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1.  Significant lethality following liver resection in A20 heterozygous knockout mice uncovers a key role for A20 in liver regeneration 
Cell Death and Differentiation  2015;22(12):2068-2077.
Hepatic expression of A20, including in hepatocytes, increases in response to injury, inflammation and resection. This increase likely serves a hepatoprotective purpose. The characteristic unfettered liver inflammation and necrosis in A20 knockout mice established physiologic upregulation of A20 as integral to the anti-inflammatory and anti-apoptotic armamentarium of hepatocytes. However, the implication of physiologic upregulation of A20 in modulating hepatocytes' proliferative responses following liver resection remains controversial. To resolve the impact of A20 on hepatocyte proliferation and the liver's regenerative capacity, we examined whether decreased A20 expression, as in A20 heterozygous knockout mice, affects outcome following two-third partial hepatectomy. A20 heterozygous mice do not demonstrate a striking liver phenotype, indicating that their A20 expression levels are still sufficient to contain inflammation and cell death at baseline. However, usually benign partial hepatectomy provoked a staggering lethality (>40%) in these mice, uncovering an unsuspected phenotype. Heightened lethality in A20 heterozygous mice following partial hepatectomy resulted from impaired hepatocyte proliferation due to heightened levels of cyclin-dependent kinase inhibitor, p21, and deficient upregulation of cyclins D1, E and A, in the context of worsened liver steatosis. A20 heterozygous knockout minimally affected baseline liver transcriptome, mostly circadian rhythm genes. Nevertheless, this caused differential expression of >1000 genes post hepatectomy, hindering lipid metabolism, bile acid biosynthesis, insulin signaling and cell cycle, all critical cellular processes for liver regeneration. These results demonstrate that mere reduction of A20 levels causes worse outcome post hepatectomy than full knockout of bona fide liver pro-regenerative players such as IL-6, clearly ascertaining A20's primordial role in enabling liver regeneration. Clinical implications of these data are of utmost importance as they caution safety of extensive hepatectomy for donation or tumor in carriers of A20/TNFAIP3 single nucleotide polymorphisms alleles that decrease A20 expression or function, and prompt the development of A20-based liver pro-regenerative therapies.
doi:10.1038/cdd.2015.52
PMCID: PMC4816110  PMID: 25976305
2.  Pain typology and incident endometriosis 
Human Reproduction (Oxford, England)  2015;30(10):2427-2438.
STUDY QUESTION
What are the pain characteristics among women, with no prior endometriosis diagnosis, undergoing laparoscopy or laparotomy regardless of clinical indication?
SUMMARY ANSWER
Women with surgically visualized endometriosis reported the highest chronic/cyclic pain and significantly greater dyspareunia, dysmenorrhea, and dyschezia compared with women with other gynecologic pathology (including uterine fibroids, pelvic adhesions, benign ovarian cysts, neoplasms and congenital Müllerian anomalies) or a normal pelvis.
WHAT IS KNOWN ALREADY
Prior research has shown that various treatments for pain associated with endometriosis can be effective, making identification of specific pain characteristics in relation to endometriosis necessary for informing disease diagnosis and management.
STUDY DESIGN, SIZE, DURATION
The study population for these analyses includes the ENDO Study (2007–2009) operative cohort: 473 women, ages 18–44 years, who underwent a diagnostic and/or therapeutic laparoscopy or laparotomy at one of 14 surgical centers located in Salt Lake City, UT or San Francisco, CA. Women with a history of surgically confirmed endometriosis were excluded.
PARTICIPANTS/MATERIALS, SETTING AND METHODS
Endometriosis was defined as surgically visualized disease; staging was based on revised American Society for Reproductive Medicine (rASRM) criteria. All women completed a computer-assisted personal interview at baseline specifying 17 types of pain (rating severity via 11-point visual analog scale) and identifying any of 35 perineal and 60 full-body front and 60 full-body back sites for which they experienced pain in the last 6 months.
MAIN RESULTS AND THE ROLE OF CHANCE
There was a high prevalence (≥30%) of chronic and cyclic pelvic pain reported by the entire study cohort regardless of post-operative diagnosis. However, women with a post-operative endometriosis diagnosis, compared with women diagnosed with other gynecologic disorders or a normal pelvis, reported more cyclic pelvic pain (49.5% versus 31.0% and 33.1%, P < 0.001). Additionally, women with endometriosis compared with women with a normal pelvis experienced more chronic pain (44.2 versus 30.2%, P = 0.04). Deep pain with intercourse, cramping with periods, and pain with bowel elimination were much more likely reported in women with versus without endometriosis (all P < 0.002). A higher percentage of women diagnosed with endometriosis compared with women with a normal pelvis reported vaginal (22.6 versus 10.3%, P < 0.01), right labial (18.4 versus 8.1%, P < 0.05) and left labial pain (15.3 versus 3.7%, P < 0.01) along with pain in the right/left hypogastric and umbilical abdominopelvic regions (P < 0.05 for all). Among women with endometriosis, no clear and consistent patterns emerged regarding pain characteristics and endometriosis staging or anatomic location.
LIMITATIONS, REASONS FOR CAUTION
Interpretation of our findings requires caution given that we were limited in our assessment of pain characteristics by endometriosis staging and anatomic location due to the majority of women having minimal (stage I) disease (56%) and lesions in peritoneum-only location (51%). Significance tests for pain topology related to gynecologic pathology were not corrected for multiple comparisons.
