Choi, Siu Cheong. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2008. / Includes bibliographical references (leaves 132-148). / Abstracts in English and Chinese. / Acknowledgement --- p.i / Abstract --- p.ii / Abbreviation --- p.v / List of Figures --- p.viii / List of Tables --- p.xii / Table of Content --- p.xiii / Chapter Chapter 1: --- General Introduction / Chapter 1.1 --- Introduction --- p.1 / Chapter 1.1.1 --- Treatment resistance in cancer --- p.1 / Chapter 1.1.1.1 --- Surgery --- p.2 / Chapter 1.1.1.2 --- Chemotherapy --- p.3 / Chapter 1.1.1.3 --- Radiotherapy --- p.3 / Chapter 1.1.1.4 --- Hormonal therapy --- p.4 / Chapter 1.1.2 --- Hypoxia/reoxygenation and its correlation with treatment resistance --- p.5 / Chapter 1.1.3 --- Aim of the study --- p.6 / Chapter Chapter 2: --- The drug sensitivity in HepG2 cells and A431 cells / Chapter 2.1 --- Introduction --- p.8 / Chapter 2.1.1 --- Treatment of cancer --- p.8 / Chapter 2.1.2 --- Drug resistance --- p.9 / Chapter 2.2 --- Materials and Methods --- p.10 / Chapter 2.2.1 --- Cell culture --- p.10 / Chapter 2.2.2 --- Drugs --- p.10 / Chapter 2.2.3 --- MTT assay --- p.11 / Chapter 2.3 --- Results --- p.12 / Chapter 2.3.1 --- The drugs to which G10HR and G20HR cells were more resistant --- p.12 / Chapter 2.3.2 --- "The drugs of which GP, G10HR and G20HR cells have similar response" --- p.12 / Chapter 2.3.3 --- The drugs to which A10HR and A20HR cells were more resistant --- p.17 / Chapter 2.3.4 --- The drugs to which A10HR and/or A20HR cells were more sensitive --- p.17 / Chapter 2.3.5 --- "The drugs which AP, A10HR and A20HR cells have similar response" --- p.18 / Chapter 2.4 --- Discussion --- p.24 / Chapter 2.4.1 --- Camptothecin and 10-hydroxy camptothecin --- p.27 / Chapter 2.4.2 --- Etoposide --- p.30 / Chapter 2.4.3 --- Hydrogen peroxide --- p.32 / Chapter 2.4.4 --- Interferons --- p.32 / Chapter 2.4.4.1 --- Interferon alpha --- p.33 / Chapter 2.4.4.2 --- Interferon gamma --- p.34 / Chapter 2.4.5 --- Methotrexate --- p.35 / Chapter 2.4.6 --- Vincristine --- p.36 / Chapter Chapter 3: --- The resistance mechanism of doxorubicin in A431 cells / Chapter 3.1 --- Introduction --- p.38 / Chapter 3.1.1 --- Chemotherapeutic resistance --- p.38 / Chapter 3.1.2 --- Tumor hypoxia --- p.39 / Chapter 3.1.3 --- Structure and function of doxorubicin --- p.39 / Chapter 3.1.4 --- Clinical use of doxorubicin --- p.40 / Chapter 3.1.5 --- Mechanisms of doxorubicin resistance --- p.41 / Chapter 3.1.6 --- Structure and function of P-glycoprotein --- p.42 / Chapter 3.1.7 --- Drug resistance contributed by P-glycoprotein and the solution --- p.43 / Chapter 3.1.8 --- Epigenetic modulation of mdr1 --- p.45 / Chapter 3.2 --- Materials and Methods --- p.47 / Chapter 3.2.1 --- Cell culture --- p.47 / Chapter 3.2.2 --- MTT assay --- p.47 / Chapter 3.2.3 --- Reverse transcription polymerase chain reaction (RT-PCR) --- p.47 / Chapter 3.2.4 --- Western blot analysis --- p.48 / Chapter 3.2.5 --- Doxorubicin efflux assay --- p.50 / Chapter 3.2.6 --- Drug sensitivity of A431 cells treated with verapamil --- p.50 / Chapter 3.2.7 --- Treatment with DNA methyltransferase inhibitor --- p.51 / Chapter 3.2.8 --- Drug sensitivity of A431 cells treated with 5-Aza-dC --- p.51 / Chapter 3.2.9 --- Methylation-specific PCR (MSP) --- p.51 / Chapter 3.2.10 --- Bisulfite genomic DNA sequencing --- p.52 / Chapter 3.3 --- Results --- p.54 / Chapter 3.3.1 --- Drug