Molecular and Clinical Characterization of Postpartum-Associated Breast Cancer

Background: Postpartum-associated breast cancer (PPBC) cases have worse outcomes and overall survival compared to other breast cancer cases. However, it is not well understood how tumor clinical and molecular characteristics and treatment patterns vary according to time since last childbirth. Methods: This dissertation had two aims (1) to examine clinical and molecular tumor features among cases who were recently (≤10 years prior), or remotely (>10 years prior) postpartum, or nulliparous prior to diagnosis (2) to describe the distribution of tumor stage, treatment initiation delay, prolonged treatment duration, and treatment modalities according to age at diagnosis and recency of pregnancy. Data from the Carolina Breast Cancer Study was utilized to achieve these aims. Results: For Aim 1 women who were recently postpartum (N=618) were more frequently lymph node positive, ER/PR negative, and IHC-based triple negative compared to nulliparous (N=360) women. However, these characteristics were not significantly different compared to remotely postpartum (N=1086) women, suggesting that differences were due to parity rather than recency. Compared to nulliparous women, recently parous had significant enrichment for adaptive immunity, T cells, B cells, CD8 T cells, activated CD8 T cells/NK cells, T follicular helper cells and higher overall immune cell composition. There was no significant difference in immune cell scores between recently vs. remotely postpartum women, but immune cell scores were attenuated among remotely postpartum and only CD8 T cells were significantly enriched in remotely postpartum vs. nulliparous groups. Aim 2 included 1179 premenopausal cases with information on treatment patterns. Recently postpartum women were significantly less likely to experience treatment initiation delay and prolonged treatment duration compared to nulliparous women. Recently postpartum women were also significantly more likely to have mastectomy and chemotherapy. However, these associations were attenuated after taking tumor characteristics including stage and lymph node status into account. Conclusions: These results suggest a dominant effect of parity (vs. nulliparity) and a lesser effect of recency of pregnancy on breast tumor features. Disparities in outcomes among PPBC cases are unlikely to be related to under-treatment.Doctor of Philosoph

REPRODUCTIVE AND HORMONAL FACTORS IN RELATION TO LUNG CANCER AMONG NEPALI WOMEN

Over 50% of global lung cancer incidence occurs in less developed regions (LDRs). Despite this, little is known regarding lung cancer risk factors in LDRs such as Nepal. Using data from a hospital-based case-control study conducted in B. P. Koirala Memorial Cancer Hospital (Nepal, 2009-2012), relationships between reproductive and hormonal factors and lung cancer were examined among women aged 23-85 years. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using multivariable logistic regression. Among postmenopausal women, those with a younger age at menopause (<45years; 45-49years) had an increased odds of lung cancer compared to those with an older (¡Ý50years) age at menopause (OR=2.14, 95%CI=1.09, 4.17; OR=1.93, 95%CI=1.07, 3.51, respectively), after adjusting for age and cumulative active smoking. This is the first study to characterize these relationships among Nepali women. Further research is needed to elucidate the role of age at menopause in lung cancer within this understudied population

Reproductive and Hormonal Factors in Relation to Lung Cancer Among Nepali Women

Background: Of the 1.8 million global incident lung cancer cases estimated in 2012, approximately 60% occurred in less developed regions. Prior studies suggest sex differences in lung cancer risk and a potential role for reproductive and hormonal factors in lung cancer among women. However, the majority of these studies were conducted in developed regions. No prior study has assessed these relationships among Nepali women.Methods: Using data from a hospital-based case-control study conducted in B. P. Koirala Memorial Cancer Hospital (Nepal, 2009–2012), relationships between reproductive and hormonal factors and lung cancer were examined among women aged 23–85 years. Lung cancer cases (n = 268) were frequency-matched to controls (n = 226) based on age (±5 years), ethnicity and residential area. The main exposures in this analysis included menopausal status, age at menarche, age at menopause, menstrual duration, gravidity, and age at first live-birth. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression.Results: Among postmenopausal women, those with a younger age at menopause (&lt;45 years; 45–49 years) had an increased odds of lung cancer compared to those with an older (≥50 years) age at menopause [OR (95%CI): 2.14 (1.09, 4.17); OR (95% CI): 1.93 (1.07, 3.51)], after adjusting for age and cumulative active smoking years. No statistically significant associations were observed with the other reproductive and hormonal factors examined.Conclusion: These results suggest that Nepali women with prolonged exposure to endogenous ovarian hormones, via later age at menopause, may have a lower odds of lung cancer