WIDER IMPLICATIONS OF THE FINDINGS
Results of our research suggest that while women with endometriosis appear to have higher pelvic pain, particularly dyspareunia, dysmenorrhea, dyschezia and pain in the vaginal and abdominopelvic area than women with other gynecologic disorders or a normal pelvis, pelvic pain is commonly reported among women undergoing laparoscopy, even among women with no identified gynecologic pathology. Future research should explore causes of pelvic pain among women who seek out gynecologic care but with no apparent gynecologic pathology. Given our and other's research showing little correlation between pelvic pain and rASRM staging among women with endometriosis, further development and use of a classification system that can better predict outcomes for endometriosis patients with pelvic pain for both surgical and nonsurgical treatment is needed.
STUDY FUNDING/COMPETING INTERESTS
Supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development (contracts NO1-DK-6-3428, NO1-DK-6-3427, and 10001406-02). The authors have no potential competing interests.
doi:10.1093/humrep/dev147
PMCID: PMC4573450  PMID: 26269529
endometriosis; epidemiology; laparoscopy; dysmenorrhea; dyspareunia
3.  Lifestyle modification intervention improves glycemic control in Mongolian adults who are overweight or obese with newly diagnosed type 2 diabetes 
Obesity Science & Practice  2016;2(3):303-308.
Summary
Objective
To evaluate the effectiveness of a weight loss intervention in Mongolian adults with newly diagnosed type 2 diabetes mellitus and with BMIs ≥ 25.0 kg/m2.
Methods
Eighty participants (33 men/47 women) aged 32–56 years old received education sessions to improve nutritional habits and increase physical activity. Participants were counselled in‐person on two occasions with regular follow‐up by phone to eat less (reduce calorie intake by 30–40% and consume fewer fatty foods), shift food intake to earlier in a day and increase physical activity such as walking, jogging, running and biking. Measurements were performed before and after the 6‐month intervention.
Results
After 6 months, the average weight loss was 4.3 ± 4.7 kg, representing a 4.9 ± 5.4% reduction in body weight (p < 0.0001). Mean HbA1c decreased from 8.5 ± 2.7% to 6.0 ± 1.8% (p < 0.0001), and the percent of individuals with HbA1c in the diabetic range dropped from 76.3% to 27.5%. These changes were accompanied by marked improvements in cardiovascular risk factors, including total cholesterol (3.92 ± 1.02 to 3.13 ± 0.80 mmol/l; p < 0.0001) and triglycerides (2.11 ± 0.82 to 1.54 ± 0.51 mmol/l; p < 0.0001), and modest reductions in systolic and diastolic blood pressure (p < 0.05).
Conclusion
The remarkable improvement in glycemic control and lipid profile in participants suggests that a lifestyle modification intervention targeting weight loss may be highly effective for early diabetes treatment and prevention in Mongolians.
doi:10.1002/osp4.56
PMCID: PMC5043476  PMID: 27708847
Diabetic by HbA1c; obesity; risk factors of diabetes; T2DM; weight loss; weight management; weight management intervention in Mongolians
4.  Why are there race/ethnic differences in adult body mass index–adiposity relationships? A quantitative critical review 
Summary
Body mass index (BMI) is now the most widely used measure of adiposity on a global scale. Nevertheless, intense discussion centers on the appropriateness of BMI as a phenotypic marker of adiposity across populations differing in race and ethnicity. BMI-adiposity relations appear to vary significantly across race/ethnic groups, but a collective critical analysis of these effects establishing their magnitude and underlying body shape/composition basis is lacking. Accordingly, we systematically review the magnitude of these race-ethnic differences across non-Hispanic (NH) white, NH black and Mexican American adults, their anatomic body composition basis and potential biologically linked mechanisms, using both earlier publications and new analyses from the US National Health and Nutrition Examination Survey. Our collective observations provide a new framework for critically evaluating the quantitative relations between BMI and adiposity across groups differing in race and ethnicity; reveal new insights into BMI as a measure of adiposity across the adult age-span; identify knowledge gaps that can form the basis of future research and create a quantitative foundation for developing BMI-related public health recommendations.
doi:10.1111/obr.12358
PMCID: PMC4968570  PMID: 26663309
Adiposity; allometric analysis; body composition; body shape; nutritional assessment
5.  Trace element analysis of human urine collected after administration of Gd-based MRI contrast agents: characterizing spectral interferences using inorganic mass spectrometry 
Analysis of human urine is commonly used in biomonitoring studies to assess exposure to essential (e.g., Cu, Zn, Se) and non-essential (Pb, Cd, Pt) trace elements. These data are also used in epidemiological studies to evaluate potential associations between trace element exposure and various health outcomes within a population. Today most trace element analyses are typically performed using quadrupole-based inductively coupled plasma mass spectrometry (Q-ICP-MS). However, there is always the potential for spectral interferences with Q-ICP-MS instrumentation, especially when analyzing human specimens that may contain medications and other exogenous substances. Moreover, such xenobiotics may be unknown to the investigators.
