CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior / Para determinar a prevalÃncia de alguns fatores de risco do cÃncer de mama, quantificar os fatores de risco de maior prevalÃncia, delimitar grupos de maior risco e sugerir possÃveis medidas de intervenÃÃo para prevenÃÃo primÃria, analisou-se uma populaÃÃo de 425 funcionÃrias da Maternidade Escola Assis Chateaubriand da Universidade Federal do CearÃ, de vÃrios nÃveis sociais e padrÃes raciais, mediante a aplicaÃÃo de um formulÃrio com o levantamento de 30 variÃveis e realizou-se a mensuraÃÃo do peso, altura, circunferÃncia da cintura e do quadril.Calculou-se com estes dados a relaÃÃo cintura/quadril, o Ãndice de massa corpÃrea e o Ãndice de Gail de todas as entrevistadas. Dos fatores de risco levantados, encontrou-se em 222 (52,2%) funcionÃrias o Ãndice de massa corpÃrea acima de 25, a relaÃÃo cintura/quadril maior do que 0,8 em 391 (92,1%) e o sedentarismo em 314 (73,1%) das entrevistadas. O grupo de maior risco encontrado e que merece seguimento diferenciado à formado pelos seguintes subgrupos: as 222 (52,2%) funcionÃrias com o Ãndice de massa corpÃrea maior ou igual a 25, as 34 (11,3%) que tiveram o primeiro filho apÃs os trinta anos, as 34 (11,3%) que fazem ou fizeram terapia de reposiÃÃo hormonal, as 2 (0,5%) portadoras de cÃncer de mama e as 15 (20,8%) com parentes de primeiro grau acometidos de cÃncer de mama. SÃo medidas possÃveis de intervenÃÃo para o grupo de maior risco, para prevenÃÃo primÃria do cÃncer de mama: orientaÃÃes dietÃticas e reeducaÃÃo alimentar, com periÃdico controle das medidas biomÃtricas e um programa de condicionamento fÃsico no ambiente de trabalho. / A group of 425 female staff from the school maternity hospital Assis Chateaubriand (Federal University of CearÃ, Brazil), of varied ethnicity and socioeconomic status, were given a questionnaire containing 30 variables and subjected to weight, height, waist and hip circumference measurements in order to determine the prevalence of a number of risk factors for breast cancer, quantify the most prevalent risk factors, define high-risk groups and suggest intervention measures for primary prevention. All subjects had their waist/hip ratio, body mass index (BMI) and Gail index calculated. Within the risk factors surveyed, 222 (52.2%) subjects had a BMI of 25 or more, 391 (92.1%) presented a waist/hip ratio above 0.8, and 314 (73.1%) were found to be sedentary. The following subgroups displayed the highest risk, demanding specific follow-up measures: the 222 (52.2%) subjects with BMI≥25, 34 subjects (11.3%) who bore their first child after age 30, 34 subjects (11.3%) receiving hormone replacement therapy then or previously, 2 subjects (0.5%) diagnosed with breast cancer, and 15 subjects (20.8%) with first-degree relatives diagnosed with breast cancer. Intervention measures for primary breast cancer prevention in the highest-risk group would include dietary counseling and reeducation with periodical biometric measurements and on-the-job physical exercise programs.

