cell cycle analysis showed that therapeutic inhibition of the MDM2-p53 interaction by MI-773 causes cell cycle arrest at the first checkpoint (G1). In situ TUNEL revealed a significant higher number of cells undergoing apoptosis in UMPDX- HACC-5 tumors treated with MI-773 compared to vehicle control (p<0.05). Using the same xenograft model, immunohistochemistry assay showed that MI-773 not only increased the percentage of p53-positive cells (p<0.001), but also caused a partial translocation of p53 to the cytoplasm. MI-773 reduces the fraction of cancer stem cells (CSC) and prevents recurrence in ACC. Treatment with MI-773 as single agent or combined with cisplatin significantly reduced the fraction of CSC (p<0.05). Notably, not a single animal treated with neoadjuvant MI-773 presented recurrence even after 300 days of follow-up. In contrast, 62,5% of mice that received vehicle control experienced tumor reappearance within this time period (p=0.0097). Conclusions: In summary, these studies demonstrate that therapeutic inhibition of the MDM2-p53 interaction with MI-773 is an effective anti-tumor strategy that mediates tumor regression, sensitizes tumors to cisplatin and prevents recurrence in this pre-clinical model of ACC. Collectively, these data suggest that patients with adenoid cystic carcinoma might benefit from MDM2-targeted therapies.

Introdução: O carcinoma adenoide cístico (CAC) é uma das neoplasias de glândula salivar mais comuns para o qual não se encontra quimioterapia eficaz. Um conceito emergente na terapia do câncer é atingir proteínas especificas do tumor. MDM2 (murine double minute 2) é um importante inibidor do supressor tumoral p53, e sua expressão é aumentada em CAC. O objetivo do Artigo 1 foi avaliar o efeito de um novo inibidor da interação MDM2-p53 (MI-773) no CAC in vitro e in vivo. O Artigo 2 teve como objetivo entender o papel da combinação de MI-773 com cisplatina, além de avaliar a recorrência de CAC frente a regime neoadjuvante de MI-773. Materiais e Métodos: 3 modelos de xenoenxerto derivado de paciente (XEDP, UM-PDXHACC- 5; ACCx6; ACCx9) e 5 culturas primarias de CAC (UM-HACC-1, -2A, -2B, -5, -6) foram usados para experimentos in vitro e in vivo. Ensaio de Sulforrodamina B (SRB) foi realizado para avaliar o efeito dos agentes experimentais na viabilidade celular, além de determinar valores de IC50. Western blots revelaram a expressão de p53, fosfo-p53, MDM2, p21, PUMA, BAX, Bcl-2 e Bcl-xL. Lâminas histológicas (UMPDX- HACC-5) foram avaliadas por imunohistoquímica e imunofluorescência para determinar a localização de p53. Técnica de TUNEL in situ revelou o número de células de UM-PDX-HACC-5 no processo de apoptose. Citometria de fluxo foi realizada para determinar o efeito da terapia na proporção de células-tronco tumorais (ALDHhighCD44high) e para avaliar o ciclo celular. Para os estudos in vivo, animais transplantados com tumores (UM-PDX-HACC5, ACCx6, ou ACCx9) receberam protocolo terapêutico (MI-773 – gavagem; cisplatina – injeção intraperitoneal; ou veículo controle) conforme indicado. ANOVA, seguido de testes post-hoc (Tukey), Mann-Whitney U-test ou Student’s t-test foram usados para determinar as diferenças no crescimento tumoral, peso, volume, apoptose, viabilidade celular, expressão de TUNEL e p53. Significância estatística: p<0.05. Resultados: MI-773 causa regressão do tumor em todos os modelos préclínicos de CAC. Doses diárias de 100mg/kg de MI-773 reduziram significativamente o volume tumoral quando comparado com doses intermediárias (10 ou 50 mg/kg MI-773) ou veículo controle, em todos os modelos de CAC. Alternativamente, camundongos transplantados