Thesis (M.A.)--University of Toronto, 2004. / Adviser: Lana Stermac.

Diss. (sammanfattning) Uppsala : Univ., 2004. / Härtill 4 uppsatser.

Thesis (M.S.P.H.)--University of Michigan, 1939.

Thesis (M.S.P.H.)--University of Michigan, 1939.

Thesis (M.S.)--Brigham Young University. Dept. of Chemical Engineering, 2007. / Includes bibliographical references (p. 79-82).

Up to 20% of breast cancer patients who undergo presurgical (neoadjuvant) chemotherapy have no response to treatment. Standard-of-care imaging modalities, including MRI, CT, mammography, and ultrasound, measure anatomical features and tumor size that reveal response only after months of treatment. Recently, non-invasive, near-infrared optical markers have shown promise in indicating the efficacy of treatment at the outset of the chemotherapy treatment. For example, frequency domain Diffuse Optical Spectroscopic Imaging (DOSI) can be used to characterize the optical scattering and absorption properties of thick tissue, including breast tumors. These parameters can then be used to calculate tissue concentrations of chromophores, including oxyhemoglobin, deoxyhemoglobin, water, and lipids. Tumors differ in hemoglobin concentration, as compared with healthy background tissue, and changes in hemoglobin concentration during neoadjuvant chemotherapy have been shown to correlate with efficacy of treatment. Using DOSI early in treatment to measure chromophore concentrations may be a powerful tool for guiding neoadjuvant chemotherapy treatment. Previous frequency-domain DOSI systems have been limited by large device footprints, complex electronics, high costs, and slow acquisition speeds, all of which complicate access to patients in the clinical setting. In this work a new digital DOSI (dDOSI) system has been developed, which is relatively inexpensive and compact, allowing for use at the bedside, while providing unprecedented measurement speeds. The system builds on, and significantly advances, previous dDOSI setups developed by our group and, for the first time, utilizes hardware-integrated custom board-level direct digital synthesizers (DDS) and analog to digital converters (ADC) to generate and directly measure signals utilizing undersampling techniques. The dDOSI system takes high-speed optical measurements by utilizing wavelength multiplexing while sweeping through hundreds of modulation frequencies in tens of milliseconds. The new dDOSI system is fast, inexpensive, and compact without compromising accuracy and precision.

Cisplatin is a commonly used chemotherapeutic agent for multiple solid tumors. However, cisplatin-induced neurotoxicity, nephrotoxicity and hearing loss hamper its use in clinical setting. Although, neurotoxicity and nephrotoxicity can be prevented, there is no cure for cisplatin-induced hearing loss. Cisplatin-induced hearing loss results from damage to outer hair cells (OHCs) in basal turn of the cochlea, to spiral ganglion neurons (SGN), stria vascularis (SV) and fibrocytes of spiral ligament (SL). At the cellular level, cisplatin produces profound increases in reactive oxygen species (ROS) that stimulate cell signaling pathways leading to cochlear inflammation, apoptosis and permanent hearing loss. Thus, potential otoprotective drugs should target oxidative stress and inflammatory mechanisms without interfering with cisplatin chemotherapeutic efficacy. In this study, I characterized the otoprotective actions of the green tea extract, epigallocatechin 3-gallate (EGCG), which possesses anti-oxidant, anti-inflammatory and anti-tumor properties. Oral administration of EGCG to male Wistar rats reduced cisplatin-induced hearing loss, assessed by auditory brainstem responses. These changes were associated with a reduction in cisplatin-induced loss of OHCs primarily in the basal region of the cochlea, along with reduced oxidative stress, inflammatory and apoptotic markers. In addition, EGCG protected against cisplatin-induced decrease in inner hair cell (IHCs) ribbon synapses, labeled with CtBP2. EGCG also protected against cisplatin-induced loss of Na+/K+ ATPase α1 immunoreactivity in the stria vascularis and spiral ligament. In vitro studies using University Bristol/Organ of Corti-1 (UB/OC-1) cells showed that EGCG reduced cisplatin-induced ROS generation and the activation of ERK and STAT1, while it preserved the activity of STAT3 and levels of Bcl-xL. Moreover, EGCG suppressed oxidative stress, inflammatory and apoptotic markers in cisplatin-treated UB/OC-1 cells. Co-administration of EGCG did not alter cisplatin-induced apoptosis of human-derived head and neck cancer cells, ovarian cancer cells or colon cancer cells. In studies using a xenograft model of head and neck cancer in severe combined immunodeficient (SCID) mice, I showed that EGCG did not interfere with cisplatin chemotherapeutic efficacy. These data suggest that EGCG is a potential otoprotective agent for treating cisplatin-induced hearing loss without compromising its chemotherapeutic efficacy.