In a recent study focusing on environmental exposures and endometriosis: Endometriosis: Natural History, Diagnosis, and Outcomes (ENDO Study), urine specimens (n=619) were collected from participating women upon enrollment into the study or prior to surgery or pelvic magnetic resonance imaging (MRI), and analyzed for 21 trace elements by Q-ICP-MS. Here we report on some anomalous results observed for Se and Pt with elevated concentrations up to several orders of magnitude greater than what might be expected based on established reference intervals. Further investigations using Sector Field (SF-) ICP-MS instrumentation led to identification of doubly charged and polyatomic gadolinium (Gd) species traced to a Gd-based contrast agent that was administered to some subjects just prior to urine collection. Specifically, interferences from Gd2+ and several minor polyatomics were identified as interferences on all of the major isotopes of Se including 74Se, 76Se, 77Se, 78Se, 80Se, and 82Se. While trace amounts of Pt were present in the urine, a number of Gd-containing polyatomic species were also evident as major interferences on all isotopes of Pt (190Pt, 192Pt, 194Pt, 195Pt, 196Pt, and 198Pt), including Gd-chlorides, Gd-argides, and Gd-oxides. These observations underscore the importance of considering potential isobaric interferences when interpreting unusual trace element results for clinical specimens.
doi:10.1039/C3JA30331D
PMCID: PMC4935091  PMID: 27397951
6.  Persistent organic pollutants (POPs) and fibroids: results from the ENDO Study 
To evaluate the association between persistent organic pollutants (POPs) and uterine fibroids we used previously collected data from a cohort of women 18–44 years of age undergoing laparoscopy or laparotomy at 14 participating hospital surgical centers (n=473). POP concentrations were measured in omental fat and serum. Presence of fibroids was defined based on a postoperative diagnosis (n=99). Odds ratios (OR) and 95% confidence interval (CI) for each POP by biologic medium was estimated using unconditional logistic regression adjusted for identified covariates. Concentrations were higher in omental fat than in serum for all POPs. Serum p,p′-dichlorodiphenyldichloroethylene (p,p′-DDE) was the only POP associated with fibroids [per 1-SD increase in log-transformed p,p′-DDE OR (95% CI): 1.37 (1.05–1.80)]. In analyses excluding women diagnosed with endometriosis, a number of polychlorinated biphenyls (PCBs) measured in omental fat were associated with fibroids [PCB 99: 1.64 (1.08, 2.49); PCB 138: 1.64 (1.03, 2.59); PCB 146: 1.54 (1.01, 2.37); PCB 153: 1.88 (1.12, 3.13); PCB 196: 1.60 (1.02, 2.51); PCB 206: 1.52 (1.01, 2.29)]. Although exploratory, our study suggests that PCBs may be associated with fibroids in the absence of other gynecologic disorders such as endometriosis, but the associations varied by biologic media with more POPs emerging when quantified in fat.
doi:10.1038/jes.2014.31
PMCID: PMC4410838  PMID: 24802554
epidemiology; uterine fibroids; persistent organic pollutants; omental fat; serum
7.  Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia 
The Pharmacogenomics Journal  2015;15(4):372-379.
The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of anti-cancer drugs. We hypothesized that variants of ABCB1 affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL). We studied 522 Danish children with ALL, 93% of all those eligible. Risk of relapse was increased 2.9-fold for patients with the 1199GA variant versus 1199GG (P=0.001), and reduced 61% and 40%, respectively, for patients with the 3435CT or 3435TT variants versus 3435CC (overall P=0.02). The degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was more prominent in patients with 3435TT variant versus 3435CT/3435CC (P=0.01/P<0.0001). We observed more liver toxicity after high-dose methotrexate in patients with 3435CC variant versus 3435CT/TT (P=0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms, efficacy and toxicity in the treatment of ALL, and ABCB1 1199G>A may be a new possible predictive marker for outcome in childhood ALL.
doi:10.1038/tpj.2014.81
PMCID: PMC4762905  PMID: 25582575
8.  An Immunocompetent, Orthotopic Mouse Model of Epithelial Ovarian Cancer Utilizing Tissue Engineered Tumor Cell Sheets 
Despite the development of a myriad of anticancer drugs that appeared promising in preclinical ovarian cancer animal models, they failed to predict efficacy in clinical testing. To improve the accuracy of preclinical testing of efficacy and toxicity, including pharmacokinetic and pharmacodynamic evaluations, a novel animal model was developed and characterized. In this study, murine ID8 (epithelial ovarian cancer [EOC]) cells as injected cell suspensions (ICS) and as intact cultured monolayer cell sheets (CS) were injected or surgically grafted, respectively, into the left ovarian bursa of 6–8 week-old, female C57BL/6 black mice and evaluated at 8 and 12 weeks after engraftment. Tumor volumes at 8 weeks were as follows: 30.712±18.800 mm3 versus 55.837±10.711 mm3 for ICS and CS, respectively, p=0.0990 (n=5). At 12 weeks, tumor volumes were 128.129±44.018 mm3 versus 283.953±71.676 mm3 for ICS and CS, respectively, p=0.0112 (n=5). The ovarian weights at 8 and 12 weeks were 0.02138±0.01038 g versus 0.04954±0.00667 g for ICS and CS, respectively (8 weeks), p=0.00602 (n=5); and 0.10594±0.03043 g versus 0.39264±0.09271 g for ICS and CS, respectively (12 weeks), p=0.0008 (n=5). These results confirm a significant accelerated tumorigenesis in CS-derived tumors compared with ICS-derived tumors when measured by tumor volume/time and ovarian weight/time. Furthermore, the CS-derived tumors closely replicated the metastatic spread found in human EOC and histopathological identity with the primary tumor of origin.