sensitivity of A431 cells to doxorubicin --- p.54 / Chapter 3.3.2 --- Expression profile of mdrl and P-glycoprotein in A431 cells --- p.54 / Chapter 3.3.3 --- Dox efflux-pump activity in A431 cells --- p.57 / Chapter 3.3.4 --- Drug sensitivity of A431 cells in the presence of verapamil --- p.59 / Chapter 3.3.5 --- Expression profile of mdrl in A431 cells in the presence of 5- Aza-dC --- p.59 / Chapter 3.3.6 --- Drug sensitivity of A431 cells in the presence of 5-Aza-dC --- p.62 / Chapter 3.3.7 --- Methylation status of mdrl promoter region --- p.64 / Chapter 3.3.8 --- Bisulfite genomic DNA sequencing of the mdrl promoter --- p.64 / Chapter 3.4 --- Discussion --- p.67 / Chapter Chapter 4: --- The resistance mechanism of cisplatin in HepG2 cells / Chapter 4.1 --- Introduction --- p.70 / Chapter 4.1.1 --- Tumor hypoxia and chemotherapeutic resistance --- p.70 / Chapter 4.1.2 --- Cisplatin and its action mechanism --- p.71 / Chapter 4.1.3 --- Mechanisms of cisplatin resistance --- p.74 / Chapter 4.1.4 --- Mismatch repair genes --- p.79 / Chapter 4.1.5 --- Epigenome and drug resistance in cancer --- p.80 / Chapter 4.2 --- Materials and Methods --- p.84 / Chapter 4.2.1 --- Cell culture --- p.84 / Chapter 4.2.2 --- MTT assay --- p.84 / Chapter 4.2.3 --- Reverse transcription polymerase chain reaction (RT-PCR) --- p.84 / Chapter 4.2.4 --- Oligonucleotide transfection --- p.85 / Chapter 4.2.5 --- Treatment with DNA methyltransferase inhibitor --- p.86 / Chapter 4.2.6 --- Drug sensitivity of HepG2 cells treated with 5-Aza-dC --- p.87 / Chapter 4.2.7 --- Treatment with histone deacetylase inhibitor --- p.87 / Chapter 4.2.8 --- Drug sensitivity of HepG2 cells treated with TSA --- p.87 / Chapter 4.3 --- Results --- p.89 / Chapter 4.3.1 --- Drug sensitivity of HepG2 cells to cisplatin --- p.89 / Chapter 4.3.2 --- Expression profile of the MMR genes in HepG2 cells --- p.89 / Chapter 4.3.3 --- Drug sensitivity of HepG2 cells to cisplatin after the knock- down of PMS2 --- p.91 / Chapter 4.3.4 --- Expression profile of MMR genes in the presence of 5-Aza-dC --- p.95 / Chapter 4.3.5 --- Drug sensitivity of HepG2 cells to cisplatin after the addition of 5-Aza-dC --- p.95 / Chapter 4.3.6 --- Expression profile of MMR genes in the presence of trichostatin A --- p.98 / Chapter 4.3.7 --- Sensitivity of HepG2 cells to cisplatin after the addition of trichostatin A --- p.98 / Chapter 4.4 --- Discussion --- p.101 / Chapter Chapter 5: --- The role of PMS2 in cisplatin-induced apoptosis / Chapter 5.1 --- Introduction --- p.105 / Chapter 5.1.1 --- Apoptosis --- p.105 / Chapter 5.1.2 --- Extrinsic pathway of apoptosis --- p.106 / Chapter 5.1.3 --- Intrinsic pathway of apoptosis --- p.106 / Chapter 5.1.4 --- Cisplatin-induced apoptosis --- p.107 / Chapter 5.1.5 --- MMR and apoptosis --- p.109 / Chapter 5.2 --- Materials and Methods --- p.111 / Chapter 5.2.1 --- Cell culture --- p.111 / Chapter 5.2.2 --- Flow cytometric analysis of apoptosis --- p.111 / Chapter 5.2.3 --- Oligonucleotide transfection --- p.111 / Chapter 5.2.4 --- Western blot analysis --- p.111 / Chapter 5.2.5 --- Drug and antibodies --- p.112 / Chapter 5.3 --- Results --- p.113 / Chapter 5.3.1 --- Cisplatin induced apoptosis --- p.113 / Chapter 5.3.2 --- Knockdown of PMS2 by siRNA --- p.113 / Chapter 5.3.3 --- Cisplatin-induced apoptosis involved caspases --- p.115 / Chapter 5.3.4 --- Protein expressions of anti-apoptotic genes --- p.119 / Chapter 5.3.5 --- Protein expressions of pro-apoptotic genes --- p.119 / Chapter 5.3.6 --- Protein expressions of apoptotic proteins after knockdown of PMS2 --- p.122 / Chapter 5.4 --- Discussion --- p.124 / Chapter Chapter 6: --- General discussion and conclusion / Chapter 6.1 --- Diverse sensitivity for hypoxia/reoxygenation treated cells to anticancer drugs --- p.128 / Chapter 6.2 --- Resistance mechanism of doxorubicin in A10HR and A20HR cells --- p.129 / Chapter 6.3 --- Resistance mechanism of cisplatin in G10HR and G20HR cells --- p.129 / Chapter 6.4 --- The role of PMS2 as a direct signaling molecule and the alteration of apoptotic proteins in cisplatin-induced apoptosis --- p.130 / Chapter 6.5 --- Future work --- p.131 / References --- p.132

癌症復發往往伴隨著耐藥性和轉移率的增加。目前我們仍未完全瞭解確切的腫瘤逃脫機制。皮下無水酒精注射（PEI）已經被用於治療肝細胞癌（HCC）幾十年，而PEI治療後的癌症復發仍然是該方法的一個主要限制。最近有許多證據表明癌細胞能夠逆轉化學誘導的細胞凋亡過程而得以存活，這有可能是其中一個導致癌細胞復發的原因。這篇論文的重點在於研究肝癌細胞HepG2經歷乙醇誘導凋亡事件後存活下來的後果。 / 這個研究首先證實肝癌細胞 HepG2能從乙醇誘導凋亡事件後存活下來。然後我們對存活下來的肝癌細胞HepG2進行增殖率，耐藥性，運動性以及侵襲性的研究。結果表明，存活下來的HepG2有46%的乙醇耐藥性和84%的高運動性。然後爲了發現存活下來的HepG2是否對其他臨床常用藥物也同樣具有耐藥性，4種臨床常用藥物包括阿黴素，紫杉醇，順鉑，5-氟尿嘧啶（5Fu）均被用於測試。有趣的是，存活下來的HepG2對5-氟尿嘧啶變得更加敏感，平均敏感性下降了58.2%。 / 總的來說，我們的研究結果表明肝癌細胞可從乙醇誘導凋亡事件中恢復過來。此外，存活下來的細胞變得更具有耐藥性和侵入性。這種恢復過程可能是導致癌症復發的原因之一。出乎意料的是，雖然所有存活下來的細胞對乙醇具耐受性，但是它們對於5-氟尿嘧啶均變得更加敏感。這些結果表明，乙醇和5-氟尿嘧啶的聯合治療可能有助於提高PEI治療效果從而預防肝癌癌症復發。 / Cancer relapse, associated with increased drug resistance and higher rate of metastasis, often occurs after chemotherapy. The cancer escape mechanisms are still incompletely understood. Percutaneous ethanol injection (PEI) has been used for treating hepatocellular carcinoma (HCC) for decades, but the recurrence after PEI treatment remains a major limitation. Recently there are mounting evidences showing that cancer cells could survive from chemical-induced apoptosis, suggesting a potential route through which cancer relapse may occur. This thesis focuses on the consequences of the recovery of HepG2 cells from ethanol-induced apoptotic event. / This study verified that HepG2 cells could recover from ethanol-induced apoptosis. Proliferation rate, drug resistance, motility and invasiveness were investigated in recovered HepG2 cells. On average, the recovered HepG2 cell clones were found to be 46% more resistant to ethanol and 84% higher in motility than the parental cell clones. And then four commonly used clinical drugs were assayed to determine whether the recovered cell clones were also resistant to other clinical drugs, including doxorubicin, docetaxel, cisplatin and 5-fluorouracil (5-Fu). Interestingly, the recovered clones became 58.2% more sensitive to 5-fluorouracil on average. / In conclusion, our findings showed that HepG2 cells can recover from ethanol-induced apoptotic event. In addition, some cell clones recovered from apoptosis became more resistant to ethanol and some became more invasive. Such recovery might be one of the reasons causing cancer recurrence. Unexpectedly, although the recovered cell clones were more resistant to ethanol, they became more sensitive to 5-Fu treatment. These results indicated that ethanol-5-Fu combined treatment might be useful in enhancing the PEI treatment and preventing HCC cancer recurrence. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Wang, Shanshan. / Thesis (Ph.D.) Chinese University of Hong Kong, 2014. / Includes bibliographical references (leaves 115-130). / Abstracts also in Chinese.