Made available in DSpace on 2015-07-22T20:50:34Z (GMT). No. of bitstreams: 0 Previous issue date: 2009-11-26 / Método: Levantamento manual das faturas apresentadas em cobrança referente aos tratamentos quimioterápicos aplicados aos participantes da CASSI –Caixa de Assistência dos Funcionários do Banco do Brasil, nos Estados de São Paulo e Rio de Janeiro no período de julho/2004 a fevereiro/2005 inclusive, totalizando 228.555 beneficiários e abrangendo uma rede de 12.912 prestadores de serviços, sendo destes apenas 90 conveniados para serviços na especialidade de oncologia, incluindo a quimioterapia. Resultado: Das 1.177.050 faturas apresentadas, apenas 81.097 eram oriundas dos prestadores incluídos no estudo, ou seja, conveniados para tratamento quimioterápico. Como estes prestadores eram não apenas especialistas em Oncologia, mas muitas vezes hospitais gerais, o número de cobranças relativas aos serviços de quimioterapia foi reduzido para 3.401, que constituiu o universo de nosso estudo. Nestas guias foram cobrados 129 medicamentos distintos em 11.394 registros, sendo que de apenas 70 princípios ativos distintos. A participação de mercado dos quimioterápicos genéricos foi da ordem de 0,53% considerando o valor cobrado, e 1,52% considerando a quantidade de medicamentos cobrados. Os medicamentos de Referência ocuparam o segundo lugar na participação de mercado, com relação à quantidade, com 35,39% e os medicamentos Similares, em primeiro lugar, com 63,09% dos medicamentos cobrados. Conclusão: Apesar da disponibilidade de quimioterápicos genéricos, não houve significativa participação dos mesmos nas cobranças apresentadas pelos prestadores. Constatamos a participação de mercado dos quimioterápicos genéricos em 1,5% se considerada a quantidade de medicamentos, e 0,5% se considerados o valor. É importante uma maior participação da Operadora na decisão responsável pelo tratamento indicado, bem como do participante. De outra forma, o caos já previsto se agrava, já que os recursos são finitos também para a Saúde. / Objective: To quantify the market share of the generic chemotherapeutic drugs in a Self-Managed Healthcare Plan Service. Methods: Manual survey of featured bills charging the chemotherapeutic treatments applied to the participants of “CASSI – Caixa de Assistência de Funcionários do Banco do Brasil”;/Assistance relief of the Banco do Brasil employees;/in the states of São Paulo e Rio de Janeiro in the period of July/2004 to February/2005 inclusively, totalizing 228.555 beneficiaries and involving a web of 12.912 service providers, who only 90 had agreements to services focused on oncology, included chemotherapy. Result: From the 1.177.050 featured bills, only 81.097 derived from the service providers included in the study, that is, holding agreements to chemotherapeutic treatment. As these service providers weren’t just experts on Oncology, but usually also general hospitals, the number of bills concerning about the chemotherapy services was reduced to 3.401, which constitutes the universe of our study. These payable documents charged 129 distinct medicines in 11.394 registers, for 70 distinct active principles. The market share of the generic chemotherapeutic was rated in 0,53% considering the charged value, and 1.52% considering the quantity of charged medications. The Reference medications occupied the second place in the market share, with regard to quantity, with 35,39% and the Similar medications, in first place, with 63,09% of the charged medications. Conclusion: Despite the availability of the Generic chemotherapeutic drugs, their market share was not expressive on the bills presented by the service providers. We verified the market share of the Generic chemotherapeutic in 1,5% if considering the quantity of medications, and 0,5 if considering the value. It’s important a bigger participation of the Healthcare Plan Service on the responsible decision about the indicated treatment, as well as the participator’s. In terms, the chaos, which had already been foreseen, aggravates itself, for the resources are also limited to Health. / TEDE / BV UNIFESP: Teses e dissertações

