737 research outputs found
Abstract 3294: Breast cancer extent and survival in diabetic women in a Finnish population based cohort
No full textAbstract
Introduction: Breast cancer and diabetes are two major health problems for women. Around 1.7 million new breast cancer cases are diagnosed each year, making breast cancer the most common cancer type in women. Number of people with diabetes is estimated to be 415 million worldwide, thus one in 11 adults have diabetes. However, evidence on the association between diabetes and breast cancer prognosis is controversial. We estimated breast cancer extent at diagnosis and survival in a Finnish population-based cohort of female breast cancer patients.
Materials and methods: All newly diagnosed breast cancer cases among women in Finland between 1995 and 2013 were identified from comprehensive national Finnish Cancer Registry. To minimize possible bias due to differing participation in cancer screening the study population was limited to women with at least one mammography screening before the diagnosis. In total 45,786 cases were included in our study cohort. Information on recorded diagnoses of diabetes, hypertension, hypercholesterolemia and obesity from in- and outpatient hospital visits during 1995-2013 were obtained from national Care Register for Health Care maintained by National Institute for Health and Welfare. Logistic regression was used to evaluate the risk of having cancer extended to axillary lymph nodes or beyond at diagnosis. Cox regression was used to evaluate risk of breast cancer death and overall mortality after the diagnosis. Analyses were adjusted for age, comorbidities and number of mammography screens before the diagnosis. Survival analyses were further adjusted for tumor extent and primary treatment.
Results: In total 1,419 women had diabetes. Compared to non-diabetic women, breast cancer was more often advanced to axillary lymph-nodes (OR 1.19; 95% CI 1.05-1.34) or metastatic at diagnosis (OR 1.58; 95% CI 1.26-1.97) in diabetic women. Nevertheless, during the median follow-up of 6.9 year after the diagnosis, risk of breast cancer death did not differ between diabetic and non-diabetic women (0.99; 95% CI 0.81-1.21). Overall risk of death was elevated among diabetic women (HR 1.34; 95% CI 1.19-1.51).
Conclusion: Diabetic women have more often advanced tumor extent at diagnosis compared to non-diabetic women. However, diabetes did not affect disease-specific survival within 6.9 years after the diagnosis.
Citation Format: Mika Murto, Miia Artama, Kala Visvanathan, Teemu Murtola. Breast cancer extent and survival in diabetic women in a Finnish population based cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3294. doi:10.1158/1538-7445.AM2017-3294</jats:p
Identification and Evaluation of the Minimum Unit of a KALA Peptide Required for Gene Delivery and Immune Activation
No full textThe KALA peptide (WEAKLAKALAKALAKHLAKALAKALKA) is an amphiphilic peptide that forms an a-helical structure at physiological pH. We previously reported that, when a plasmid DNA-encapsulating liposomal membrane is modified with the KALA peptide, transgene expression and immune activation are facilitated in bone marrow-derived dendritic cells (BMDCs). However, the minimum unit of the KALA peptide and the importance of its secondary structure for these activities are not completely known at this time. We herein report on the identification of the minimum unit of the KALA peptide (short-KALA) required for activity, as determined by the stepwise removal of "K-A-L-A" units. We evaluated the activities of 4 types of short-KALAs by modifying plasmid DNA-encapsulating multi-functional envelop-type nano devices. Among the peptides tested, a short-KALA3 (WEAKLAKALAKALA) was the shortest KALA peptide that could form an alpha-helical structure, as well as to elicit transgene expression and immune activation in BMDCs. Furthermore, the function of the short-KALA3 as an inducer of cellular uptake was retained, while uptake was completely lost in more shortened versions of KALA (short KALA4), in that transgene expression and immunological activation were both completely lost. These collective data show that the KALA peptide must form an alpha-helical structure to induce cellular uptake in BMDCs. (C) 2017 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved
Sogdian and Early Islamic Coins from Kafir Kala (Uzbekistan)
No full textThe Author presents a numismatic catalogue of the coins that have been recovered from the archaeological site of Kafir Kala, near Samarkand in Uzbekistan. The Sogdian citadel was excavated by the University of Bologna, from 2002 to 2008