Linfomas pertencem a um grupo de neoplasias em que há proliferação monoclonal de linfócitos malignos, sendo uma das neoplasias mais frequentemente diagnosticadas em cães. Podem ser classificados quanto à forma anatômica em multicêntrico, mediastinal, digestório e extranodal. Dentre os extranodais, os linfomas cutâneos são classificados histologicamente como epiteliotrópicos e não epiteliotrópicos e são predominantemente de imunfenótipo T, com raros casos do tipo B. A principal característica histopatológica do linfoma epiteliotrópico em cães é o tropismo das células neoplásicas pela epiderme, mucosa ou estruturas anexas, enquanto o linfoma não epiteliotrópico é caracterizado pela infiltração dérmica e subcutânea sem invasão das estruturas anexas. Os linfomas cutâneos caninos têm progressão rápida, são considerados bastante agressivos e com mau prognóstico, com baixa taxa de resposta à quimioterapia. Um dos fatores que podem contribuir para isso é a resistência das células a múltiplas drogas e entre esses mecanismos de resistência estão o efluxo de drogas do meio intracelular para o extracelular por meio dos transportadores da família ABC, como a glicoproteína-P, MRP (multiple resistance protein) e BCRP (breast câncer resistance protein) e da LRP (lung resistance protein), uma proteína vault responsável pelo transporte nucleocitoplasmático. O objetivo deste estudo foi caracterizar imunofenotipicamente os linfomas cutâneos, a proliferação celular por meio do marcador Ki67, a expressão das proteínas de resistência glicoproteína-P, MRP, BCRP e LRP e avaliar a relação dessas proteínas com a sobrevida dos animais. Foi realizado um estudo retrospectivo com 21 casos de cães linfomas cutâneos com diagnóstico histopatológico. A técnica de imunoistoquímica foi utilizada para determinar a imunofenotipagem dos linfomas pelos marcadores CD3 e CD20, a proliferação celular por Ki67 e a expressão de glicoproteína-P, MRP, BCRP e LRP. Dos 21 animais, 38% tiveram diagnóstico histopatológico de linfoma epiteliotrópico, 52% eram linfomas não epiteliotrópicos, 5% dos casos de linfoma não tiveram epiteliotropismo definido e 5% foram classificados como neoplasia de células redondas. O imunofenótipo predominante foi CD3+CD20- (76%), 15% dos casos eram CD3-CD20+ e 9% eram CD3+CD20+. A mediana de células marcadas para Ki67 foi de 31%. Com relação aos marcadores de resistência a múltiplas drogas, a mediana da marcação de glicoproteína-P foi de 40%, a de LRP foi de 65% enquanto para MRP e BCRP, 19% e 23%, respectivamente. Os linfomas cutâneos não epiteliotrópicos foram mais frequentes que os epiteliotrópicos e o imunfenótipo predominante foi o T. A ocorrência de linfócitos CD3-CD20+ e CD3+CD20+ indica a necessidade de mais estudos e um painel mais amplo de anticorpos para subtipagem desses linfomas. A glicoproteína-P teve maior expressão nos linfomas não epiteliotrópicos do que nos epiteliotrópicos e não houve correlação entre as proteínas de resistência e o tempo de sobrevida dos animais, sugerindo que, além da biologia da neoplasia, outros mecanismos de resistência a múltiplas drogas diferente dos estudados possam ter um papel relevante na baixa resposta do linfoma cutâneo à quimioterapia. / Lymphoma is a group of blood cell tumors that develop from monoclonal proliferation of malignant lymphocytes. Lymphoma is the most frequent neoplasia in dogs and can be anatomically classified in multicentric, mediastinal, digestive and extranodal. Cutaneous lymphomas an extranodal type of lymphoma are classified histologically in epitheliotropic and non-epitheliotropic and are predominantly of T-cell immunophenotype, and rare cases of B cell phenotype. The main histopathological characteristic of epitheliotropic lymphoma in dogs is the tropism of neoplastic cells by the epidermis, mucosa or adjacent structures, while non-epitheliotropic lymphoma is characterized by dermal and subcutaneous infiltration without invasion of adjacent structures. Canine cutaneous lymphomas have rapid progression, are considered very aggressive and have poor prognosis. These dogs, usually have a low rate of response to chemotherapy which can be associated to an antineoplastic resistance. Among mechanisms of resistance are efflux of drugs from intracellular to extracellular through ABC family transporters such as P-glycoprotein, MRP (multple resistance protein) and BCRP (breast cancer resistance protein) and LRP (lung resistance protein), a vault protein responsible for nucleocytoplasmic transport. The aim of this study was to characterize immunophenotypically cutaneous lymphomas, measure cell proliferation using the Ki67 marker, the expression of resistance proteins P-glycoprotein, MRP, BCRP and LRP and to evaluate the relationship of these proteins with the survival of the animals. A retrospective study was performed with 21 cases of dogs with cutaneous lymphoma with histopathological diagnosis. Immunohistochemical was used to immunophenotyping of lymphomas by CD3 and CD20 markers, Ki67 cell proliferation, and P-glycoprotein, MRP, BCRP and LRP expression. Of the 21 animals, 38% had histopathological diagnosis of epitheliotropic lymphoma, 52% were non-epitheliotropic lymphomas, 5% of lymphoma cases had no definition and 5% were classified as round cell neoplasia. The predominant immunophenotype was CD3+CD20- (76%), 15% of the cases were CD3-CD20 + and 9% were CD3 + CD20 +. The median of cells labeled for Ki67 was 31%. Regarding the markers of resistance to multiple drugs, the median of the P-glycoprotein label was 40%, which 65% of LRP while for MRP and BCRP, 19% and 23%, respectively. Non-epitheliotropic cutaneous lymphomas were more frequent than epitheliotropic lymphomas and the predominant immunophenotype was T. The occurrence of CD3-CD20+ and CD3+CD20+ lymphocytes indicates the need for further studies and a wider panel of antibodies for subtyping these lymphomas. P-glycoprotein had higher expression in non-epitheliotropic lymphomas than in epitheliotropic lymphomas and there was no correlation between resistance proteins and survival time of the animals, suggesting that in addition to the biology of neoplasia other mechanisms of resistance to multiple drugs different from those studied may play a relevant role in the low response of cutaneous lymphoma to chemotherapy.