doi:10.1089/ten.tec.2014.0040
PMCID: PMC4291163  PMID: 24745555
9.  Increased urinary cobalt and whole blood concentrations of cadmium and lead in women with uterine leiomyomata: Findings from the ENDO Study 
Multiple trace elements have estrogen receptor activity, but the association of these elements with uterine leiomyoma has not been defined. A cohort of 473 women aged 18–44 undergoing surgery for benign gynecologic indications provided whole blood and urine specimens for trace element analysis, which was performed by inductively coupled plasma mass spectrometry. The surgeon documented whether fibroids were present. Geometric mean concentrations were compared between women with and without fibroids, and logistic regression models were generated to assess the impact of the concentration of each trace element on the odds of fibroids. In multivariate regressions, odds of a fibroid diagnosis was higher with increased whole blood cadmium (AOR 1.44, 95% CI 1.02, 2.04) and lead (AOR 1.31 95% CI 1.02, 1.69), and urine cobalt (AOR 1.31, 95% CI 1.02, 1.70). Increased exposure to trace elements may contribute to fibroid growth, and fibroids may serve as a reservoir for these elements.
doi:10.1016/j.reprotox.2014.06.007
PMCID: PMC4280339  PMID: 24994689
Cadmium; Fibroids; Lead; Leiomyoma; Mercury; Metals; Trace Elements; Toxic Exposures
10.  Design and Characterization of Bioengineered Cancer-Like Stem Cells 
PLoS ONE  2015;10(10):e0141172.
Cancer stem cells (CSCs) are a small subset of cancer cells responsible for maintenance and progression of several types of cancer. Isolation, propagation, and the differentiation of CSCs in the proper stem niches expose the intrinsic difficulties for further studies. Here we show that induced cancer like stem cells (iCLSCs) can be generated by in vitro oncogenic manipulation of mouse embryonic stem cells (mESCs) with well-defined oncogenic elements; SV40 LTg and HrasV12 by using a mouse stem virus long terminal repeat (MSCV-LTR)-based retroviral system. The reprogrammed mESCs using both oncogenes were characterized through their oncogenic gene expression, the enhancement of proliferation, and unhampered maintenance of stem properties in vitro and in vivo. In addition, these transformed cells resulted in the formation of malignant, immature ovarian teratomas in vivo. To successfully further expand these properties to other organs and species, more research needs to be done to fully understand the role of a tumor- favorable microenvironment. Our current study has provided a novel approach to generate induced cancer like stem cells through in vitro oncogenic reprogramming and successfully initiated organ-specific malignant tumor formation in an orthotopic small animal cancer model.
doi:10.1371/journal.pone.0141172
PMCID: PMC4619203  PMID: 26488294
11.  Antitumor Efficacy of Colon-Specific HPMA Copolymer/9-Aminocamptothecin Conjugates in Mice Bearing Human-Colon Carcinoma Xenografts 
Macromolecular bioscience  2009;9(11):1135-1142.
The antitumor activity of a colon-specific N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer – 9-aminocamptothecin (9-AC) conjugate (P-9-AC) was assessed in orthotopic and subcutaneous animal (HT29 xenograft) tumor models. P-9-AC treatment of mice bearing orthotopic colon tumors, with a dose of 3 mg/kg of 9-AC equivalent every other day for 6 weeks, resulted in regression of tumors in 9 of 10 mice. A lower dose of P-9-AC (1.25 mg/kg of 9-AC equivalent) every other day for 8 weeks inhibited subcutaneous tumor growth in all mice. No liver metastases were observed. Colon-specific release of 9-AC from polymer conjugates enhanced antitumor activity and minimized the systemic toxicity.
Graphical abstract
doi:10.1002/mabi.200900147
PMCID: PMC4613765  PMID: 19685500
antitumor efficacy; colon-specific drug delivery; HPMA-copolymer/9-aminocamptothecin conjugate; human-colon carcinoma xenografts
12.  An estrogen-induced endometrial hyperplasia mouse model recapitulating human disease progression and genetic aberrations 
Cancer Medicine  2015;4(7):1039-1050.
Endometrial hyperplasia (EH) is a condition originating from uterine endometrial glands undergoing disordered proliferation including the risk to progress to endometrial adenocarcinoma. In recent years, a steady increase in EH cases among younger women of reproductive age accentuates the demand of therapeutic alternatives, which emphasizes that an improved disease model for therapeutic agents evaluation is concurrently desired. Here, a new hormone-induced EH mouse model was developed using a subcutaneous estradiol (E2)-sustained releasing pellet, which elevates the serum E2 level in mice, closely mimicking the effect known as estrogen dominance with underlying, pathological E2 levels in patients. The onset and progression of EH generated within this model recapitulate a clinically relevant, pathological transformation, beginning with disordered proliferation developing to simple EH, advancing to atypical EH, and then progressing to precancerous stages, all following a chronologic manner. Although a general increase in nuclear progesterone receptor (PR) expression occurred after E2 expression, a total loss in PR was noted in some endometrial glands as disease advanced to simple EH. Furthermore, estrogen receptor (ER) expression in the nucleus of endometrial cells was reduced in disordered proliferation and increased when EH progressed to atypical EH and precancerous stages. This EH model also resembles other pathological patterns found in human disease such as leukocytic infiltration, genetic aberrations in β-catenin, and joint phosphatase and tensin homolog/paired box gene 2 (PTEN/PAX2) silencing. In summary, this new and comprehensively characterized EH model is cost-effective, easily reproducible, and may serve as a tool for preclinical testing of therapeutic agents and facilitate further investigation of EH.
