Thesis (Ph.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / Cancer, the second most common cause of death in the United States, is a collection of diseases caused by uncontrolled cell growth and metastasis. The main treatment for cancer is chemotherapy, which generally kills fast growing cells nonspecifically and has many side effects. A different type of cancer treatment, called targeted therapy, aims to avoid general toxicity by using drugs that block the activity of specific gene products, usually encoded by oncogenes, which have been shown to drive tumor growth. To date, targeted therapies, alone or in combination with chemotherapies, have mainly been successful in rare subsets of patients with tumors addicted to single oncogenes. This has created a rationale to mainly treat patients with an oncogene-addiction (such as those carrying mutated or overexpressed kinases) with targeted therapies like erlotinib and trastuzumab, which inhibit human epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2/ErbB2), respectively. Here, evidence is provided that targeted therapies are also effective in tumors that are dependent on multiple growth factors - a phenomenon that is called combinatorial ligand addiction. Specifically, it is shown that ligands that bind the EGFR family and the hepatocyte growth factor receptor (HGFR/MET) can activate protein kinase B (PKB/ AKT) across a broad set of cancer cell lines, suggesting that ligand signaling is redundant and widespread. It is also shown that ErbB ligands have distinct signaling dynamics and strengths, which provides a rationale for investigating each component of the ErbB signaling network. Using a systematic approach, we found that ErbB3 is an imp01tant therapeutic target even though it is not overexpressed and lacks kinase activity. Furthermore, it is shown that cell lines with and without known oncogene-addiction express autocrine ligands and have improved growth inhibition with drug combinations that include autocrine ligand-blocking antibodies. This research demonstrates that combinatorial ligand addiction creates a new rationale for therapeutic combinations to improve efficacy and prevent resistance in cancer cells that are treated with current targeted drugs. / 2031-01-01

Thesis (M.S.)--Boston University / This study was designed to determine whether education, marital status, sex, age and religion are factors influencing the time lapse between onset of symptoms and the seeking of medical attention with cancer of the colon.

Since the discovery of anti-tumor activity of cisplatin in 1960, significant progress has been made in treating metastatic or advanced cancer with cisplatin and platinum compounds. Platinum compounds covalently bind to DNA and disrupt DNA function. They are also known to bind with amino acids like methionine, histidine and cysteine to form cisplatin-protein adducts which are responsible for most of its cytotoxicity and side effects. Recent articles on cisplatin-protein have shown that adding bulky adjuncts to cisplatin or using different platinum compounds varies the degree and extent of reaction thus possibly reducing cisplatin resistance and side effects. One of the proteins to study is cytochrome C, which is an intermediate in apoptosis (a controlled form of cell death used to kill cells in the process of development or in response to infection or DNA damage). Cytochrome C activates caspase 9, a cysteine protease, which in turn goes on to activate caspases 3 and 7, which are responsible for destroying the cell from within. In this study, we tried to examine how various platinum compounds like cis-Pt(NH3)2Cl2, cis-Pt(NH3)2(NO3)2, Pt(en)(NO3)2, Pt(Me4en)(NO3)2, Pt(NH3)2 (oxalate), Pt(en)(oxalate),Pt(Me4en)(oxalate), which have different ligands/bulk, react with cytochrome C in different physiological conditions. This research project subsequently focused on three main aspects: 1) to determine whether the concentration of platinum compounds made a difference in the reaction rate, 2) to determine whether the pH of the buffer shows any difference in the reaction rate, 3) to determine how the ligands coordinated to the platinum affected the rate. We used 1) HPLC with vitamin B12 (cyanocobalamin) as an internal standard. 