Evaluation of “Dream Herb,” Calea zacatechichi

A recent surge in the use of dietary supplements, including herbal remedies, necessitates investigations into their safety profiles. “Dream herb,” Calea zacatechichi, has long been used in traditional folk medicine for a variety of purposes and is currently being marketed in the US for medicinal purposes, including diabetes treatment. Despite the inherent vulnerability of the renal system to xenobiotic toxicity, there is a lack of safety studies on the nephrotoxic potential of this herb. Additionally, the high frequency of diabetes-associated kidney disease makes safety screening of C. zacatechichi for safety especially important. We exposed human proximal tubule HK-2 cells to increasing doses of this herb alongside known toxicant and protectant control compounds to examine potential toxicity effects of C. zacatechichi relative to control compounds. We evaluated both cellular and mitochondrial functional changes related to toxicity of this dietary supplement and found that even at low doses evidence of cellular toxicity was significant. Moreover, these findings correlated with significantly elevated levels of nephrotoxicity biomarkers, lending further support for the need to further scrutinize the safety of this herbal dietary supplement

Reproductive and Hormonal Factors in Relation to Lung Cancer Among Nepali Women

Partial funding for Open Access provided by the UMD Libraries' Open Access Publishing Fund.Background: Of the 1.8 million global incident lung cancer cases estimated in 2012, approximately 60% occurred in less developed regions. Prior studies suggest sex differences in lung cancer risk and a potential role for reproductive and hormonal factors in lung cancer among women. However, the majority of these studies were conducted in developed regions. No prior study has assessed these relationships among Nepali women. Methods: Using data from a hospital-based case-control study conducted in B. P. Koirala Memorial Cancer Hospital (Nepal, 2009–2012), relationships between reproductive and hormonal factors and lung cancer were examined among women aged 23–85 years. Lung cancer cases (n = 268) were frequency-matched to controls (n = 226) based on age (±5 years), ethnicity and residential area. The main exposures in this analysis included menopausal status, age at menarche, age at menopause, menstrual duration, gravidity, and age at first live-birth. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression. Results: Among postmenopausal women, those with a younger age at menopause (<45 years; 45–49 years) had an increased odds of lung cancer compared to those with an older (≥50 years) age at menopause [OR (95%CI): 2.14 (1.09, 4.17); OR (95% CI): 1.93 (1.07, 3.51)], after adjusting for age and cumulative active smoking years. No statistically significant associations were observed with the other reproductive and hormonal factors examined. Conclusion: These results suggest that Nepali women with prolonged exposure to endogenous ovarian hormones, via later age at menopause, may have a lower odds of lung cancer

In vitro exposure of Adhatoda zeylanica to human renal cells lacks acute toxicity

Adhatoda zeylanica is a dietary supplement ingredient present in several types of dietary supplements, including weight loss, respiratory relief, and immune regulating products. Due to its reported wide range of uses in folk medicine, it was hypothesized that it may have the potential to target multiple organs and lead to a range of toxicity features. As a preliminary evaluation of the safety of this herbal ingredient, an investigation into its effects on the kidney was sought. An in vitro study of its potential nephrotoxicity using the HK-2 human proximal tubule cell line in a variety of functional indicators was performed to capture both general forms of cellular toxicity as well as ones that are specific to proximal tubules. A. zeylanica was only capable of inducing detrimental short-term toxicity to HK-2 cells at relatively high treatment concentrations when exposed directly to the cells. The lack of acute and potent toxicity of A. zeylanica under our experimental conditions calls for further studies to better define its toxicant threshold and establish safe dosage levels

Abstract P631: Association Between Suboptimal Sleep Duration and Cardiovascular Disease Prevalence Among Asian Americans