com tumores UM-PDX-HACC-5 receberam doses semanais de MI-773 (200 mg/kg) e/ou cisplatina (5 mg/kg) por 30 dias, a fim de se avaliar o efeito da combinação das drogas. MI-773, como agente único, causou regressão tumoral, sendo mais efetivo do que a cisplatina. Cisplatina, por outro lado, mostrou limitado efeito terapêutico, estabilizando o crescimento tumoral. Notavelmente, a combinação MI-773 + cisplatina foi mais efetiva do que os agentes isoladamente, e não foi verificada retomada do tumor no período pósoperatório. Importantemente, os protocolos experimentais não comprometeram a saúde geral dos animais. Coletivamente, estes resultados in vivo demonstram que MI-773 atua como mediador na regressão tumoral de CAC e sensibiliza os tumores à cisplatina. A inibição terapêutica da interação MDM2-p53 ativa p53 e induz apoptose. MI-773 potentemente induz expressão de p53, seu alvo p21 e proteínas relacionadas à apoptose, como PUMA, BAX, Bcl-2 e Bcl-xL in vitro e in vivo. Análise do ciclo celular mostrou que a inibição terapêutica da interação MDM2-p53 por MI- 773 causa parada no ciclo celular no primeiro ponto de checagem (G1). Marcação por TUNEL revelou número significativamente maior de células em apoptose quando tumores de UM-PDX-HACC-5 foram tratados com MI-773 em comparação com controle (p<0.05) Utilizando o mesmo modelo de xenoenxerto, a técnica de imunohistoquímica mostrou que MI-773 não somente aumentou a porcentagem de células p53-positivas (p<0.001), como causou uma translocação parcial de p53 ao citoplasma. MI-773 reduz a fração de células-tronco tumorais (CTT) e previne recorrência do CAC. Tratamento com MI-773 como agente único ou combinado com cisplatina reduziu a fração de CTT (p<0.05). Notavelmente, nenhum animal tratado com regime neoadjuvante de MI-773 apresentou recorrência tumoral mesmo após 300 dias de acompanhamento. Em contraste, em 62,5% dos animais do grupo controle houve recorrência (p=0.0097). Conclusões: Em resumo, os estudos demonstram que a inibição terapêutica da interação MDM2-p53 com MI-773 é uma estratégia antitumoral eficaz, é capaz de sensibilizar tumores à cisplatina e previne recorrência neste modelo pré-clínico de CAC. Coletivamente, os dados sugerem que pacientes com carcinoma adenoide cístico podem ser beneficiados através de terapias-alvo contra MDM2. / Introduction: Adenoid cystic carcinoma (ACC) is one of the most common salivary gland malignancies for which no effective chemotherapy is available. An emerging concept in cancer therapy is to target specific tumor-related proteins. Murine double minute 2 (MDM2) is an important inhibitor of the tumor suppressor p53 and has been found overexpressed in ACC. Paper #1 aimed to evaluate the effect of a novel small molecule inhibitor of the MDM2-p53 interaction (MI-773) on ACC in vitro and in vivo. Paper #2 aimed to understand the role of combining MI-773 with cisplatin, and to evaluated ACC recurrence using a neoadjuvant regimen of MI-773. Material and Methods: 3 patient-derived xenograft (PDX) models (UM-PDX-HACC-5; ACCx6; ACCx9) and 5 low passage primary human ACC cells pools (UM-HACC-1, -2A, -2B, - 5, -6) were used for in vivo and in vitro experiments. Sulforhodamine B (SRB) assay was performed to evaluate the effect of experimental agents on ACC cell viability and to determine IC50 values. Western blots revealed the expression of p53, phosphop53, MDM2, p21, PUMA, BAX, Bcl-2 and Bcl-xL. Histological sections from UM-PDXHACC- 5 tumors were stained using immunohistochemistry and immunofluorescence techniques to determine p53 status. In situ TUNEL staining revealed the number of UM-PDX-HACC-5 cells undergoing