Functional analysis of the ATM-p53-p21 pathway in the LRF CLL4 trial: blockade at the level of p21 is associated with short response duration.

PURPOSE: This study sought to establish whether functional analysis of the ATM-p53-p21 pathway adds to the information provided by currently available prognostic factors in patients with chronic lymphocytic leukemia (CLL) requiring frontline chemotherapy. EXPERIMENTAL DESIGN: Cryopreserved blood mononuclear cells from 278 patients entering the LRF CLL4 trial comparing chlorambucil, fludarabine, and fludarabine plus cyclophosphamide were analyzed for ATM-p53-p21 pathway defects using an ex vivo functional assay that uses ionizing radiation to activate ATM and flow cytometry to measure upregulation of p53 and p21 proteins. Clinical endpoints were compared between groups of patients defined by their pathway status. RESULTS: ATM-p53-p21 pathway defects of four different types (A, B, C, and D) were identified in 194 of 278 (70%) samples. The type A defect (high constitutive p53 expression combined with impaired p21 upregulation) and the type C defect (impaired p21 upregulation despite an intact p53 response) were each associated with short progression-free survival. The type A defect was associated with chemoresistance, whereas the type C defect was associated with early relapse. As expected, the type A defect was strongly associated with TP53 deletion/mutation. In contrast, the type C defect was not associated with any of the other prognostic factors examined, including TP53/ATM deletion, TP53 mutation, and IGHV mutational status. Detection of the type C defect added to the prognostic information provided by TP53/ATM deletion, TP53 mutation, and IGHV status. CONCLUSION: Our findings implicate blockade of the ATM-p53-p21 pathway at the level of p21 as a hitherto unrecognized determinant of early disease recurrence following successful cytoreduction.

Homozygous deletion mapping in myeloma samples identifies genes and an expression signature relevant to pathogenesis and outcome.

PURPOSE: Myeloma is a clonal malignancy of plasma cells. Poor-prognosis risk is currently identified by clinical and cytogenetic features. However, these indicators do not capture all prognostic information. Gene expression analysis can be used to identify poor-prognosis patients and this can be improved by combination with information about DNA-level changes. EXPERIMENTAL DESIGN: Using single nucleotide polymorphism-based gene mapping in combination with global gene expression analysis, we have identified homozygous deletions in genes and networks that are relevant to myeloma pathogenesis and outcome. RESULTS: We identified 170 genes with homozygous deletions and corresponding loss of expression. Deletion within the "cell death" network was overrepresented and cases with these deletions had impaired overall survival. From further analysis of these events, we have generated an expression-based signature associated with shorter survival in 258 patients and confirmed this signature in data from two independent groups totaling 800 patients. We defined a gene expression signature of 97 cell death genes that reflects prognosis and confirmed this in two independent data sets. CONCLUSIONS: We developed a simple 6-gene expression signature from the 97-gene signature that can be used to identify poor-prognosis myeloma in the clinical environment. This signature could form the basis of future trials aimed at improving the outcome of poor-prognosis myeloma.

Deletions of CDKN2C in Multiple Myeloma: Biological and Clinical Implications

Purpose: Deletions of chromosome 1 have been described in 7% to 40% of cases of myeloma with inconsistent clinical consequences. CDKN2C at 1p32.3 has been identified in myeloma cell lines as the potential target of the deletion. We tested the clinical impact of 1p deletion and used high-resolution techniques to define the role of CDKN2C in primary patient material.Experimental Design: We analyzed 515 cases of monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), and newly diagnosed multiple myeloma using fluorescence in situ hybridization (FISH) for deletions of CDKN2C. In 78 myeloma cases, we carried out Affymetrix single nucleotide polymorphism mapping and U133 Plus 2.0 expression arrays. In addition, we did mutation, methylation, and Western blotting analysis.Results: By FISH we identified deletion of 1p32.3 (CDKN2C) in 3 of 66 MGUS (4.5%), 4 of 39 SMM (10.3%), and 55 of 369 multiple myeloma cases (15%). We examined the impact of copy number change at CDKN2C on overall survival (OS), and found that the cases with either hemizygous or homozygous deletion of CDKN2C had a worse OS compared with cases that were intact at this region (22 months versus 38 months; P = 0.003). Using gene mapping we identified three homozygous deletions at 1p32.3, containing CDKN2C, all of which lacked expression of CDKN2C. Cases with homozygous deletions of CDKN2C were the most proliferative myelomas, defined by an expression-based proliferation index, consistent with its biological function as a cyclin-dependent kinase inhibitor.Conclusions: Our results suggest that deletions of CDKN2C are important in the progression and clinical outcome of myeloma.