Byline: Santhosh Nadarajah, Stanford Cntr for Asian Health Rsch and Education, Stanford, CA; Risa Akiba; Isabelle Maricar; Sanah Vohra; Armaan Jamal; Yuichiro Yano; Tali Elfassy; Malathi Srinivasan; Gloria Kim; Latha Palaniappan; Karina Kim; Eugene Yang Importance: Cardiovascular disease (CVD) risk and prevalence is widely varied among Asian Americans. The American Heart Association recently added healthy sleep to its metrics used to define ideal cardiovascular health. Little is known about the association between sleep and CVD prevalence among Asian subgroups. Hypothesis: The association between suboptimal sleep duration and CVD risk prevalence will differ by Asian American subgroup. Methods: We analyzed results from the National Health Interview Survey (2012-2018, N=234,126), a nationally representative sample. Participants (age>40 years old) included 214,956 non-Hispanic Whites (NHWs), 3,043 Asian Indians, 3,993 Chinese, 4,719 Filipinos, and 7,603 other Asians. Suboptimal sleep was self-reported and defined as 9 hours. CVD was defined as self-reported stroke, heart attack, coronary artery disease, or angina. We used multivariable logistic regression models to ascertain the association. All analyses included complex survey design considerations. Results: Suboptimal sleep duration was associated with higher CVD prevalence for NHWs and all Asians, but in Asian subgroup stratified analyses, suboptimal sleep was only associated with higher CVD prevalence among Other Asians. Conclusions: Our results show heterogeneity in the association between sleep duration and CVD prevalence among Asian subgroups, however further research is needed to better understand these relationships.Professiona

In vitro exposure of Adhatoda zeylanica to human renal cells lacks acute toxicity

Adhatoda zeylanica is a dietary supplement ingredient present in several types of dietary supplements, including weight loss, respiratory relief, and immune regulating products. Due to its reported wide range of uses in folk medicine, it was hypothesized that it may have the potential to target multiple organs and lead to a range of toxicity features. As a preliminary evaluation of the safety of this herbal ingredient, an investigation into its effects on the kidney was sought. An in vitro study of its potential nephrotoxicity using the HK-2 human proximal tubule cell line in a variety of functional indicators was performed to capture both general forms of cellular toxicity as well as ones that are specific to proximal tubules. A. zeylanica was only capable of inducing detrimental short-term toxicity to HK-2 cells at relatively high treatment concentrations when exposed directly to the cells. The lack of acute and potent toxicity of A. zeylanica under our experimental conditions calls for further studies to better define its toxicant threshold and establish safe dosage levels. Keywords: Kidney proximal tubule, Adhatoda zeylanica, Nephrotoxicity, HK-

Comparison of diglycolic acid exposure to human proximal tubule cells in vitro and rat kidneys in vivo

Diglycolic acid (DGA) is present in trace amounts in our food supply and is classified as an indirect food additive linked with the primary GRAS food additive carboxymethyl cellulose (CMC). Carboxymethyl starches are used as a filler/binder excipient in dietary supplement tablets and a thickening ingredient in many other processed foods. We sought to utilize the human proximal tubule HK-2 cell line as an in vitro cellular model system to evaluate its acute nephrotoxicity of DGA. We found that DGA was indeed toxic to HK-2 cells in all in vitro assays in our study, including a highly sensitive Luminex assay that measures levels of an in vitro biomarker of kidney-specific toxicity, Kidney Injury Molecule 1 (KIM-1). Interestingly, in vitro KIM-1 levels also correlated with in vivo KIM-1 levels in urine collected from rats treated with DGA by daily oral gavage. The use of in vitro and in vivo models towards understanding the effectiveness of an established in vitro system to predict in vivo outcomes would be particularly useful in rapidly screening compounds that are suspected to be unsafe to consumers. The merit of the HK-2 cell model in predicting human toxicity and accelerating the process of food toxicant screening would be especially important for regulatory purposes. Overall, our study not only revealed the value of HK-2 in vitro cell model for nephrotoxicity evaluation, but also uncovered some of the mechanistic aspects of the human proximal tubule injury that DGA may cause. Keywords: Kidney proximal tubule, HK-2 cells, Diglycolic acid, Nephrotoxicit