apoptosis. Flow cytometry was carried out to determine the effect of therapy on the proportion of cancer stem cells (ALDHhighCD44high) and for cell cycle analysis. For in vivo studies, mice harboring UM-PDX-HACC5, ACCx6, or ACCx9 tumors were treated following specific therapeutic protocol (MI-773 – gavage; cisplatin – intraperitoneal injection; or vehicle control), as opportunely indicated. One-way ANOVA, followed by post-hoc tests (Tukey), Mann-Whitney U-test or Student’s t-test were used to determine significant differences in tumor growth, weight, volume, apoptosis levels, cell viability, TUNEL and p53 expression. Significance was determined at p<0.05. Results: MI-773 caused tumor regression in all ACC PDX models. Daily doses of 100 mg/kg MI- 773 significantly reduced tumor volume when compared to intermediate doses (10 or 50 mg/kg MI-773) or vehicle-treated controls in all ACC xenograft models. Alternatively, mice harboring UM-PDX-HACC-5 tumors received either weekly doses of MI-773 (200 mg/kg) and/or cisplatin (5 mg/kg) for 30 days, in order to evaluate the effect of this drug combination. MI-773 as single agent caused tumor regression, being more effective than single agent cisplatin. Cisplatin showed limited therapeutic response stabilizing tumor growth. Notably, combination of MI-773 with cisplatin was more effective than single agent therapies and no tumor rebound was observed during the follow up period. Importantly, experimental protocols did not compromise the overall health status of mice. Collectively, these in vivo results demonstrate that MI-773 mediates ACC tumor regression, and sensitizes ACC xenograft tumors to cisplatin. Therapeutic inhibition of the MDM2-p53 interaction activates p53 and induces apoptosis. MI-773 potently induced the expression of p53, its downstream target p21 and apoptosis-related proteins PUMA, BAX, Bcl-2 and Bcl-xL in vitro and in vivo. Cell cycle analysis showed that therapeutic inhibition of the MDM2-p53 interaction by MI-773 causes cell cycle arrest at the first checkpoint (G1). In situ TUNEL revealed a significant higher number of cells undergoing apoptosis in UMPDX- HACC-5 tumors treated with MI-773 compared to vehicle control (p<0.05). Using the same xenograft model, immunohistochemistry assay showed that MI-773 not only increased the percentage of p53-positive cells (p<0.001), but also caused a partial translocation of p53 to the cytoplasm. MI-773 reduces the fraction of cancer stem cells (CSC) and prevents recurrence in ACC. Treatment with MI-773 as single agent or combined with cisplatin significantly reduced the fraction of CSC (p<0.05). Notably, not a single animal treated with neoadjuvant MI-773 presented recurrence even after 300 days of follow-up. In contrast, 62,5% of mice that received vehicle control experienced tumor reappearance within this time period (p=0.0097). Conclusions: In summary, these studies demonstrate that therapeutic inhibition of the MDM2-p53 interaction with MI-773 is an effective anti-tumor strategy that mediates tumor regression, sensitizes tumors to cisplatin and prevents recurrence in this pre-clinical model of ACC. Collectively, these data suggest that patients with adenoid cystic carcinoma might benefit from MDM2-targeted therapies.

The present paper deals with a study of a two variable polynomial Pn(x) analogues to the Legendre polynomial Pn(x). The paper contains differential recurrence relations, a partial differential equation, double generating functions, double and triple hypergeometric forms, a special property and a bilinear double generating function for the newly defined polynomials Pn,k(x, y).