Made available in DSpace on 2014-06-11T19:31:09Z (GMT). No. of bitstreams: 0 Previous issue date: 2002-09-06Bitstream added on 2014-06-13T19:01:30Z : No. of bitstreams: 1 fonseca_cs_dr_jabo.pdf: 347869 bytes, checksum: 2e79231f69a8f91eea4c79be2928563c (MD5) / A cisplatina é um agente antineoplásico utilizado em oncologia veterinária, sendo indicada no tratamento adjuvante de várias neoplasias, contudo, sua eficácia terapêutica é, muitas vezes, limitada por seu efeito nefrotóxico e emetogênico. Neste estudo, objetivou-se avaliar um novo protocolo quimioterápico, utilizando associação do methimazole e do ondansetron à cisplatina, além de tentar minimizar o tempo de fluidoterapia. Foram utilizados 12 cães, machos, divididos em quatro grupos experimentais, sendo constituídos de três animais por grupo. Os grupos foram divididos de acordo com o tempo de fluidoterapia: G1 (sem fluidoterapia), G2 (uma hora de fluidoterapia antes da cisplatina), G3 (uma hora de fluidoterapia antes da cisplatina e uma hora após) e G4 (duas horas de fluidoterapia antes da cisplatina e uma após). Todos os animais receberam cisplatina na dose de 70 mg/m2, por via intravenosa, diluída em solução fisiológica 0,9%, e administrada por um período de 20 minutos. Os ciclos de quimioterapia foram realizados em intervalos de três semanas totalizando três ciclos. O ondansetron foi administrado na dose de 0,4 mg/kg, por via intravenosa, a cada 8 horas, no dia da quimioterapia e a seguir a cada 12 horas por dois dias, começando 30 minutos antes do início da quimioterapia. O methimazole foi administrado na dose de 40mg/kg, por via oral, 30 minutos antes da cisplatina e quatro horas após. Foram avaliados os parâmetros hematológicos, bioquímicos, urinários e dosagem de tiroxina e triiodotironina a cada sete dias até o término do experimento. Pelos resultados obtidos observou-se que este protocolo é eficaz e seguro quando os animais permanecem por um período de duas a três horas sob fluidoterapia, visto que não apresentaram alterações clínicas laboratoriais decorrentes do uso da quimioterapia... / The cisplatin is an antineoplasic agent used in veterinary oncology, being indicated to the adjuvant treatment of several neoplasms, however, its therapeutic effectiveness is, a lot of times, limited by its nephrotoxic and emetogenic effects. The objective of this study was evaluating a new chemotherapic protocol, using association of methimazole and ondansetron to the cisplatin, besides trying to minimize the time of saline diuresis. Twelve male dogs were divided in four experimental groups, being constituted of three animals by group. The groups were divided according to the time of saline diuresis: G1 (without saline diuresis), G2 (an hour of saline diuresis before the cisplatin), G3 (an hour of saline diuresis before the cisplatin and one hour after) and G4 (two hours of saline diuresis before the cisplatin and one after). All animals received cisplatin in the dose of 70 mg/m2, for intravenous road, diluted in physiologic solution 0,9%, and administered by a period of 20 minutes. The chemotherapy cycles were accomplished in intervals of three weeks with three cycles. Ondansetron was administered in the dose of 0,4 mg/kg, for intravenous road, at every 8 hours, in the day of the chemotherapy and to proceed every 12 hours for two days, beginning 30 minutes before the beginning of the chemotherapy. Methimazole was administered orally in the dose of 40mg/kg, 30 minutes before the cisplatin and four hours after. The hematological, biochemical, urinary parameters and dosage of tiroxin and triiodotironine were evaluated every seven days until the end of the experiment. It was observed that this protocol is effective and safe when the animals stay for a period of two or three hours under saline diuresis, because they didn't present clinical and laboratory alterations of the use of chemotherapy... (Complete abstract, access undermentioned eletronic address)