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by Chiu-lun Fok. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1991. / Includes bibliographical references. / List of Abbreviations --- p.i / Abstract --- p.iii / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1 --- General Properties of Oxalysine --- p.1 / Chapter 1.1.1 --- Chemical Structure and Properties --- p.1 / Chapter 1.1.2 --- Biological Properties --- p.2 / Chapter 1.1.2.1 --- Antimicrobial Activity --- p.2 / Chapter 1.1.2.2 --- Antitumor Activity --- p.2 / Chapter 1.1.2.3 --- Immunomodulatory Activity --- p.5 / Chapter 1.1.2.4 --- Other Biological Properties --- p.5 / Chapter 1.1.3 --- Pharmacokinetics and Toxicity --- p.6 / Chapter 1.2 --- General Properties of Ribosome-Inactivating and Abortifacient Proteins --- p.8 / Chapter 1.2.1 --- Research History --- p.8 / Chapter 1.2.1.1 --- Ribosome-Inactivating Proteins --- p.8 / Chapter 1.2.1.2 --- Abortifacient Proteins --- p.9 / Chapter 1.2.2 --- Relationship between Ribosome- Inactivating Proteins and Abortifacient Proteins --- p.10 / Chapter 1.2.3 --- Distribution --- p.11 / Chapter 1.2.4 --- Physicochemical Characteristics --- p.12 / Chapter 1.2.5 --- Biological Properties --- p.13 / Chapter 1.2.5.1 --- Effect on Protein Synthesis --- p.13 / Chapter 1.2.5.2 --- Effect on the Immune System --- p.14 / Chapter 1.2.5.3 --- Cytotoxic and Antitumor Activities --- p.16 / Chapter 1.2.5.4 --- Termination of Pregnancy --- p.17 / Chapter 1.2.5.5 --- Antiviral Activity --- p.18 / Chapter 1.2.6 --- The Study on Luffaculin --- p.19 / Chapter 1.3 --- Aim of the Present Study --- p.20 / Chapter 1.3.1 --- Oxalysine --- p.20 / Chapter 1.3.2 --- Luffaculin --- p.20 / Chapter Chapter 2 --- Materials and Methods --- p.22 / Chapter 2.1 --- Materials --- p.22 / Chapter 2.2 --- Methods --- p.30 / Chapter 2.2.1 --- In Vivo Drug Treatment --- p.30 / Chapter 2.2.2 --- Isolation and Preparation of Cells --- p.30 / Chapter 2.2.2.1 --- Peritoneal Exudate Cells --- p.30 / Chapter 2.2.2.2 --- Spleen Cells --- p.30 / Chapter 2.2.2.3 --- Ficoll-Paque Separation of Lymphocytes --- p.31 / Chapter 2.2.2.4 --- Congo Red-Stained Yeast Cells --- p.31 / Chapter 2.2.3 --- Lymphocyte Transformation --- p.32 / Chapter 2.2.4 --- Haemolytic Plaque Assay --- p.33 / Chapter 2.2.5 --- Phagocytic Activity --- p.33 / Chapter 2.2.6 --- Macrophage-Mediated Cytostatic Activity --- p.34 / Chapter 2.2.7 --- Delayed Type Hypersensitivity (DTH) --- p.35 / Chapter 2.2.8 --- Production of and Assay for Interleukin-2(IL-2) --- p.36 / Chapter 2.2.9 --- Cytotoxicity of the Drugs on Various Cell Lines --- p.38 / Chapter 2.2.9.1 --- Trypan Blue Exclusion Method --- p.38 / Chapter 2.2.9.2 --- Neutral Red Uptake Method --- p.38 / Chapter 2.2.10 --- Cytostatic Effect of the Drugs on Various Cell Lines --- p.39 / Chapter 2.2.11 --- Evaluation of Antitumor Activity (In Vivo ) --- p.40 / Chapter 2.2.11.1 --- Tumor Size --- p.40 / Chapter 2.2.11.2 --- Survival Study --- p.40 / Chapter 2.2.12 --- TLC Analysis --- p.40 / Chapter 2.2.13 --- Preparation of Ribosome-Inactivating and Abortifacient Proteins --- p.41 / Chapter 2.2.13.1 --- Trichosanthin (TCS) --- p.41 / Chapter 2.2.13.2 --- Luffaculin (LFC) --- p.42 / Chapter 2.2.14 --- Protein Determination --- p.42 / Chapter 2.2.15 --- Statistical Analysis --- p.43 / Chapter Chapter 3 --- The Immunomodulatory and Antitumor Activities of Oxalysine (OXL) --- p.44 / Chapter 3.1 --- Introduction --- p.44 / Chapter 3.2 --- The Immunomodulatory Activity of Oxalysine --- p.46 / Results --- p.46 / Chapter 3.2.1 --- Effect of Oxalysine on the Proliferation of Mouse Splenocytes --- p.46 / Chapter 3.2.2 --- Effect of In Vitro Oxalysine Exposure on the Response of Murine