A sobrevida de crianças que foram submetidos a tratamento antineoplásico tem se acrescentado nos últimos anos devido às novas alternativas de tratamento. Os sobreviventes de câncer infantil com frequência podem apresentar efeitos tardios decorrentes do tratamento antineoplásico. Diferentes órgãos podem apresentar efeitos tardios incluindo os dentes. Algumas anomalias dentárias são associadas aos efeitos da quimioterapia e/ou radioterapia. O estudo da influência do tratamento antineoplásico sobre a ocorrência de anomalias dentárias, permite saber quais os possíveis desafios no tratamento odontológico nos sobreviventes de câncer infantil. Este estudo, avaliou as anomalias dentárias e a idade dentária através de radiografias panorâmicas em sobreviventes de câncer infantil e compará-la com radiografias panorâmicas de indivíduos saudáveis. Foram avaliadas 111 radiografias panorâmicas de sobreviventes de câncer infantil comparadas a 111 radiografias panorâmicas de indivíduos saudáveis pareadas por idade e gênero respeito ao grupo de estudo, com análise de tipo duplo cego. Foram avaliadas um total de 16 tipos de anomalias dentárias de forma, tamanho, número assim como anomalias do desenvolvimento da raiz dentária classificadas em 5 tipos diferentes. A idade dentária foi avaliada pelo método de Demirjiam. A microdontia, hipodontia e anomalias do desenvolvimento da raiz foram as anomalias dentárias que apresentaram maior ocorrência nos sobreviventes de câncer da infância quando comparado a indivíduos saudáveis (p=<0,05). A microdontia esteve associada à idade de diagnóstico menor a 5 anos de idade (p=<0,04). O dente não irrompido teve associação com indivíduos que foram submetidos a quimioterapia concomitante com radioterapia (p=<0,001). Anomalias dentárias com uma quantidade >10 estiveram presentes somente no grupo de estudo. A idade dentária não apresentou diferença significativa entre os grupos (p=>0,05). Conclui-se que Indivíduos submetidos a quimioterapia e/ou radioterapia durante a infância apresentaram maior ocorrência de desenvolver anomalias dentárias. Porém, a idade dentária sugere não ser afetada pela quimioterapia e/ou radioterapia. / Children who have been undergone antineoplastic treatment have increased the survival due to new treatment alternatives. The childhood cancer survivors may have frequently late effects from antineoplastic treatment. Different organs may have late effects including the teeth. Some dental anomalies are associated as late effects of chemotherapy and/or radiotherapy. To study the antineoplastic treatment influence on the occurrence of dental anomalies allows to know the possible challenges in dental care of childhood cancer survivors. This study evaluated dental abnormalities and the dental maturity by panoramic radiographs in childhood cancer survivors and to compare it with panoramic radiographs of healthy individuals. A total of 111 panoramic radiographs of childhood cancer survivors compared to 111 panoramic radiographs of healthy individuals were evaluated. They were matched for age and gender regarding the childhood cancer survivor, with a double-blind type analysis. A total of 16 types of dental anomalies of shape, size, number and developmental anomalies of the dental root were classified into 5 different types. Dental maturity was assessed by the Demirjian method. Microdontia, hypodontia, and root anomalies were the dental anomalies that presented a higher prevalence in CCS when compared to healthy individuals (p = <0.05). Microdontia was associated with a diagnosis age younger than 71 months of age (p = <0.04). The impacted tooth was associated with individuals who underwent chemotherapy concomitantly with radiotherapy (p <0.001). Individuals with an amount of 10 or > 10 dental anomalies were present only in the CCS group. Dental maturity did not present a significant statistical difference between CCS and healthy individuals. It was concluded that individuals undergoing chemotherapy and/or radiotherapy during childhood had a higher prevalence of dental. However, dental maturity suggests that it is not affected by chemotherapy and/or radiotherapy.