doi:10.1002/cam4.445
PMCID: PMC4529342  PMID: 25809780
Endometrial cancer; endometrial hyperplasia; estrogen; mouse model
13.  Thermosensitive Progesterone Hydrogel: A Safe and Effective New Formulation for Vaginal Application 
Pharmaceutical Research  2015;32(7):2266-2279.
Purpose
The safe and functional delivery of progesterone through the vaginal route remains an unmet clinical need. The purpose of this work is to prepare a new progesterone (P4) gel for vaginal application using a thermosensitive mucoadhesive polymer, glycol chitin (GC).
Method
Thermogelling, mucoadhesive, mechanical, and viscoelastic properties of GC and the new formulation were evaluated using rheometry. In vitro release profile and the bioactivity of P4 were determined using vaginal fluid simulant (VFS) pH 4.2, and PR-reporter gene assay, respectively. In vitro safety of the formulations was tested using (VK2/E6E7) vaginal epithelial cell line and Lactobacillus Crispatus. Finally, in vivo safety and the efficacy of this formulation were evaluated using an endometrial hypoplasia mouse model.
Results
Results shows the aqueous solution of 5%; (w/v) GC loaded with 0.1%; (w/v) P4 prepared in pH 4.2, (GC-P4), forms a thermosensitive mucoadhesive hydrogel and can maintain stable physical properties at 37°C. GC-P4 gel release 50% of P4 in 4 h after exposure to VFS, and no significant decrease in % viability of VK2/E6E7 or Lactobacillus was found after exposure to 5% GC or GC-P4. GC-P4 does not exhibit obvious toxicities to vaginal tissue in vivo even after repeated application. Efficacy studies indicated that GC-P4 was capable of preventing the progression of simple endometrial hyperplasia (SEH) to complex atypical endometrial hyperplasia (CAEH) in vivo.
Conclusions
Results indicates that GC-P4 retains many characteristics for an effective vaginal delivery system for P4. Therefore we believe that GC-P4 formulation is a promising alternative to current vaginal P4 formulation.
Electronic supplementary material
The online version of this article (doi:10.1007/s11095-014-1616-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s11095-014-1616-8
PMCID: PMC4452141  PMID: 25609012
glycol chitin; mucoadhesive; progesterone; thermosensitive; vaginal gel
14.  Trace Elements and Endometriosis: The ENDO Study 
Reproductive toxicology (Elmsford, N.Y.)  2013;0:10.1016/j.reprotox.2013.05.009.
There has been limited study of trace elements and endometriosis. Using a matched cohort design, 473 women aged 18–44 years were recruited into an operative cohort, along with 131 similarly-aged women recruited into a population cohort. Endometriosis was defined as surgically visualized disease in the operative cohort, and magnetic resonance imaging diagnosed disease in the population cohort. Twenty trace elements in urine and three in blood were quantified using inductively coupled plasma mass spectrometry. Logistic regression estimated the adjusted odds (aOR) of endometriosis diagnosis for each element by cohort. No association was observed between any element and endometriosis in the population cohort. In the operative cohort, blood cadmium was associated with a reduced odds of diagnosis (aOR=0.55; 95% CI: 0.31, 0.98), while urinary chromium and copper reflected an increased odds (aOR=1.97; 95% CI: 1.21, 3.19; aOR=2.66; 95% CI: 1.26, 5.64, respectively). The varied associations underscore the need for continued research.
doi:10.1016/j.reprotox.2013.05.009
PMCID: PMC3836840  PMID: 23892002
arsenic; cadmium; chromium; endometriosis; lead; metals; mercury; trace elements
15.  Perfluorochemicals and Endometriosis The ENDO Study 
Epidemiology (Cambridge, Mass.)  2012;23(6):799-805.
Background:
Environmental chemicals may be associated with endometriosis. No published research has focused on the possible role of perfluorochemicals (PFCs) despite their widespread presence in human tissues.
Methods:
We formulated two samples. The first was an operative sample comprising 495 women aged 18–44 years scheduled for laparoscopy/laparotomy at one of 14 participating clinical sites in the Salt Lake City or San Francisco area, 2007–2009. The second was a population-based sample comprising 131 women matched to the operative sample on age and residence within a 50-mile radius of participating clinics. Interviews and anthropometric assessments were conducted at enrollment, along with blood collection for the analysis of nine PFCs, which were quantified using liquid chromatography-tandem mass spectrometry. Endometriosis was defined based on surgical visualization (in the operative sample) or magnetic resonance imaging (in the population sample). Using logistic regression, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for each PFC (log-transformed), adjusting for age and body mass index, and then parity.