2) Separate samples of platinum compounds with bovine serum albumin were then subjected to dialysis and were then sent to the Materials Characterization Center for analysis by ICP-AES spectroscopy. In summary, the following conclusions are stated: •The leaving group, pH, bulk and the concentration play a very vital role in determining the reaction rate for platinum-cytochrome C interactions. •Chlorides form excellent leaving groups followed by oxalates then nitrates. •Pt(en) reacts faster than Pt(NH3)2 which reacts faster than Pt(Me4en). •Nitrates, Pt(en) and few oxalate form multiple products showing non-specific binding. Only cis-Pt(NH3)2Cl2 and Pt(Me4en)(oxalate) formed predominately a single product showing target specific binding. •cis-Pt(NH3)2Cl2 showed an increased reaction rate at lower pH while cis-Pt(NH3)2(NO3)2 and Pt(Me4en)(NO3)2 showed higher reactions at higher pH. •Despite platinum compound was present in significant molar excess relative to cytochrome C, at the end of 21 hrs there was a significant amount of unreacted cytochrome C left except in case of cis-Pt(en)Cl2 which reacted with the whole cytochrome C in less than ten minutes. •We saw the rate of reaction in order of cis-Pt(en)Cl2 > Pt(en)(oxalate) > cis-Pt(NH3)2Cl2 > Pt(en)(NO3)2 > cis-Pt(NH3)2(NO3)2 > cis-Pt(NH3)2(oxalate) > Pt(Me4en)(oxalate) > Pt(Me4en)(NO3)2

Bakgrund: Bröstcancer är den vanligaste cancerformen bland kvinnor. Behandlingsalternativen är cytostatika, kirurgi och antihormonbehandling som resulterar i påfrestande biverkningar. Behandlingarna påverkar kvinnorna på flera olika sätt och det kan leda till ett lidande och minskat välbefinnande. Sjuksköterskan har flera ansvarsområden gällande omvårdnaden av patienten. Metod: En litteraturöversikt där vetenskapliga artiklar med kvalitativ ansats analyserades. Syfte: Syftet var att belysa kvinnors upplevelser av sin sexualitet under och efter behandling mot bröstcancer. Resultat: I analysen framkom fem teman 1) Förlorat bröst en känsla av vanställdhet, 2) självbilden och kroppsuppfattningen förändrades, 3) Förändrad sexuell hälsa, 4) Biverkningar och komplikationer påverkade den sexuella hälsan och 5) En önskan om öppenhet. Konklusion: Behandlingarna påverkade kvinnornas självbild, sexualitet och femininitet i olika grad vilket kan härledas till att alla upplevelser är individuella. En önskan om öppenhet kring samtal om den sexuella hälsan fanns. Med hjälp av information, stöd samt att inleda samtal om den sexuella hälsan och kvinnornas självbild kan det leda till att kvinnan upplever en god omvårdnad. / Background: Breast cancer is the most common form of cancer among women. The treatment options are chemotherapy, surgery and anti-hormone treatment that are carried out in stressful side effects. The treatment affects women in several different ways and can lead to suffering and reduced well-being. The nurse has several areas of responsibility regarding the care of the patient. Method: A literature review in which scientific articles with a qualitative approach were analyzed. Aim: The purpose was to describe women’s experiences of their sexuality during and after breast cancer treatment. Findings: The analysis revealed five themes 1) Lost breast a feeling of disfigurement, 2) self-image and body perception changed, 3) Changed sexual health, 4) Side effects and complications affected sexual health and 5) A desire for openness. Conclusion: The treatment affected the women’s self-image, sexuality, and femininity to varying degrees, which can be attributed to the fact that all experiences are individual. There was a desire for openness about conversations about sexual health. With the help of information, support and initiating conversations about sexual health and women’s self-image, it can lead to the women experiencing good care.