INTRODUÇÃO: O câncer de mama é a neoplasia maligna que mais atinge o sexo feminino, sendo responsável por cerca de 20% dos óbitos por câncer entre as mulheres. Os tratamentos utilizados promovem, de modo geral, alterações na auto-imagem, na imagem corporal, no auto-conceito e na função sexual feminina. Assim, objetiva-se avaliar a presença ou não de disfunções sexuais em mulheres com câncer de mama tratadas cirurgicamente. MÉTODOS: foram avaliadas pelo período de um ano, 52 mulheres entre 50 e 60 anos de idade, divididas em dois grupos: controle, composto por 37 mulheres com tumores benignos de mama e 15 submetidas à mastectomia radical, utilizando o Watts Sexual Function Questionnaire (WSFQ), que avalia os quatro componentes da experiência sexual, incluindo as percepções sobre desejo sexual, interesse, orgasmo e satisfação, específico para avaliar a sexualidade em sujeitos com patologias clínicas, previamente aplicado na população brasileira. A este questionário foram acrescidas questões qualitativas visando a avaliação e observação das reações das pacientes frente ao diagnóstico cirúrgico e as possíveis alterações advindas da mastectomia radical na auto-estima, no humor, na capacidade de planejar o futuro e na manutenção do relacionamento afetivo-sexual. Testes estatísticos para medidas repetidas, análise de correlação entre variáveis e análise exploratória de dados multidimencionais estão entre as técnicas estatísticas utilizadas para avaliar o conjunto de dados. RESULTADOS: As principais variações detectadas ao longo do tempo, foram o desejo sexual, no grupo controle e na excitação no grupo cirúrgico. Avaliando-se o impacto do tempo observou-se uma piora na fase do desejo das pacientes pertencentes ao grupo controle comparado ao grupo de mastectomia radical. Dentre as pacientes submetidas à mastectomia, 37,5% das que realizaram reconstrução mamária tem melhor auto-imagem e exercem sua sexualidade adequadamente. A realização do processo de elaboração do luto foi observada durante as diversas etapas do tratamento do câncer de mama. Observou-se amplitude de variações nos sentimentos / atitudes que a doença causa em cada paciente, não sendo possível uma padronização do comportamento e complementando de forma decisiva na avaliação objetiva realizada através da escoragem WSFQ. CONCLUSÃO: Pacientes submetidas à mastectomia radical apresentaram indícios de transtorno de excitação, quando comparadas à mulheres com tumores benignos de mama nas quais observa-se falta de desejo sexual. / INTRODUCTION: breast cancer is the malign neoplasia what most gets female sex, being responsible for about 20% from cancer\'s death among women. The treatments used to promote alterations on self-image, on body image body, into the self-concept and on the female sexual function. So, we aim to access the presence or not sexual dysfunctions in women with breast cancer submitted to surgery treatment. METHODS: were evaluated by a period of one year, 52 women among 50 and 60 years old, divided in two groups: control, compounded by 37 women with benign breast tumors and 15 submitted to radical mastectomy, using the Watts Sexual Function Questionnaire (WSFQ), that assesses the four components from sexual experience, including the perceptions of sexual desire, interest, orgasm and satisfaction, specific to evaluate sexuality in subjects with clinics pathologies previously applied on Brazilian population. For this questionnaire have been added qualitative questions aimed the appraisal and observation from patients reactions to surgical diagnosis and the possible occurring alterations of radical mastectomy in self-steam, in humor, in the capacity of planning future and at the maintenance of the affective-sexual relationships. Statistic tests about repetitive measures, analysis between correlation variables and analysis of multidimencional exploratory data are among the statistics techniques used to evaluate the data set. RESULTS: the main variations detected in a long of the time, was the sexual desire in control group and in excitation in surgical group. Evaluating the impact of the time observed, considering comparatively both groups, there was a worsening in phase of desire in control group when compared to radical mastectomy group. Among the patients submitted to the mastectomy, 37.5% of that carried out mammary reconstruction has better self -image and exercise its sexuality adequately. The achievement of the trial of elaboration of the mourning process was observed during the diverse phases of the breast cancer treatment. It was seen amplitude of variations in feelings / attitudes that illness causes in each patient, not being possible a stardandization of the behavior and complementary of decisive form in the objective evaluation carried out through the WSFQ score CONCLUSION: Patients submitted to radical mastectomy presented indications of perturbation of excitement, when compared to women with benign breast tumors when were observed lack of sexual deseire.