Results:
Serum perfluorooctanoic acid (PFOA; OR = 1.89 [95% CI = 1.17–3.06]) and perfluorononanoic acid (2.20 [1.02–4.75]) were associated with endometriosis in the operative sample; findings were moderately attenuated with parity adjustment (1.62 [0.99–2.66] and 1.99 [0.91–4.33], respectively). Perfluorooctane sulfonic acid (1.86 [1.05–3.30]) and PFOA (2.58 [1.18–5.64]) increased the odds for moderate/severe endometriosis, although the odds were similarly attenuated with parity adjustment (OR = 1.50 and 1.86, respectively).
Conclusions:
Select PFCs were associated with an endometriosis diagnosis. These associations await corroboration.
doi:10.1097/EDE.0b013e31826cc0cf
PMCID: PMC4122261  PMID: 22992575
16.  Risk factors associated with endometriosis: importance of study population for characterizing disease in the ENDO Study 
OBJECTIVE
We sought to identify risk factors for endometriosis and their consistency across study populations in the Endometriosis: Natural History, Diagnosis, and Outcomes (ENDO) Study.
STUDY DESIGN
In this prospective matched, exposure cohort design, 495 women aged 18–44 years undergoing pelvic surgery (exposed to surgery, operative cohort) were compared to an age- and residence-matched population cohort of 131 women (unexposed to surgery, populationcohort). Endometriosis was diagnosed visually at laparoscopy/laparotomy or by pelvic magnetic resonance imaging in the operative and population cohorts, respectively. Logistic regression estimated the adjusted odds ratios (AORs) and 95% confidence intervals (CIs) for each cohort.
RESULTS
The incidence of visualized endometriosis was 40% in the operative cohort (11.8% stage 3–4 by revised criteria from the American Society for Reproductive Medicine), and 11% stage 3–4 in the population cohort by magnetic resonance imaging. An infertility history increased the odds of an endometriosis diagnosis in both the operative (AOR, 2.43; 95% CI, 1.57–3.76) and population (AOR, 7.91; 95% CI, 1.69–37.2) cohorts. In the operative cohort only, dysmenorrhea (AOR, 2.46; 95% CI, 1.28–4.72) and pelvic pain (AOR, 3.67; 95% CI, 2.44–5.50) increased the odds of diagnosis, while gravidity (AOR, 0.49; 95% CI, 0.32–0.75), parity (AOR, 0.42; 95% CI, 0.28–0.64), and body mass index (AOR, 0.95; 95% CI, 0.93–0.98) decreased the odds of diagnosis. In all sensitivity analyses for different diagnostic subgroups, infertility history remained a strong risk factor.
CONCLUSION
An infertility history was a consistent risk factor for endometriosis in both the operative and population cohorts of the ENDO Study. Additionally, identified risk factors for endometriosis vary based upon cohort selection and diagnostic accuracy. Finally, endometriosis in the population may be more common than recognized.
doi:10.1016/j.ajog.2013.02.040
PMCID: PMC4114145  PMID: 23454253
Body mass index; dysmenorrhea; endometriosis; epidemiology; infertility; laparoscopy; magnetic resonance imaging; risk factors
17.  Bisphenol A and Phthalates and Endometriosis, The ENDO Study 
Fertility and sterility  2013;100(1):162-169.e2.
Objective
To explore the relation between bisphenol A and 14 phthalate metabolites and endometriosis.
Design
Matched cohort design.
Setting
14 clinical centers in Salt Lake City, Utah or San Francisco, California, 2007–2009.
Patients
The operative cohort comprised 495 women undergoing laparoscopy/laparotomy, while the population cohort comprised 131 women matched on age and residence.
Interventions
None
Main Outcome Measure(s)
Surgically visualized or pelvic magnetic resonance imaging (MRI) diagnosed endometriosis in the two cohorts, respectively.
Results
Odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression adjusting for age, body mass index and creatinine. In the population cohort, six phthalate metabolites (mBP, mCMHP, mECPP, mEHP, mEHHP, and mEOHP) were significantly associated with approximately a twofold increase in the odds of an endometriosis diagnosis. Two phthalates were associated with endometriosis in the operative cohort when restricting to visualized and histologic endometriosis (mOP; OR=1.38; 95% CI 1.10, 1.72), or when restricting comparison women to those with a postoperative diagnosis of a normal pelvis (mEHP; OR=1.35; 95% CI 1.03, 1.78).
Conclusions
Select phthalates were associated with higher odds of an endometriosis diagnosis for women with MRI diagnosed endometriosis. The lack of consistency of findings across cohorts underscores the impact of methodology on findings.