Splenocytes to Mitogens --- p.46 / Chapter 3.2.3 --- Effect of In Vivo Oxalysine Treatment on the Response of Murine Splenocytes to Mitogens --- p.49 / Chapter 3.2.4 --- Effect of Oxalysine on Delayed Type Hypersensitivity (DTH) Response --- p.51 / Chapter 3.2.5 --- Effect of Oxalysine on the In Vitro Phagocytic Activity of Mouse Peritoneal Macrophages --- p.51 / Chapter 3.2.6 --- Effect of Oxalysine on Macrophage- Mediated Cytostatic Activity --- p.53 / Chapter 3.2.7 --- Effect of Oxalysine on the Humoral Response to SRBC --- p.55 / Discussion --- p.59 / Chapter 3.3 --- Mechanistic Studies on Inhibition of Mitogen´ؤ Induced Lymphocyte Transformation by Oxalysine --- p.62 / Results --- p.62 / Chapter 3.3.1 --- Lack of Direct Cytotoxic Effect of Oxalysine on Mouse Splenocytes In Vitro --- p.62 / Chapter 3.3.2 --- Effect of Oxalysine on the Kinetics of Con A-Induced Lymphoproliferative Response --- p.62 / Chapter 3.3.3 --- Time Course Studies on the Effect of Oxalysine on Mitogen-Induced Lymphocyte Transformation --- p.64 / Chapter 3.3.3.1 --- Preincubation of Oxalysine --- p.64 / Chapter 3.3.3.2 --- Delayed Addition of Oxalysine --- p.67 / Chapter 3.3.4 --- Effect of Exogenous IL-2 on the Oxalysine-Mediated Suppression of Lymphocyte Blastogenesis --- p.69 / Chapter 3.3.5 --- Effect of Oxalysine on the Activity of IL-2 Containing Medium to Maintain the Proliferation of the IL´ؤ2 Dependent CTLL-2 Cells --- p.73 / Chapter 3.3.6 --- Production of IL-2 from Splenocytes of Oxalysine´ؤTreated Mice --- p.75 / Chapter 3.3.7 --- The In Vitro Effect of Oxalysine on the Production of IL-2 from Con A-Activated Mouse Splenocytes --- p.75 / Discussion --- p.79 / Chapter 3.4 --- The Antitumor Activity of Oxalysine --- p.83 / Results --- p.83 / Chapter 3.4.1 --- Cytotoxicity of Oxalysine on Various Tumor Cell Lines --- p.83 / Chapter 3.4.2 --- Cytostatic Effect of Oxalysine on Various Tumor Cell Lines --- p.85 / Chapter 3.4.3 --- Effect of Oxalysine on the Survival of Tumor-Bearing Mice --- p.93 / Chapter 3.4.4 --- Effect of Oxalysine on the Growth of Transplantable Tumor Cells In Vivo --- p.95 / Discussion --- p.100 / Chapter 3.5 --- General Discussion --- p.102 / Chapter Chapter 4 --- The Immunomodulatory and Cytotoxic Properties of Luffaculin (LFC) --- p.104 / Chapter 4.1 --- Introduction --- p.104 / Chapter 4.2 --- The Immunomodulatory Activity of Luffaculin --- p.106 / Results --- p.106 / Chapter 4.2.1 --- Lack of Direct Cytotoxic Effect of LFC on Mouse Splenocytes In Vitro --- p.106 / Chapter 4.2.2 --- Effect of Luffaculin on the Proliferation of Mouse Splenocytes --- p.108 / Chapter 4.2.3 --- Inhibition of the Mitogen-Induced Lymphocyte Transformation by Luffaculin --- p.108 / Chapter 4.2.4 --- Effect of Luffaculin on Delayed Type Hypersensitivity (DTH) Response --- p.114 / Chapter 4.2.5 --- Primary Humoral Immune Response to SRBC in Luffaculin-Treated Mice --- p.114 / Chapter 4.2.6 --- Effect of Luffaculin on Phagocytosis of Macrophages In Vitro --- p.117 / Chapter 4.2.7 --- Effect of Luffaculin on Macrophage- Mediated Cytostatic Activity --- p.117 / Chapter 4.2.8 --- Production of Interleukin´ؤ2 from Splenocytes of Luffaculin-Treated Mice --- p.119 / Discussion --- p.122 / Chapter 4.3 --- The Cytotoxic and Cytostatic Effects of Luffaculin on Various Tumor Cell Lines --- p.125 / Results --- p.125 / Chapter 4.3.1 --- Cytotoxicity of Luffaculin on Various Tumor Cell Lines --- p.125 / Chapter 4.3.2 --- Cytostatic Effect of Luffaculin on Various Tumor Cell Lines --- p.127 / Discussion --- p.138 / Chapter 4.4 --- General Discussion --- p.140 / References --- p.143

by Wong Yee Wah. / Thesis (M.Ph.)--Chinese University of Hong Kong, 1987. / Bibliography: leaves 130-148.