The multisystemic tumors characteristic of the monogenic neoplastic diseases, tuberous sclerosis complex (TSC) and lymphangioleiomyomatosis (LAM), share common signaling aberrations upon the loss of heterozygosity in either the TSC1 or TSC2 genes. However, their physical manifestations are vastly different and can generally be classified as being either neurological (TSC) or mesenchymal (TSC & LAM; referred to herein as LAM for simplicity) in origin. In this study, I present a comprehensive stem cell model of LAM utilizing multiple TSC2 knockout (TSC2-/-) pluripotent stem cell lines differentiated to the putative cell of origin for mesenchymal tumors, neural crest cells (NCCs). TSC2-/- NCCs faithfully recapitulate LAM phenotypes and temporal RNA-seq analysis of neural and neural crest differentiation was performed to model disease pathogenesis. Analysis revealed immediate activation of stress response signaling resulting in protein aggregation and lysosome and autophagosome accumulation upon neuralization in TSC2-/- cells. This resulted in acute and lasting effects specific to neural progenitor cells (NPCs), that are transient and ameliorated in NCCs. These lineage-specific effects resulted in selective sensitization of NPCs to cell death via proteasome inhibition, suggesting a potential therapeutic avenue for neurological TSC, but not LAM. Thus, a genome-wide CRISPR knockout screen was performed in TSC2-/- NCCs. Analysis of synthetic lethal genes reveals pathways previously targeted for LAM, but provides gene-level resolution to the vulnerable nodes within these pathways. Importantly, 18 novel gene targets were identified that display synthetic lethality to TSC2-/- cells with high specificity. 3 genes within this list were targetable using commercially available small molecule inhibitors, one of which, FGFR1, shows highly selective lethal targeting of TSC2-/- NCCs. Importantly, this model system, paired with the expansive resource of transcriptomic and synthetic lethal data, serves as a foundation for the development of next generation treatment strategies for LAM, and potentially the entire spectrum of TSC manifestations.

Hot flashes are one of the most bothersome symptoms experienced by women who have undergone breast cancer treatment-induced menopause. This vasomotor symptom has been hypothesized to be responsible for decreased sleep quality. This study further investigated the relationship between hot flashes and sleep quality in this population. The convenience sample consisted of 30 women being seen at an outpatient clinic in a comprehensive cancer center in southwest Florida. All participants were between the ages of 36-65, had a diagnosis of breast cancer and were currently taking a selective estrogen receptor modulator for at least six weeks. The participants completed the Hot Flash Diary, Hot Flash Questionnaire, Hot Flash Related Daily Interference Scale, Pittsburgh Sleep Quality Index and a demographic form. The mean sleep score of the sample was 9.33 (SD= 4.4). Global sleep scores above five are indicative of poor sleep quality, and global sleep scores of eight or more have been linked to cancer-related fatigue. Sleep was strongly correlated with hot flash distress (r = .754, p. = .000) and hot flash severity (r = .718, p. = .000) and moderately correlated with hot flash interference (r = .507, p. = .004) and hot flash frequency while asleep (r = .680, p. = .000). The small sample size was a study limitation. However, study results do support findings from previous studies. This study addresses a symptom management problem that may give nurses better understanding of the experiences of their patients. These findings also may assist patients in helping their providers to understand the frustration they are experiencing with regard to their decreased sleep quality.

Research has demonstrated that cancer patients report problems with cognitive functioning related to their cancer and their cancer treatments. Cognitive complaints refer to subjective reports of problems such as decreased memory, attention, concentration, and language skills. These problems with cognitive functioning can interfere with a person’s quality of life. The current measures of cognitive complaints have poor or unknown psychometric properties. Therefore, the present study sought to examine the psychometric properties of a newly developed measure of cognitive complaints for cancer patients, the Functional Assessment of Cancer Therapy Cognitive Scale (FACT-Cog). Eighty-two patients were administered a comprehensive battery of neuropsychological tests assessing memory, executive functioning, motor, and attention, as well as a battery of psychosocial measures six months or twelve months after receiving a bone marrow transplant. Results indicated that the internal consistency reliability of the FACT-Cog was high. Concurrent validity was evidenced by the significant relationship of the FACT-Cog to another measure of cognitive complaints. Convergent validity is evidenced by the significant relationship of the FACT-Cog to measures of depression, fatigue, anxiety, mental well-being, and physical well-being. Divergent validity was evidenced by the lack of significant relationship of the FACT-Cog to a measure of extroversion. In contrast, there was limited support for the criterion validity of the FACT-Cog as evidenced by the limited significant relationships with neuropsychological test scores. The FACT-Cog did not demonstrate superior psychometric properties to an existing measure of cognitive complaints (EORTC-CF). Future research should investigate the relationship of cognitive complaints to cognitive performance utilizing longitudinal designs, other clinical populations, and neuropsychological tests that require sustained effort.