Modifying Antigen-Encapsulating Liposomes with KALA Facilitates MHC Class I Antigen Presentation and Enhances Anti-tumor Effects
No full textFor a successful anti-cancer vaccine, antigen presentation on the major histocompatibility complex (MHC) class I is a requirement. To accomplish this, an antigen must be delivered to the cytoplasm by overcoming the endosome/lysosome. We previously reported that a lipid nanoparticle modified with a KALA peptide (WEAKLAKALAKALAKHLAKALAICALICA), an alpha-helical cationic peptide, permits the encapsulated pDNA to be efficiently delivered to the cytoplasm in bone marrow derived dendritic cells (BMDCs). Herein, we report on the use of KALA-modified liposomes as an antigen carrier, in an attempt to induce potent antigen-specific cellular immunity. The subcutaneous injection of KALA-modified ovalbumin (OVA)-encapsulating liposomes (KALA-OVA-LPs) elicited a much more potent OVA-specific cytotoxic T lymphocyte activity and anti-tumor effect in comparison with particles that were modified with octa-arginine (R8), a cell-penetrating peptide (R8-OVA-LPs). In addition, the numbers of OVA-specific CD8(+) T cells were increased by immunization the KALAOVA-LPs. The treatment of BMDCs with KALA-OVA-LPs induced a substantial MHC class I antigen presentation. Furthermore, the acidic pH-dependent membrane destabilization activity of KALA-OVA-LPs strongly suggests that they are able to escape from endosomes/lysosomes and thereby deliver their cargos to the cytoplasm. Collectively, the KALAmodified liposome is a potential antigen delivery platform for use as a protein vaccine
Consecutive real quadratic fields with large class numbers
No full textFor a given positive integer , we prove that there are at least
integers such that the real quadratic fields have class numbers essentially as
large as possible.Comment: 7 pages; strengthened the results and added a co-author; comments are
welcome
Risks and Benefits of Surgical Preventive Strategies for Ovarian Cancer
No full textOvarian cancer is the deadliest gynecologic cancer and the fifth leading cause of cancer deaths among U.S. women. Due to the lack of effective screening tests, preventive surgeries are a critical component of reducing the burden of ovarian cancer. Surgeries to prevent ovarian cancer are structured around the removal of the ovaries (bilateral oophorectomy) and fallopian tubes (bilateral salpingectomy). However, the long-term risks and benefits of preventive surgeries for ovarian cancer remain poorly understood. The objectives of this dissertation were (1) to examine the uptake of opportunistic salpingectomy (OS) and factors associated with an increased likelihood of OS, (2) to evaluate the prevalence and predictors of occult cancer at the time of OS and bilateral salpingo-oophorectomy (BSO), and (3) to examine the association between BSO and distribution of fat and lean body mass.
For the first study, we utilized inpatient and outpatient claims from 48 million privately insured women between 2010 and 2017. We found that OS for ovarian cancer prevention has rapidly diffused into clinical practice with the speed of adoption bolstered by the release of recommendations from national societies. In 2010, OS accounted for <1% of all sterilization encounters and benign hysterectomies compared to 20% of all sterilization encounters and benign hysterectomies in 2017. The largest increase in OS for sterilization rates occurred in women <45 years, while the largest increase in hysterectomy and OS rates occurred in women 45-55 years. OS rates increased in all U.S. geographic regions, in both rural and urban areas, across all types of health plans, and in women with and without a family history of breast or ovarian cancer.
For the second study, we utilized inpatient and outpatient claims from 538,471 privately insured women undergoing benign gynecologic surgery between 2010 and 2017. The age-adjusted prevalence of occult cancer was 0.053% (95% CI: 0.047-0.059) overall and 0.042% (95% CI: 0.014-0.048) after excluding women with a family history of and genetic susceptibility to breast or ovarian cancer. The prevalence was similar in women undergoing OS for sterilization and hysterectomy and BSO. Independent predictors of an occult cancer diagnosis at surgery included age, family history of and genetic susceptibility to breast or ovarian cancer, surgical indication, and pre-surgical comorbidities. No women with an occult cancer diagnosis developed peritoneal cancer after BSO. In women without an occult cancer diagnosis, 12 developed peritoneal cancer after BSO (age-adjusted incidence: 4.57 per 100,000 women).