Metastasis is the leading cause of poor prognosis for individuals diagnosed with cancer. Breast cancer is particularly prevalent with 1 in 10 women receiving a breast cancer diagnosis in her lifetime. There are various types of breast cancers that are distinguished by molecular subtype as defined by specific biomarker expression profiles: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). The subtypes defined by the varying expression of these receptors respond differently to cancer treatments. For example, luminal A ([ER/PR+] HER2- KI67-) responds well to endocrine therapy and patients generally have a good prognosis, whereas triple negative breast cancer (TNBC) ([ER/PR-] HER2- basal marker+) has no specific targeted treatment available and the prognosis is usually poor. Patients with the HER2 subtype often develop resistance to the treatment specific to the breast cancer molecular subtype. Since 90% of all cancer-related deaths are due to metastatic disease, effectively treating all of these types of breast cancers before metastasis is an important factor in achieving a more positive outcome, In order for metastasis to occur, a tumor cell must have the ability to mobilize, intravasate into the vasculature, and then extravasate and proliferate into a tumor at a distant site. Numerous biological and environmental factors must facilitate each of these steps in order for metastasis to occur. One biomarker of metastasis is a tumor microenvironment of metastasis (TMEM). A TMEM is the physical apposition of a Mena-expressing tumor cell, a macrophage (a type of white blood cell), and an endothelial cell (a blood vessel cell). Each TMEM component plays a key role in breast cancer biology. The automated clinical assay MetaSite BreastTM was developed by MetaStat, Inc. to quantify TMEMs. The MetaSiteTM score directly correlates with risk of developing metastasis. The Mena protein is involved in cell motility and expressed isoforms can either promote metastasis (for example, MenaINV), or protect and prevent metastasis (for example, Mena11a). These isoforms are not expressed in a binary manner and studies have shown that the ratio of MenaINV to Mena11a can give insight into the pro-metastatic/anti-metastatic biology of the cell. To indirectly measure the amount of MenaINV, the Z-score of Mena11a is subtracted from the Z-score of pan-Mena (all Mena isoforms), yielding a theoretical maximum amount of MenaINV, called Menacalc. This process is performed by quantitative analysis of multiplexed immunofluorescence staining through the MenaCalcTM assay developed by MetaStat, Inc. The results of this study demonstrated that MenaCalcTM is a high-performing, high-throughput assay that was clinically validated under CLIA-approved protocol in January 2016. The assay surpassed all benchmark goals for precision and performance. For both day-to-day and run-to-run operations, precision and reproducibility were analyzed using Pearson’s R and slope. The day-to-day reproducibility yielded Pearson’s R values of 0.879 and 0.853 comparing Day 1 vs. Day 2 and Day 2 vs. Day 3, respectively. The slopes for the same comparisons were 0.985 and 0.982, respectively. The analysis of run-to-run precision had Pearson’s R values of 0.999 and 0.994 comparing Day 1 vs. Day 2 and Day 2 vs. Day 3, respectively. The slopes were 0.999 for both comparisons. The development of such an assay brings new elements of precision and reproducibility to the current market of breast cancer biomarker tests. Statistical analysis revealed a wide range of MenaCalcTM scores that were independent of total Mena expression. Individual images showed a range of MenaCalcTM values from a low of only 2.9% of cells with a high MenaCalcTM score to a high of 97.4% of cells with a high MenaCalcTM score. Regions of high MenaCalcTM scores correlated with areas of invasive tumor. Preliminary data assessing the synergistic use of both the MetaSite BreastTM and the MenaCalcTM assays were promising. These data suggests that both physical MetaSiteTM structures and protein expression levels can be used to more thoroughly understand the biology of breast cancer and the path to metastasis. Three clusters of combined MetaSiteTM/MenaCalcTM scores were observed: MetaSiteTM low/MenaCalcTM low, MetaSiteTM low/MenaCalcTM high, MetaSiteTM high/MenaCalcTM high. Because a MetaSiteTM High/MenaCalcTM Low score combination was not observed, a high MenaCalcTM score may be necessary for TMEM formation. Studies are ongoing to further evaluate the synergy of the MetaSite BreastTM and the MenaCalcTM in order to bring more power to the assessment of metastatic risk. / 2016-12-16T00:00:00Z