doi:10.1016/j.fertnstert.2013.03.026
PMCID: PMC3700684  PMID: 23579005
Bisphenol A; endometriosis; endocrine disrupting chemicals; epidemiology; phthalates
18.  COMPARATIVE PHARMACOKINETICS OF PAMAM-OH DENDRIMERS AND HPMA COPOLYMERS IN OVARIAN-TUMOR-BEARING MICE 
The purpose of this study was to model data from a head to head comparison of the in vivo fate of hyper-branched PAMAM dendrimers with linear HPMA copolymers in order to understand the influence of molecular weight (MW), hydrodynamic size (Rh) and polymer architecture on biodistribution in tumor-bearing mice using compartmental pharmacokinetic analysis. Plasma concentration data was modeled by two-compartment analysis using Winnonlin® to obtain elimination clearance (E.CL) and plasma exposure (AUCplasma). Renal clearance (CLR) was calculated from urine data collected over 1 week. A plasma-tumor link model was fitted to experimental plasma and tumor data by varying the tumor extravasation (K4, K6) and elimination (K5) rate constants using multivariable constrained optimization solver in Matlab®. Tumor exposures (AUCtumor) were computed from area under the tumor concentration time profile curve by the linear trapezoidal method. Along with MW and Rh, polymer architecture was critical in affecting the blood and tumor pharmacokinetics of the PAMAM-OH dendrimers and HPMA copolymers. Elimination clearance decreased more rapidly with increase in hydrodynamic size for PAMAM-OH dendrimers as compared to HPMA copolymers. HPMA copolymers were eliminated renally to a higher extent than PAMAM-OH dendrimers. These results are suggestive of a difference in extravasation of polymers of varying architecture through the glomerular basement membrane. While the linear HPMA copolymers can potentially reptate through a pore smaller in size than their hydrodynamic radii in a random coil conformation, PAMAM dendrimers have to deform in order to permeate across the pores. With increase in molecular weight or generation, the deforming capacity of PAMAM-OH dendrimers is known to decrease, making it harder for higher generation PAMAM-OH dendrimers to sieve through the glomerulus as compared to HPMA copolymers of comparable molecular weights. PAMAM-OH dendrimer had greater tumor extravsation rate constants and higher tumor to plasma exposure ratios than HPMA copolymers of comparable molecular weights which indicated that in the size range studied, when in circulation, PAMAM-OH dendrimers had a higher affinity to accumulate in the tumor than the HPMA copolymers.
doi:10.1007/s13346-012-0119-6
PMCID: PMC3685189  PMID: 23795337
poly(amido amine) (PAMAM) dendrimer; N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer; polymer architecture; compartmental pharmacokinetics
19.  IN UTERO EXPOSURES AND ENDOMETRIOSIS, THE ENDO STUDY 
Fertility and sterility  2012;99(3):790-795.
Objective
To assess in utero exposures and the odds of an endometriosis diagnosis.
Design
Matched cohort design.
Setting
Fourteen participating clinical centers in geographically defined areas in Utah and California.
Study cohorts
The operative cohort comprised 473 women undergoing laparoscopy/laparotomy, and was matched on age and residence to a population cohort comprising 127 women undergoing pelvic magnetic resonance imaging (MRI), 2007–2009.
Interventions
None
Main outcome measures
Women completed standardized interviews prior to surgery or MRI regarding in utero exposures: mothers’ lifestyle during the index pregnancy, and the index woman’s gestation and birth size. Endometriosis was defined as visually confirmed disease in the operative cohort, and MRI visualized disease in the population cohort. The odds of an endometriosis diagnosis and corresponding 95% confidence intervals (AOR; 95% CI) were estimated for each exposure by cohort using logistic regression and adjusting for current smoking, age at menarche, body mass index, and study site.
Results
Endometriosis was diagnosed in 41% and 11% of women in the operative and population cohorts, respectively. In the primary analysis, AORs were elevated for maternal vitamin usage (1.27; 95% CI =0.85–1.91), maternal cigarette smoking (1.16; 95% CI=0.61–2.24), and low birth weight (1.1; 95% CI=0.92–1.32). Reduced odds were observed for maternal usage of caffeine (0.99; 95% CI=0.64–1.54), alcohol (0.82; 95% CI=0.35–1.94), paternal cigarette smoking (0.72; 95% CI=0.43–1.19) and preterm delivery (0.98; 95% CI=0.47–2.03). Sensitivity analyses mostly upheld the primary results except for a decreased AOR for preterm birth (0.41; 95% CI=0.18–0.94) when restricting to visualized and histologically-confirmed endometriosis in the operative cohort.
Conclusions
In utero exposures were not significantly associated with the odds of an endometriosis diagnosis in either cohort.
doi:10.1016/j.fertnstert.2012.11.013
PMCID: PMC3604121  PMID: 23211710
endometriosis; epidemiology; in utero; ovarian dysgenesis hypothesis
20.  Comparing Apples and Pears: Women's Perceptions of Their Body Size and Shape 
Journal of Women's Health  2012;21(10):1074-1081.
Abstract
Background
Obesity is a growing public health problem among reproductive-aged women, with consequences for chronic disease risk and reproductive and obstetric morbidities. Evidence also suggests that body shape (i.e., regional fat distribution) may be independently associated with risk, yet it is not known if women adequately perceive their shape. This study aimed to assess the validity of self-reported body size and shape figure drawings when compared to anthropometric measures among reproductive-aged women.
Methods
Self-reported body size was ascertained using the Stunkard nine-level figures and self-reported body shape using stylized pear, hourglass, rectangle, and apple figures. Anthropometry was performed by trained researchers. Body size and body mass index (BMI) were compared using Spearman's correlation coefficient. Fat distribution indicators were compared across body shapes for nonobese and obese women using analysis of variance (ANOVA) and Fisher's exact test. Percent agreement and kappa statistics were computed for apple and pear body shapes.