For the last study, we used data from a population-based cross-sectional survey of 3,764 women with information on total and regional fat and lean body mass assessed using dual-energy x-ray absorptiometry (DXA) scans. We found that women with a history of BSO were more likely to have increased fat mass and decreased lean mass, particularly in the trunk and arms, compared to women without a history of BSO. The association between BSO and body composition was stronger in women who reported BSO <45 years and women with a normal body mass index at DXA scan.
Overall, the results of this dissertation provide some of the first evidence showing a significant nationwide increase in the performance of OS for ovarian cancer prevention. Given the low prevalence of occult ovarian cancer in average-risk women and uncertainties regarding the efficacy of OS, whether OS for ovarian cancer prevention should be offered to all average-risk women warrants further investigation. In addition, our findings identify a subset of women who may benefit from additional monitoring after BSO. Collectively the results enhance our understanding of the risks and benefits of new and established preventive surgeries for ovarian cancer
Using Polygenic Risk Scores in Risk Prediction: From Health Care Costs to Absolute Risk
No full textPolygenic risk scores (PRSs) are powerful tools that summarize cumulative additive effects of genetic variants, and have had increasingly more applications to risk stratification and clinical decision making with regards to chronic diseases. However, limitations to the use of polygenic risk scores include a lack of focus on a broader set of health outcomes, rather than disease incidence; the potential ramifications of PRS estimation uncertainty to affect clinical decision making; and the disparity in the efficacy of risk prediction in diverse populations, which could lead to exacerbating health inequities. Here, we analyze the joint association between PRS of a broad set of common diseases and related risk factors in the Atherosclerosis Risk in Communities study with health care expenditure and show that polygenic predisposition can predict future inpatient health care costs for males and females. We further explore the uncertainty in PRS construction by providing a framework for determining the impact of the posterior standard deviation of PRSs derived from Bayesian algorithms in clinical decision making, and find that such uncertainty makes little impact in the ranking and selection of individuals based on breast cancer risk within UK Biobank European ancestry women. Finally, we propose a flexible model for evaluation of the absolute risk of a disease and mortality taking into consideration polygenic predisposition, self-identified race and ethnicity, and genetic ancestry. Application of the model to All of Us individuals reveals importance of contextualization of risk using our framework to understand the true impact of the differential burden of polygenic risk across individuals of diverse background. Overall, this thesis advances understanding of the complex impact of polygenic predisposition to diseases and traits on the entire life-course of individuals, going beyond disease incidence and taking into account racial, ethnic and ancestral diversity
Using Polygenic Risk Scores in Risk Prediction: From Health Care Costs to Absolute Risk
No full textPolygenic risk scores (PRSs) are powerful tools that summarize cumulative additive effects of genetic variants, and have had increasingly more applications to risk stratification and clinical decision making with regards to chronic diseases. However, limitations to the use of polygenic risk scores include a lack of focus on a broader set of health outcomes, rather than disease incidence; the potential ramifications of PRS estimation uncertainty to affect clinical decision making; and the disparity in the efficacy of risk prediction in diverse populations, which could lead to exacerbating health inequities. Here, we analyze the joint association between PRS of a broad set of common diseases and related risk factors in the Atherosclerosis Risk in Communities study with health care expenditure and show that polygenic predisposition can predict future inpatient health care costs for males and females. We further explore the uncertainty in PRS construction by providing a framework for determining the impact of the posterior standard deviation of PRSs derived from Bayesian algorithms in clinical decision making, and find that such uncertainty makes little impact in the ranking and selection of individuals based on breast cancer risk within UK Biobank European ancestry women. Finally, we propose a flexible model for evaluation of the absolute risk of a disease and mortality taking into consideration polygenic predisposition, self-identified race and ethnicity, and genetic ancestry. Application of the model to All of Us individuals reveals importance of contextualization of risk using our framework to understand the true impact of the differential burden of polygenic risk across individuals of diverse background. Overall, this thesis advances understanding of the complex impact of polygenic predisposition to diseases and traits on the entire life-course of individuals, going beyond disease incidence and taking into account racial, ethnic and ancestral diversity
THE ASSOCIATIONS BETWEEN MAJOR DEPRESSIVE DISORDER, BREAST CANCER TREATMENT AND OUTCOMES
No full textBreast cancer remains a leading cause of morbidity and mortality among women in the United States, with disease recurrence being a major concern. Emerging evidence suggests that mental health may impact disease progression and survival. Depression, in particular, is reported in up to 60% of women with breast cancer, with the prevalence of clinically diagnosed major depressive disorder (MDD) ranging from 10% to 35%. Despite the potentially high prevalence of depression, the direction and magnitude of the relationship between depression and breast cancer outcomes remains to be clearly defined. Depression has been linked to increased breast cancer mortality in a few observational studies. Studies investigating the association between depression and breast cancer recurrence are inconclusive and have limitations in data ascertainment and small sample sizes.