A fissura labiopalatina (FL/P) é uma das malformações craniofaciais mais comuns em humanos, com variação epidemiológica nas diferentes populações. Possui diferentes apresentações clínicas, divergindo de acordo com a extensão e estruturas acometidas, podendo acometer somente o lábio ou lábio e palato em conjunto, uni ou bilateralmente, de maneira completa ou incompleta ou apenas o palato (FP) tanto completa como incompletamente. Podem fazer parte de um quadro sindrômico, recebendo a denominação de FL/P sindrômica ou acontecer como um fenótipo isolado, sendo chamada de FL/P isolada ou não sindrômica. Em relação a etiologia da FL/P não sindrômica, a literatura afirma ser multifatorial com a predisposição genética associada a fatores ambientais. Apesar de se apresentarem frequentemente associadas, a FL/P e FP não sindrômicas são consideradas etiologicamente e embriologicamente distintas. Objetivo: Aprofundar e ampliar o conhecimento das FP isoladas não sindrômicas, descrevendo o fenótipo principal (FP isolada) e seus subfenótipos clínicos, investigando o fator genético relacionado à recorrência por meio do histórico familial e buscando elucidar possível fatores ambientais envolvidos por meio do histórico gestacional. Material e métodos: Foram coletados dados de 165 prontuários médicos de pacientes com FP isolada não sindrômica matriculados no Hospital de Reabilitação de Anomalias Craniofaciais da Universidade de São Paulo (HRAC-USP). Para a coleta desses dados foram analisados segmentos do prontuário referentes a atendimentos realizados no HRACUSP em diferentes setores. Resultados: Em 165 pacientes estudados, o sexo feminino foi o mais acometido com 106 casos (64,24%) encontrados. O tipo de FP predominante foi a incompleta correspondendo a 88,48% da amostra total, sendo dentre elas a fissura de palato duro parcial a mais prevalente. Em cinco casos não foi possível realizar a classificação nos grupos referentes ao tipo de fissura adotados, sendo necessária a criação de um grupo de classificação adicional. Recorrência familial positiva foi relatada em 28,47% de 144 casos em que havia informação, e na maioria das vezes havia apenas 1 outro familiar acometido. A média da idade das mães e dos pais no momento da concepção foi de 26,9 e 31,4 anos, respectivamente. A porcentagem de abortos anteriores foi de 11,95% dos 92 casos informados e a consanguinidade foi de 3,29% dos 91 casos informados. A intercorrência mais frequentemente relatada (25 em 154 casos informados) foi o uso de medicamentos, tais como, antibióticos, anti-hipertensivos e medicamentos que auxiliam na prevenção do parto prematuro. Conclusão: O fenótipo FP isolada possui variações quanto à extensão de cometimento, sendo que as fissuras incompletas foram as mais frequentes e o sexo feminino predominantemente acometido. Em relação ao histórico familial e gestacional os dados que mais chamaram atenção estão relacionados ao percentual de recorrência familial (28,47%) e o uso de medicação durante a gestação. / Cleft lip and palate (CL/P) is one of the most common craniofacial malformations in humans, with epidemiological variation in different populations. It has different clinical presentations that diverge according to the extension and affected structures, and may either affect the lip or lip and palate together, unilaterally or bilaterally, in a complete or incomplete way or just affect the palate (CP) completely or incompletely. CL/P can either be related to a syndrome, classified as syndromic CL/P or unrelated to a syndrome, occurring as an isolated phenotype, designated as isolated or nonsyndromic CL/P. Regarding the etiology of nonsyndromic CL/P, research indicates multifactorial causes with a genetic predisposition associated with environmental factors. Although it is often present in association, nonsyndromic CL/P and CP are considered embryologically and etiologically distinct. Objective: To deepen and broaden the knowledge of individual nonsyndromic CP, describing the main phenotype (isolated CP) and its clinical subphenotypes, investigating the genetic factors related to recurrence through family history and to elucidate possible environmental factors involving gestational history. Material and Methods: Data were collected from 165 medical patients records with isolated nonsyndromic CP enrolled at the Hospital de Reabilitação de Anomalias Craniofaciais da Universidade de São Paulo (HRAC-USP). For data collection, segments of the records pertaining to care provided by HRAC-USP in different sectors were analyzed. Results: In the 165 patients studied, females were the most affected with 106 cases (64.24%) found. The predominant type of CP was incomplete corresponding to 88.48% of the total sample, and among these incomplete CP, the clefts involving partial hard palate were the most prevalent. In five cases it was impossible to classify the type of cleft, and the creation of an additional classification group was required. Positive familial recurrence was reported in 28.47% of 144 cases where information was available and in most cases there was only one other affected family member. The average age of mothers and fathers at conception was 26.9 and 31.4 years respectively. The percentage of previous miscarriages was 11.95% of the 92 reported cases and consanguineous marriage was found in 3.29% of the 91 reported cases. The most frequently reported complication (25 in 154 reported cases) was the use of drugs such as antibiotics, antihypertensives drugs, and drugs used to prevent premature birth. Conclusion: The phenotype Isolated CP presents variations in the extent of involvement, and incomplete clefts were the most frequent, with females predominantly affected. Regarding family history and gestational data what calls more attention were the percentage of familial recurrence (28.47%) and the use of medication during pregnancy.