The purpose of this project was to design an algorithm for the management of Dermatofibrosarcom Protuberans (DFSP.) The National Cancer Center Network guidelines suggest immediate reconstruction in most cases after DFSP resection. We believe this algorithm is inadequate. Due to the infiltrating nature of DFSP, tumor margins are often positive after resection. Immediate reconstruction in the context of residual tumor is problematic because of the risk for spreading microscopic disease and the potential to compromise reconstructive options. At our institution we examined the prevalence of positive margins on permanent pathology after immediate closure following surgical resection of DFSP. Forty-one patients were identified; 25 had received treatment with surgical excision and 16 with Mohs surgery. Of the 25 patients that were treated with surgical excision, 20 underwent immediate closure and 5 underwent delayed closure after tumor resection. Eight out of 19 (40%) of patients who underwent immediate closure were found to have positive margins on permanent pathology. Given these findings, we propose a treatment algorithm focused on more conservative surgical management of DFSP in which negative margins are established before closure. Mohs surgery, which allows for immediate identification of pathology, plays a central role.

HOX proteins are evolutionarily conserved homeodomain-containing transcription factors involved in hematopoiesis and patterning during embryogenesis. Their tasks as master regulators of embryonic development are achieved in large part through their ability to interact with co-factors of the PBX and MEIS/PREP families, which constitute the broader three amino-acid loop extension (TALE) class of homeodomain proteins. HOX, MEIS, and PBX have been implicated in leukemic hematopoiesis due to their association with hematological malignancies. The oncogenic function of MEIS1 in accelerating the onset of acute myeloid leukemia induced by HOX was mapped to its C-terminal transactivation domain, which is responsive to PKA signaling. This thesis extends our understanding regarding the mechanism by which MEIS1A executes its C-terminal transactivation function in vivo. We describe the involvement of CREB and its co-activators CBP and TORC in conferring the PKA-responsiveness of the ME1S1A C terminus. CREB mutants that fail to bind CBP or TORC also fail to promote PKA induction mediated by the C terminus of ME1S1A. TORC was further shown to be capable of bypassing the need for PKA to activate transcription by MEIS1, an ability endowed by its physical interaction with MEIS1. Chromatin immunoprecipitation (ChIP) demonstrated a concerted recruitment of endogenous MEIS1, TORC2, and CREB proteins on ME1S1 target genes. In addition, this thesis also characterizes the promoter of the murine Meis1 gene. Meis1 possesses multiple transcription start sites upstream of its translation initiation site. We identified a ME1S·PBX consensus recognition site within the Meis1 promoter and showed that PBX1 binds to this sequence in vitro. Our ChIP assay results further suggest an autoregulatory mode for the Meis1 gene as revealed by a co-occupancy of endogenous CREB, TORC2, PBX1, and MEIS1 itself on the Meis1 promoter. Collectively, this thesis proposes a mechanistic action conferred by CREB, CBP and TORC in the PKA-inducible transactivation of ME1S1A, and provides new information on the Meis1 promoter.

Diss. (sammanfattning) Uppsala : Univ., 2002. / Härtill 5 uppsatser.

Thesis (Ph. D.)--Cornell University, August, 1999. / Vita. Includes bibliographical references (leaves 141-168).