A global expression-based analysis of the consequences of the t(4;14) translocation in myeloma

Purpose: Our purpose in this report was to define genes and pathways dysregulated as a consequence of the t(4;14) in myeloma, and to gain insight into the downstream functional effects that may explain the different prognosis of this subgroup.Experimental Design: Fibroblast growth factor receptor 3 (FGFR3) overexpression, the presence of immunoglobulin heavy chain-multiple myeloma SET domain (IgH-MMSET) fusion products and the identification of t(4;14) breakpoints were determined in a series of myeloma cases. Differentially expressed genes were identified between cases with (n = 55) and without (n = 24) a t(4;14) by using global gene expression analysis.Results: Cases with a t(4;14) have a distinct expression pattern compared with other cases of myeloma. A total of 127 genes were identified as being differentially expressed including MMSET and cyclin D2, which have been previously reported as being associated with this translocation. Other important functional classes of genes include cell signaling, apoptosis and related genes, oncogenes, chromatin structure, and DNA repair genes. Interestingly, 25% of myeloma cases lacking evidence of this translocation had up-regulation of the MMSET transcript to the same level as cases with a translocation.Conclusions: t(4;14) cases form a distinct subgroup of myeloma cases with a unique gene signature that may account for their poor prognosis. A number of non-t(4;14) cases also express MMSET consistent with this gene playing a role in myeloma pathogenesis.

Falls and the Social Isolation of Older Adults in the National Health and Aging Trends Study

Thesis (Ph.D.)--University of Washington, 2016-08

Low- vs. high-glycemic load diets: effects on postprandial plasma free fatty acids

Thesis (Master's)--University of Washington, 2016-06

Exploiting DNA damage repair defects for effective targeting of acute myeloid leukaemia by PARP inhibitors

Abstract for 24th Biennial Congress of the European Association for Cancer Research, 9–12 July 2016, Manchester, UK. Poster Session: Cancer Genomics, Epigenetics and Genome Instability II: Monday 11 July 2016

Sense-making in theory and practice: a metatheoretical foundation and application for health information seeking