Made available in DSpace on 2016-08-12T18:48:48Z (GMT). No. of bitstreams: 0 Previous issue date: 2015-09-10. Added 1 bitstream(s) on 2016-08-12T18:51:06Z : No. of bitstreams: 1 000857407_20170910.pdf: 828849 bytes, checksum: 3d1d6ca67089dd4d215ef86e6e490933 (MD5) Bitstreams deleted on 2017-09-11T13:55:54Z: 000857407_20170910.pdf,. Added 1 bitstream(s) on 2017-09-11T13:56:49Z : No. of bitstreams: 1 000857407.pdf: 2331591 bytes, checksum: 1fa5b1caae874d52e97bccd59a46ce2f (MD5) / Neste trabalho é apresentado o desenvolvimento de dois sensores eletroquímicos modificados para determinação sensível e seletiva de cisplatina, um dos fármacos mais frequentemente utilizados no tratamento oncológico de diversos tipos de patologias tumorais cancerosas. O primeiro sensor foi desenvolvido a base de pasta de carbono modificado com a enzima glutationa-s-transferase (GST). O biossensor é baseado na resposta inibitória da atividade enzimática da enzima GST devido à adição do fármaco cisplatina. Glutationa reduzida (GSH) e 1-cloro-2,4-dinitrobenzeno foram utilizados como substratos para a enzima GST, os quais foram adicionados na concentração de 1,0 x 10-3 mol L-1 na cela de medida. As técnicas utilizadas para a caracterização do sistema foram espectroscopia de infravermelho, voltametria cíclica e impedância eletroquímica. Os resultados quantitativos daquelas interações foram obtidos usando VOQ, observando-se uma resposta linear entre 50 e 140 μmol L-1 de cisplatina e limite de detecção de 8,8 μmol L-1 de cisplatina. O biossensor apresentou uma boa repetibilidade intra-dia com um desvio padrão relativo de 4,2% avaliando quatro curvas analíticas. O uso da pasta de carbono ofereceu a possibilidade de uma simples, rápida e eficiente renovação da camada de superfície do eletrodo, o que permitiu a utilização da mesma pasta em várias medidas durante um longo período de tempo. Adicionalmente, foi desenvolvido um sensor não enzimático no monitoramento da cisplatina usando eletrodos impressos de carbono (SPCE, screen-printed carbon electrodes) modificados com nanotubos de carbono de multiplas paredes funcionalizados com grupos carboxila (MWCNT-COOH.SPCE) da DROPSENS® (SDS 110CNT). Com o propósito de avaliar a influência dos nanotubos de carbono na resposta do sensor de cisplatina foi utilisada a técnica de voltametria cíclica. O uso do surfactante dodecilsulfato... / This thesis presents the development of two electrochemical sensors for the sensitive and selective detection of cisplatin, one of the drugs most frequently used in the oncologic treatment of several cancer tumor pathologies. The first was a biosensor based on carbon paste modified with the enzyme glutathione-s-transferase (GST). The biosensing was based on the inhibitory response of the enzymatic activity of GST due to the addition of the drug cisplatin. Reduced glutathione (GSH) and 1-chloro-2,4-dinitrobenzene were used as substrates for the GST enzyme, and were added at the concentration of 1.0 x 10-3 mol L-1 in the measuring cell. The techniques used for the characterization of the system were infrared spectroscopy, cyclic voltammetry and electrochemical impedance. The quantitative results of those interactions, obtained by square wave voltammetry (SWV) and differential pulse with adsorptive stripping voltammetry were very similar, and very promising for the analysis of cisplatin. The biosensor showed, using SWV, a linear response between 50 and 140 μmol L-1 of cisplatin. The detection limit was 8.8 μmol L-1 of cisplatin. In the intra-day repeatability studies, the relative standard deviation was 4.2%, from the analysis of four analytical curves, showing the repetitiveness of the electrochemical response of the proposed sensor. The use of the carbon paste offered the possibility of the simple, quick and efficient renewal of the surface layer of the electrode, which allowed the use of the same paste for several measurements during a long period of time. Additionally, a non-enzymatic sensor was developed for the monitoring of cisplatin using screen-printed carbon electrodes (SPCE, screen-printed carbon electrodes), functionalized with multi-walled carbon nanotubes and factory modified with carboxyl groups (MWCNT-COOH) acquired from DROPSENS® (SDS 110CNT). The electrochemical characterization...