Le rétinoblastome est une tumeur maligne de la rétine qui touche essentiellement les nourrissons et jeunes enfants. Sa prise en charge est associée à la survenue d’effets secondaires sévères, certains traitements induisant le développement de tumeurs secondaires. Dans ce contexte, la thérapie photodynamique (PDT) apparaît comme une alternative prometteuse, car elle est non mutagène et génère des effets secondaires moins importants. Elle consiste à injecter un agent photosensibilisateur (PS) - une porphyrine par exemple – puis à illuminer la zone tumorale avec un laser. L'efficacité de la PDT nécessite l'accumulation de PS dans la tumeur. Cependant, la plupart des porphyrines sont hydrophobes et s'agrègent en milieu aqueux. Leur incorporation dans un nano-vecteur peut améliorer leur distribution au cytoplasme. Malheureusement, lorsqu'elles sont encapsulées dans le cœur des nanoparticules, les molécules de PS perdent leur phototoxicité en raison de leur auto-extinction. Dans ce travail, nous avons conçu des lipo-nanoparticules biodégradables (LNP) constituées d'une nanoparticule (NP) de poly (D,L)-lactide (PLA) recouverte d'une bicouche de phospholipides (POPC-DOTAP). Un principe actif anticancéreux, la bêta-lapachone et un agent photosensibilisateur ont ensuite été co-encapsulés dans notre système en vue de favoriser un effet synergique sur le rétinoblastome. Nous avons démontré la formation effective des LNPs et leur internalisation dans les cellules de rétinoblastome en quelques heures.Enfin, nous avons démontré une amélioration de l'activité antitumorale en combinant les deux traitement dans notre système par rapport au traitement simple par PDT ou chimiothérapie. / Retinoblastoma is a malignant tumor of the retina in infants. Conventional therapies are associated to severe side effects and some of them induce secondary tumors. Therefore, photodynamic therapy (PDT) appears as a promising alternative as it is non-mutagenic and generates minimal side effects. It consists in injection of a photosensitizer (PS) like a porphyrin, and then illumination of the tumor area with a laser. The effectiveness of PDT requires the accumulation of the PS in the tumor. However, most porphyrins are hydrophobic and aggregate in aqueous medium. Their incorporation into a nanocarrier may improve their delivery to the cytoplasm. Unfortunately, when incorporated into a nanoparticle core, PS molecules lose their phototoxicity due to self-quenching. In this work, we have designed biodegradable liponanoparticles (LNPs) consisting of a poly(D,L)-lactide (PLA) nanoparticle (NP) coated with a phospholipid (POPC/DOTAP) bilayer. An anticancer drug, beta-lapachone (β-Lap), and a photosensitizer were then co-encapsulated in these LNPs for achieving synergistic effect on retinoblastoma. We have first demonstrated the effective formation of the LNPs and their internalization in retinoblastoma cells within few hours. Then we studied the cyto/phototoxicity of the system.The hybrid nanoparticles showed an improved antitumor activity when the PS and β-Lap were combined, compared to the single treatment by PDT or chemotherapy.

Contexte. Non seulement le cancer est toujours la principale cause de décès par maladie chez les enfants, mais les deux tiers des survivants présenteront, à l’âge adulte, des séquelles liées aux traitements reçus. Tel qu’il sera décrit dans le présent mémoire, le programme VIE (Valorisation, Implication, Éducation) au Centre hospitalier universitaire Sainte-Justine propose d’implanter un programme d’interventions pour sensibiliser les patients en cours de traitement et leur famille aux bienfaits d’adopter de saines habitudes de vie et les supporter dans le changement de comportements attendus. Un volet de ce programme comprend des ateliers d’éducation culinaire et nutritionnelle. Objectifs. L’objectif principal de ce projet est de développer et de valider un curriculum d’ateliers d’éducation culinaire et nutritionnelle qui permettra de répondre aux particularités d’une clientèle en oncologie pédiatrique en cours de traitements et de prévenir les complications cardiométaboliques à long terme. Un second objectif consiste au développement d’un outil d’évaluation des ateliers. Méthode. Les thèmes, les objectifs d’apprentissages et le contenu des ateliers ont fait l’objet d’un processus de développement et de validation en huit étapes, incluant la consultation d’un comité d’experts. Les recettes en démonstration ont été développées et standardisées par deux nutritionnistes de l’équipe de recherche et leur valeur nutritive analysée à l’aide d’un logiciel d’analyse nutritionnelle. Les outils d’évaluation ont été développés en fonction des objectifs d’apprentissages des ateliers en s’inspirant d’outils de mesure existants et révisés par un expert. Résultats. Six ateliers d’éducation culinaire et nutritionnelle basés sur les données probantes et l’expérience clinique de trois nutritionnistes en oncologie pédiatrique ont été développés et validés. Douze recettes en lien avec les thèmes des ateliers, deux pour chaque atelier, ont été développées, standardisées et leur valeur nutritive validée. Six questionnaires ont été développés pour mesurer la perception de l’acquisition de connaissances, l’intention d’appliquer les apprentissages et la satisfaction des participants pour chacun des ateliers. Conclusion. À notre connaissance, il s’agit du premier programme d’éducation culinaire et nutritionnelle élaboré spécifiquement pour les familles d’une clientèle d’oncologie pédiatrique en cours de traitement. Nous pensons que ce programme répondra aux besoins spécifiques des patients en oncologie pédiatrique et de leur famille et contribuera à les sensibiliser à l’importance d’instaurer ou de maintenir de saines habitudes alimentaires pendant et après les traitements du cancer. / Context. Cancer is still the main cause of death by illness in children. Furthermore, two third of the survivors will present treatment-related late effects in adulthood. As it will be described in this thesis, the VIE program (Valorisation, Implication, Education) at the Sainte-Justine University Hospital Center aims to implement an intervention program to raise awareness of patients ongoing cancer treatments and their family to the benefits of adopting a healthy lifestyle and to support them with expected behavior change. One component of this program consists in nutrition and cooking education workshops. Objectives. The main objective of this project is to develop and validate a nutrition and cooking education workshop curriculum which will address concerns specific to on-treatment pediatric oncology patients and help prevent cardiometabolic late effects. A second objective is to develop an evaluation tool for the workshops. Methodology. The workshops’ themes, specific objectives and content have been subject to an eight-steps development and validation process, including steering committee consultation. The recipes in demonstration have been developed and standardized by two research staff registered dietitians and their nutritional value analyzed with a nutritional analysis software. Evaluation tools have been developed in accordance with the workshops learning objectives, inspired by existing tools and reviewed by expert. Results. Six nutrition and cooking education workshops based on scientific evidence and clinical experience of three pediatric oncology registered dietitians have been developed and validated. Twelve recipes related to the workshops themes, two for each workshop, have been developed, standardized and their nutritional value validated. Six questionnaires have been developed for each workshop to measure participants’ perception of knowledge acquisition, behavioral intention and satisfaction. Conclusion. It is, to our knowledge, the first nutrition and cooking education workshop curriculum elaborated specifically for families of an on-treatment pediatric oncology population. We think that this program will address the needs specific to pediatric oncology patients and their family, while contributing to raise awareness to the importance of adopting and maintaining healthy eating habits during and after cancer treatments.

Les médias et les réseaux sociaux constituent une source importante de diffusion et de communication des résultats de la recherche clinique. Le terme « spin » est utilisé lorsque la présentation et l’interprétation des résultats d’une étude sont déformées par les auteurs que ce soit intentionnellement ou involontairement. Les spins exagèrent les effets bénéfiques des interventions et sous-estiment les effets indésirables. Les principaux objectifs de ce travail étaient :1) d’évaluer la prévalence des « spins » dans les articles de presse, d’identifier les différentes stratégies de spin et de développer une classification de spin ; 2) d’identifier les facteurs associés à une diffusion des résultats via les réseaux sociaux et 3) d’étudier comment les articles scientifiques rapportés avec des spins diffusent via les réseaux sociaux, à partir de l’exemple de l’essai DAPT 2014. Dans un premier temps, nous avons réalisé une revue systématique des articles de presse décrivant les résultats d’études évaluant une intervention et indexés dans la rubrique santé de Google. Nous avons développé une classification des stratégies de spin pour les articles de presse et montré que la prévalence des spins est élevée. Dans un deuxième temps, nous avons réalisé une étude de cohorte d’articles évaluant les traitements contre le cancer pour identifier les facteurs associés à une attention médiatique élevée. Le critère de jugement principal était l’attention portée par les médias et les réseaux sociaux mesuré par le « score Altmetric ». Nos résultats ont montré l’importance de l’accès libre et des communiqués de presse. Enfin, nous avons effectué une analyse systématique de l’attention portée par les médias et les réseaux sociaux autour de l'étude DAPT qui était rapporté avec des spins sous estimant les effets indésirable de l’intervention. Nous avons montré que l’interprétation des résultats par les auteurs sont rarement contredits. Ces travaux ont permis de mettre en évidence l’importance des spins dans les médias et de développer des outils (classification de spin) pour améliorer la diffusion des résultats de la recherche. / Mass media and social networks are important sources of disseminating and communicating clinical research. The term “spin” is used when the presentation and interpretation of the results of a study is distorted by the authors intentionally or unintentionally. Spins exaggerate the beneficial effects of interventions and underestimate adverse effects. The main objectives of this PhD were (I) to assess the prevalence of spin in health news, as well as identify and classify different strategies of spin; (II) to identify factors associated with dissemination of research results through online media, and (III) to explore how results of a trial reported with spin were disseminated to the scientific community and online media, using the 2014 DAPT trial as a case study. For the first aim, we performed a cross-sectional study of health news and described the distortion of research results of studies evaluating an intervention in Google health news. We developed a classification of spin for health news and showed a high prevalence of spin. For the second aim, we performed a cohort study of articles evaluating cancer treatments and identify factors associated with high online media attention. The primary outcome was the attention received by media and social networks measured by Altmetric score. Our results highlighted the importance of open access and press releases. Finally, we performed a systematic review of attention received by media and social networks surrounding the DAPT study which were reported with spin and undermine the adverse effects of the treatment. We showed that the interpretation of results by authors was rarely criticized. These results highlighted the importance of spin in mass media and provided a tool (classification of spin) to improve the dissemination of research results.