This thesis attempts to provide deeper historical and theoretical grounding for sense-making, thereby illustrating its applicability to practical information seeking research. In Chapter One I trace the philosophical origins of Brenda Dervin’s theory known as “sense making,” reaching beyond current scholarship that locates the origins of sense-making in twentieth-century Phenomenology and Communication theory and find its rich ontological, epistemological, and etymological heritage that dates back to the Pre-Socratics. After exploring sense-making’s Greek roots, I examine sense-making’s philosophical undercurrents found in Hegel’s Phenomenology of Spirit (1807), where he also returns to the simplicity of the Greeks for his concept of sense. With Chapter Two I explore sense-making methodology and find, in light of the Greek and Hegelian dialectic, a dialogical bridge connecting sense-making’s theory with pragmatic uses. This bridge between Dervin’s situation and use occupies a distinct position in sense-making theory. Moreover, building upon Brenda Dervin’s model of sense-making, I use her metaphors of gap and bridge analogy to discuss the dialectic and dialogic components of sense making. The purpose of Chapter Three is pragmatic – to gain insight into the online information-seeking needs, experiences, and motivation of first-degree relatives (FDRs) of breast cancer survivors through the lens of sense-making. This research analyses four questions: 1) information-seeking behavior among FDRs of cancer survivors compared to survivors and to undiagnosed, non-related online cancer information seekers in the general population, 2) types of and places where information is sought, 3) barriers or gaps and satisfaction rates FDRs face in their cancer information quest, and 4) types and degrees of cancer information and resources FDRs want and use in their information search for themselves and other family members. An online survey instrument designed to investigate these questions was developed and pilot tested. Via an email communication, the Susan Love Breast Cancer Research Foundation distributed 322,000 invitations to its membership to complete the survey, and from March 24th to April 5th 10,692 women agreed to take the survey with 8,804 volunteers actually completing survey responses. Of the 8,804 surveys, 95% of FDRs have searched for cancer information online, and 84% of FDRs use the Internet as a sense-making tool for additional information they have received from doctors or nurses. FDRs report needing much more information than either survivors or family/friends in ten out of fifteen categories related to breast and ovarian cancer. When searching for cancer information online, FDRs also rank highest in several of sense-making’s emotional levels: uncertainty, confusion, frustration, doubt, and disappointment than do either survivors or friends and family. The sense-making process has existed in theory and praxis since the early Greeks. In applying sense–making’s theory to a contemporary problem, the survey reveals unaddressed situations and gaps of FDRs’ information search process. FDRs are a highly motivated group of online information seekers whose needs are largely unaddressed as a result of gaps in available online information targeted to address their specific needs. Since FDRs represent a quarter of the population, further research addressing their specific online information needs and experiences is necessary.

Developmental mechanisms of stripe patterns in rodents

International audience

Efectos de una intervención educativa en los conocimientos y prácticas de los estilos de vida saludables para la prevención del cáncer de seno en estudiantes mujeres de un colegio público de la localidad de Ciudad Bolívar en Bogotá, Colombia

Objetivo: Evaluar los efectos de una intervención educativa en la práctica del autoexamen de seno, los conocimientos y práctica de los estilos de vida saludables para la prevención del cáncer de seno en estudiantes mujeres de un colegio público de la localidad de Ciudad Bolívar en Bogotá, Colombia. Materiales y métodos: Estudio de intervención, antes y después, no controlado en un periodo de seis meses con la participación de mujeres jóvenes estudiantes entre 10 y 20 años de edad. Se contemplaron cinco momentos metodológicos ejecutados en los meses de febrero en el cual se realizó la aplicación del cuestionario auto-diligenciado; de marzo en el cual las estudiantes recibieron una sesión educativa de 90 minutos y una de 60 minutos, soportadas con material audiovisual y folletos informativos. Se realizó el seguimiento prospectivo para la toma de datos en uno, tres y seis meses post-intervención. Conclusiones: 155 estudiantes fueron encuestadas. La prevalencia de práctica del autoexamen de seno fue de 78,1% (n=121). Se evidenció un cambio significativo en el conocimiento de la técnica y la práctica del autoexamen de seno, así como aumentos significativos en los conocimientos de los principales factores de riesgo para el cáncer de mama (p<,0001). En cuanto a los estilos de vida, las estudiantes mejoraron de manera significativa la práctica regular de actividad física con más de 150 minutos semanales a los 6 meses post-intervención. Conclusión: Una intervención educativa puede mejorar los conocimientos acerca de los factores de riesgo para cáncer de mama, la práctica del autoexamen de seno y los estilos de vida en mujeres jóvenes estudiantes de una localidad de bajo nivel socio-económico en Bogotá, Colombia. Estudios experimentales de alta calidad son requeridos.