The goal of this dissertation was to generate robust data on the associations between pre-diagnostic MDD and breast cancer recurrence and mortality (Aim 1) and investigate whether non-adherence to either antidepressants (Aim 2) or endocrine therapies (Aim 3) contribute to disease progression among women with MDD and breast cancer. We used electronic medical records and pharmacy data from the Veterans Affairs (VA) Healthcare System for these analyses given that the VA mandates annual depression screening, reporting national screening rates of 98%.
We observed significantly higher hazards of breast cancer recurrence and mortality among women with MDD compared to those without after adjusting for prognostic factors (Aim 1). Non-adherence to antidepressants or endocrine therapies modified the hazard of recurrence in women with MDD. Non-adherence to antidepressants in the two-years prior to cancer diagnosis was associated with an increased hazard of recurrence compared to women without MDD, whereas those who adhered had a recurrence hazard comparable to women without MDD (Aim 2). Similarly, non-adherence to endocrine therapy following cancer diagnosis was associated with an increased hazard of recurrence compared to women without MDD, whereas those who adhered had a recurrence hazard comparable to women without MDD (Aim 3).
This work provides strong evidence of an association between MDD and disease progression. It also identified non-adherence to antidepressants and endocrine therapies as risk factors for disease progression
THE ASSOCIATIONS BETWEEN MAJOR DEPRESSIVE DISORDER, BREAST CANCER TREATMENT AND OUTCOMES
No full textBreast cancer remains a leading cause of morbidity and mortality among women in the United States, with disease recurrence being a major concern. Emerging evidence suggests that mental health may impact disease progression and survival. Depression, in particular, is reported in up to 60% of women with breast cancer, with the prevalence of clinically diagnosed major depressive disorder (MDD) ranging from 10% to 35%. Despite the potentially high prevalence of depression, the direction and magnitude of the relationship between depression and breast cancer outcomes remains to be clearly defined. Depression has been linked to increased breast cancer mortality in a few observational studies. Studies investigating the association between depression and breast cancer recurrence are inconclusive and have limitations in data ascertainment and small sample sizes.
The goal of this dissertation was to generate robust data on the associations between pre-diagnostic MDD and breast cancer recurrence and mortality (Aim 1) and investigate whether non-adherence to either antidepressants (Aim 2) or endocrine therapies (Aim 3) contribute to disease progression among women with MDD and breast cancer. We used electronic medical records and pharmacy data from the Veterans Affairs (VA) Healthcare System for these analyses given that the VA mandates annual depression screening, reporting national screening rates of 98%.
We observed significantly higher hazards of breast cancer recurrence and mortality among women with MDD compared to those without after adjusting for prognostic factors (Aim 1). Non-adherence to antidepressants or endocrine therapies modified the hazard of recurrence in women with MDD. Non-adherence to antidepressants in the two-years prior to cancer diagnosis was associated with an increased hazard of recurrence compared to women without MDD, whereas those who adhered had a recurrence hazard comparable to women without MDD (Aim 2). Similarly, non-adherence to endocrine therapy following cancer diagnosis was associated with an increased hazard of recurrence compared to women without MDD, whereas those who adhered had a recurrence hazard comparable to women without MDD (Aim 3).
This work provides strong evidence of an association between MDD and disease progression. It also identified non-adherence to antidepressants and endocrine therapies as risk factors for disease progression
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