Bakgrund: Bröstcancer är den vanligaste cancerformen bland kvinnor i Sverige. Sexuell hälsa beskrivs som frånvaro av sjukdom och dysfunktion. Det påverkas av fysiskt, psykiskt, emotionellt och socialt välbefinnande i förhållande till sexualitet. Sjuksköterskans roll och ansvarsområde riktar sig i omvårdnaden. Sjuksköterskorna ska utföra en personcentrerad vård som innebär att patienten bli sedd och förstådd för sina egna individuella behov, resurser, värderingar och förväntningar. Ett bemötande med ömsesidig öppenhet är centralt. Syfte: Syftet var att beskriva upplevelsen av sexuell hälsa hos kvinnor som haft bröstcancer. Metod: Med hjälp av tio kvalitativa och kvantitativa artiklar från Cinahl complete och PubMed gjordes en litteraturöversikt. Den befintliga forskningen granskades och redovisades. En kvalitetsgranskning utfördes för att säkerställa kvaliteten av de originalartiklar som användes i resultatet. Fribergs fyra steg kring dataanalys användes för att analysera datainsamlingen.  Resultat: Tre teman utformades i resultatet “upplevelser av sexuell dysfunktion och förändringar i sexlivet”, “förändrad kroppsuppfattning efter cancerbehandling” och “upplevelsen av förändringar i relationer”.  Slutsats: Kvinnor som haft bröstcancer upplevde en negativ påverkan på deras sexuella hälsa av bröstcancerbehandlingarna. Det förekom fysiska, psykologiska och sociala förändringar i kvinnornas välbefinnande på grund av bröstcancer. Stödinsatser och tjänster som riktar sig i att främja kvinnornas sexuella och sociala välbefinnande, bör erbjudas under och efter bröstcancerbehandlingar. / Background: Breast cancer is the most common form of cancer among women in Sweden. Sexual health is described as the absence of disease and dysfunction. It is affected by physical, mental, emotional and social well-being in relation to sexuality. The nurse's role and area of responsibility is focused on nursing. The nurses must perform person-centred care which means that the patient is seen and understood with their own individual needs, resources, values and expectations. A treatment with mutual openness is central.  Aim: The aim was to describe the experiences of sexual health in women who have had breast cancer.  Method: Using ten qualitative and quantitative articles from Cinahl complete and PubMed, a literature review was made. The existing research was reviewed and reported. A quality review was performed to ensure the quality of the original articles used in the results. Friberg's four steps of data analysis were used to analyze the data collection.  Result: Three themes were formed in the result "experiences of sexual dysfunction and changes in sex life", "changed body image after cancer treatment" and "the experience of changes in relationships".  Conclusion: Women who have had breast cancer experienced a negative impact on their sexual health from the breast cancer treatments. There were physical, psychological and social changes in women's well-being due to breast cancer. Support measures and services aimed at promoting women's sexual and social well-being, should be offered during and after breast cancer treatments.