Efectos de una intervención educativa en la promoción de la actividad física, otros comportamientos saludables y los conocimientos para la prevención del cáncer de pulmón en jóvenes del colegio La Merced en Bogotá D.C., Colombia

Introducción: El cáncer de pulmón es el tipo de cáncer más mortal a nivel mundial, al cual se atribuyen una de cada cinco muertes anualmente. El objetivo de este estudio fue determinar los efectos de una intervención educativa en la promoción de la actividad física, otros comportamientos saludables y los conocimientos para la prevención del cáncer de pulmón en jóvenes estudiantes de una institución educativa pública en Bogotá, Colombia. Métodos: Estudio experimental no controlado en 243 estudiantes de sexo femenino (Edad 14±1,5 años). La intervención educativa se desarrolló en tres momentos: una sesión educativa con una duración de 60 minutos acorde a la Guía para la Comunicación Educativa en el Marco del Control del Cáncer, en Colombia. Segundo, se enviaron tres correos electrónicos con información acerca del cáncer pulmonar; finalmente se desarrollaron actividades grupales. Para la toma de datos se utilizaron el cuestionario Cáncer Awareness Measure (CAM) y el Sistema de Vigilancia de Factores de Riesgo del Comportamiento (BRFSS). La evaluación se realizó en un período de seguimiento a 1, 3 y 6 meses post-intervención. Resultados: La intervención educativa incrementó significativamente los conocimientos de las jóvenes sobre los signos de alarma del cáncer pulmonar y los principales factores de riesgo modificables, tales como el consumo de cigarrillo, la exposición al humo del mismo y el sedentarismo, al sexto mes post-intervención. Las mejoras en el cambio comportamental no lograron significancia estadística. Conclusiones: Una intervención educativa mejora los conocimientos acerca de la detección temprana y la prevención del cáncer de pulmón, así como los comportamientos saludables en jóvenes estudiantes en Bogotá, Colombia. Se requiere de estudios controlados aleatorizados.

Chemo-physical and biological mechanisms behind the anticancer activity of plasma activated Ringer's Lactate solution for the treatment of peritoneal carcinosis from primitive epithelial ovarian/tubular tumor

Cancer research and development of targeting agents in this field is based on robust studies using preclinical models. The failure rate of standardized treatment approaches for several solid tumors has led to the urgent need to fine-tune more sophisticated and faithful preclinical models able to recapitulate the features of in vivo human tumors, with the final aim to shed light on new potential therapeutic targets. Epithelial Ovarian Cancer (EOC) serous histotype (HGSOC) is one of the most lethal diseases in women due to its high aggressiveness (75% of patients diagnosed at FIGO III-IV state) and poor prognosis (less of 50% in 5 years), whose therapy often fails as chemoresistance sets in. This thesis aimed at using the novel perfusion-based bioreactor U-CUP that provides direct perfusion throughout the tumor tissue seeking to obtain an EOC 3D ex vivo model able to recapitulate the features of the original tumor including the tumor microenvironment and maintaining its cellular heterogeneity. Moreover, we optimized this approach so that it can be successfully applied to slow-frozen tumoral tissues, further extending the usefulness of this tool. We also investigated the effectiveness of Plasma Activated Ringer’s Lactate solution (PA-RL) against Epithelial Ovarian Cancer (EOC) serous histotype in both 2D and 3D cultures using ex-vivo specimens from HGSOC patients. We propose PA-RL as a novel therapy with local intraperitoneal administration, which could act on primary or metastatic ovarian tumors inducing a specific cancer cell death with reduced damage on the surrounding healthy tissues.