<p>Syftet med studien var att beskriva icke farmakologiska metoder för att reducera barns rädsla och smärta inför cancerrelaterade behandlingar och undersökningar. Studien genomfördes som en litteraturstudie med beskrivande design. 21 vetenskapliga artiklar inkluderades, analyserades och lades som grund för resultatet. Resultatet visade att distraktion var den vanligaste förekommande icke farmakologiska omvårdnadsåtgärden för att minska barns rädsla och smärta inför smärtsamma cancerrelaterade behandlingar och undersökningar. Distraktion i form av kommunikation, beröring och hjälpmedel distraherar, lugnar, ökar smärttoleransen, förbättrar vårdresultatet och ger positiva vårderfarenheter. Barn som själva fick välja distraktionsmedel visade mindre rädsla, smärta och obehag vid smärtsamma behandlingar och undersökningar. Som distraktion används kommunikation, beröring, elektroniska leksaker, såpbubblor, clowner, virtuell verklighet, filmer, musik och kalejdoskop. Kognitiv beteendeterapi (KBT) visade sig vara bra för att hjälpa barn att hantera rädslan inför provtagningar. Hypnos visade sig vara användbart till rädda och oroliga barn med tidigare vårderfarenhet för att inge trygghet och förebygga ångest. Slutsatsen är att kommunikation, åldersadekvata distraktionsmedel och mänsklig närvaro är ett billigt och effektivt komplement för sjuksköterskan att reducera barns smärta och rädsla under smärtsamma procedurer. Vidare forskning inom området behövs för att utvärdera sjuksköterskornas kunskaper om kommunikation och distraktion.</p> / <p>The aim with the study was to describe non pharmacologic methods in order to reduce children's dread and pain before cancer related treatments and surveys. The study was implemented as a literature study with descriptive design. In the study 21 scientific articles was analyzed for the result. The result showed that distraction was the most common non pharmacologic method in order to decrease children's dread and pain before painful cancer related treatments and surveys. Distraction in the form of communication, touch and accessibility distract, reassuring, increases pain tolerance, improve care results and provides positive care experience. Children who elect distracters funds showed less fear, pain and discomfort at painful treatments and surveys. As distraction was communication, contact, electronic toys, soft soap bubbles, clowns, virtual reality, films, musical and kaleidoscope used. Cognitive behavior therapy (KBT) was found to help children to handle the dread before treatments. Hypnos showed to be useful to cautious and anxious children with earlier care experience stem to submit safety and to prevent anxiety. The authors drew the conclusion that communication, age adequate distraction and human presence is a cheap and effective complements for the nurse to reduce children's pain and dread during painful procedures. Further research within the area is needed in order to evaluate the nurses' knowledge about communication and distraction.</p>

Syftet med studien var att beskriva icke farmakologiska metoder för att reducera barns rädsla och smärta inför cancerrelaterade behandlingar och undersökningar. Studien genomfördes som en litteraturstudie med beskrivande design. 21 vetenskapliga artiklar inkluderades, analyserades och lades som grund för resultatet. Resultatet visade att distraktion var den vanligaste förekommande icke farmakologiska omvårdnadsåtgärden för att minska barns rädsla och smärta inför smärtsamma cancerrelaterade behandlingar och undersökningar. Distraktion i form av kommunikation, beröring och hjälpmedel distraherar, lugnar, ökar smärttoleransen, förbättrar vårdresultatet och ger positiva vårderfarenheter. Barn som själva fick välja distraktionsmedel visade mindre rädsla, smärta och obehag vid smärtsamma behandlingar och undersökningar. Som distraktion används kommunikation, beröring, elektroniska leksaker, såpbubblor, clowner, virtuell verklighet, filmer, musik och kalejdoskop. Kognitiv beteendeterapi (KBT) visade sig vara bra för att hjälpa barn att hantera rädslan inför provtagningar. Hypnos visade sig vara användbart till rädda och oroliga barn med tidigare vårderfarenhet för att inge trygghet och förebygga ångest. Slutsatsen är att kommunikation, åldersadekvata distraktionsmedel och mänsklig närvaro är ett billigt och effektivt komplement för sjuksköterskan att reducera barns smärta och rädsla under smärtsamma procedurer. Vidare forskning inom området behövs för att utvärdera sjuksköterskornas kunskaper om kommunikation och distraktion. / The aim with the study was to describe non pharmacologic methods in order to reduce children's dread and pain before cancer related treatments and surveys. The study was implemented as a literature study with descriptive design. In the study 21 scientific articles was analyzed for the result. The result showed that distraction was the most common non pharmacologic method in order to decrease children's dread and pain before painful cancer related treatments and surveys. Distraction in the form of communication, touch and accessibility distract, reassuring, increases pain tolerance, improve care results and provides positive care experience. Children who elect distracters funds showed less fear, pain and discomfort at painful treatments and surveys. As distraction was communication, contact, electronic toys, soft soap bubbles, clowns, virtual reality, films, musical and kaleidoscope used. Cognitive behavior therapy (KBT) was found to help children to handle the dread before treatments. Hypnos showed to be useful to cautious and anxious children with earlier care experience stem to submit safety and to prevent anxiety. The authors drew the conclusion that communication, age adequate distraction and human presence is a cheap and effective complements for the nurse to reduce children's pain and dread during painful procedures. Further research within the area is needed in order to evaluate the nurses' knowledge about communication and distraction.