A 3D biomimetic in vitro model: a novel strategy to investigate glioma biology

Gliomas are one of the most frequent primary malignant brain tumors. Acquisition of stem-like features likely contributes to the malignant nature of high-grade gliomas and may be responsible for the initiation, growth, and recurrence of these tumors. In this regard, although the traditional 2D cell culture system has been widely used in cancer research, it shows limitations in maintaining the stemness properties of cancer and in mimicking the in vivo microenvironment. In order to overcome these limitations, different three-dimensional (3D) culture systems have been developed to mimic better the tumor microenvironment. Cancer cells cultured in 3D structures may represent a more reliable in vitro model due to increased cell-cell and cell-extracellular matrix (ECM) interaction. Several attempts to recreate brain cancer tissue in vitro are described in literature. However, to date, it is still unclear which main characteristics the ideal model should reproduce. The overall goal of this project was the development of a 3D in vitro model able to reproduce the brain ECM microenvironment and to recapitulate pathological condition for the study of tumor stroma interactions, tumor invasion ability, and molecular phenotype of glioma cells. We performed an in silico bioinformatic analysis using GEPIA2 Software to compare the expression level of seven matrix protein in the LGG tumors with healthy tissues. Then, we carried out a FFPE retrospective study in order to evaluate the percentage of expression of selected proteins. Thus, we developed a 3D scaffold composed by Hyaluronic Acid and Collagen IV in a ratio of 50:50. We used two astrocytoma cell lines, HTB-12 and HTB-13. In conclusion, we developed an in vitro 3D model able to reproduce the composition of brain tumor ECM, demonstrating that it is a feasible platform to investigate the interaction between tumor cells and the matrix.

Clinical End Points and Response Criteria in Mycosis Fungoides and Sezary Syndrome: A Consensus Statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research and Treatment of Cancer

Mycosis fungoides (MF) and Sezary syndrome (SS), the major forms of cutaneous T-cell lymphoma, have unique characteristics that distinguish them from other types of non-Hodgkin`s lymphomas. Clinical trials in MF/SS have suffered from a lack of standardization in evaluation, staging, assessment, end points, and response criteria. Recently defined criteria for the diagnosis of early MF, guidelines for initial evaluation, and revised staging and classification criteria for MF and SS now offer the potential for uniform staging of patients enrolled in clinical trials for MF/SS. This article presents consensus recommendations for the general conduct of clinical trials of patients with MF/SS as well as methods for standardized assessment of potential disease manifestations in skin, lymph nodes, blood, and visceral organs, and definition of end points and response criteria. These guidelines should facilitate collaboration among investigators and collation of data from sponsor-generated or investigator-initiated clinical trials involving patients with MF or SS. J Clin Oncol 29:2598-2607. (C) 2011 by American Society of Clinical Oncology

Superior outcome of women with stage I/II cutaneous melanoma: pooled analysis of four European Organisation for Research and Treatment of Cancer phase III trials.

PURPOSE: Several studies observed a female advantage in the prognosis of cutaneous melanoma, for which behavioral factors or an underlying biologic mechanism might be responsible. Using complete and reliable follow-up data from four phase III trials of the European Organisation for Research and Treatment of Cancer (EORTC) Melanoma Group, we explored the female advantage across multiple end points and in relation to other important prognostic indicators. PATIENTS AND METHODS: Patients diagnosed with localized melanoma were included in EORTC adjuvant treatment trials 18832, 18871, 18952, and 18961 and randomly assigned during the period of 1984 to 2005. Cox proportional hazard models were used to calculate hazard ratios (HRs) and 95% CIs for women compared with men, adjusted for age, Breslow thickness, body site, ulceration, performed lymph node dissection, and treatment. RESULTS: A total of 2,672 patients with stage I/II melanoma were included. Women had a highly consistent and independent advantage in overall survival (adjusted HR, 0.70; 95% CI, 0.59 to 0.83), disease-specific survival (adjusted HR, 0.74; 95% CI, 0.62 to 0.88), time to lymph node metastasis (adjusted HR, 0.70; 95% CI, 0.51 to 0.96), and time to distant metastasis (adjusted HR, 0.69; 95% CI, 0.59 to 0.81). Subgroup analysis showed that the female advantage was consistent across all prognostic subgroups (with the possible exception of head and neck melanomas) and in pre- and postmenopausal age groups. CONCLUSION: Women have a consistent and independent relative advantage in all aspects of the progression of localized melanoma of approximately 30%, most likely caused by an underlying biologic sex difference.