Results
The 131 women studied were primarily Caucasian (81%), aged 32 years, with a mean BMI of 27.1 kg/m2 (range 16.6–52.8 kg/m2). The correlation between body size and BMI was 0.85 (p<0.001). Among nonobese women, waist-to-hip ratios (WHR) were 0.75, 0.75, 0.80, and 0.82 for pear, hourglass, rectangle, and apple, respectively (p<0.001). Comparing apples and pears, the percent agreement (kappa) for WHR≥0.80 was 83% (0.55).
Conclusions
Self-reported size and shape were consistent with anthropometric measures commonly used to assess obesity and fat distribution, respectively. Self-reported body shape may be a useful proxy measure in addition to body size in large-scale surveys.
doi:10.1089/jwh.2012.3634
PMCID: PMC3466911  PMID: 22873752
21.  The Effect of Nicotinamide on Gene Expression in a Traumatic Brain Injury Model 
Microarray-based transcriptional profiling was used to determine the effect of nicotinamide on gene expression in an experimental traumatic brain injury (TBI) model. Ingenuity Pathway Analysis (IPA) was used to evaluate the effect on relevant functional categories and canonical pathways. At 24 h, 72 h, and 7 days, respectively, 70, 58, and 76%, of the differentially expressed genes were up-regulated in the vehicle treated compared to the sham animals. At 24 h post-TBI, there were 150 differentially expressed genes in the nicotinamide treated animals compared to vehicle; the majority (82%) down-regulated. IPA analysis identified a significant effect of nicotinamide on the functional categories of cellular movement, cell-to-cell-signaling, antigen presentation and cellular compromise, function, and maintenance and cell death. The canonical pathways identified were signaling pathways primarily involved with the inflammatory process. At 72 h post-cortical contusion injury, there were 119 differentially expressed genes in the nicotinamide treated animals compared to vehicle; the majority (90%) was up-regulated. IPA analysis identified a significant effect of nicotinamide on cell signaling pathways involving neurotransmitters, neuropeptides, growth factors, and ion channels with little to no effect on inflammatory pathways. At 7 days post-TBI, there were only five differentially expressed genes with nicotinamide treatment compared to vehicle. Overall, the effect of nicotinamide on counteracting the effect of TBI resulted in significantly decreased number of genes differentially expressed by TBI. In conclusion, the mechanism of the effect of nicotinamide on secondary injury pathways involves effects on inflammatory response, signaling pathways, and cell death.
doi:10.3389/fnins.2013.00021
PMCID: PMC3581799  PMID: 23550224
nicotinamide; gene expression; cortical contusion model; traumatic brain injury
22.  Association of 25-hydroxy-vitamin D levels with semen and hormonal parameters 
Asian Journal of Andrology  2012;14(6):855-859.
Vitamin D levels have been linked to various health outcomes including reproductive disorders. The purpose of this study was to explore the association between serum vitamin D level (25-hydroxy-vitamin D, or 25OHD) and semen and hormonal parameters. This is a cross-sectional study that included 170 healthy men recruited for the study of spermatogenesis from the general population. Men completed general and reproductive health questionnaires, and donated blood and semen samples. The main measures were hormonal (total and free testosterone, sex hormone-binding globulin, estradiol, follicle-stimulating hormone and luteinizing hormone) and semen parameters, adjusted (n=147) for age, body mass index (BMI), season, alcohol intake and smoking, in relation to categories of vitamin D levels, determined a priori. The mean age of the study population was 29.0±8.5 years and mean BMI was 24.3±3.2 kg m−2. The mean 25OHD was 34.1±15.06 ng ml−1. BMI showed a negative association with 25OHD. Sperm concentration, sperm progressive motility, sperm morphology, and total progressively motile sperm count were lower in men with ‘25OHD≥50 ng ml−1' when compared to men with ‘20 ng ml−1≤25OHD<50 ng ml−1'. Total sperm count and total progressive motile sperm count were lower in men with ‘25OHD<20 ng ml−1' when compared to men with ‘20 ng ml−1≤25OHD<50 ng ml−1'. The adjusted means of various hormonal parameters did not show statistical difference in the different categories of 25OHD. In conclusion, serum vitamin D levels at high and low levels can be negatively associated with semen parameters.
doi:10.1038/aja.2012.77
PMCID: PMC3720097  PMID: 23042450
low semen count; obesity; semen parameters; vitamin D
23.  COMPARATIVE BIODISTRIBUTION OF PAMAM DENDRIMERS AND HPMA COPOLYMERS IN OVARIAN TUMOR-BEARING MICE 
Biomacromolecules  2010;12(1):88-96.
The biodistribution profile of a series of linear N-(2-hydroxylpropyl)methacrylamide (HPMA) copolymers were compared with that of branched poly (amido amine) dendrimers containing surface hydroxyl groups (PAMAM-OH) in orthotopic ovarian tumor-bearing mice. Below an average molecular weight (MW) of 29 kDa, the HPMA copolymers were smaller than the PAMAM-OH dendrimers of comparable molecular weight. In addition to molecular weight, hydrodynamic size and polymer architecture affected the biodistribution of these constructs. Biodistribution studies were performed by dosing mice with 125Iodine-labeled polymers and collecting all major organ systems, carcass and excreta at defined time points. Radiolabeled polymers were detected in organ systems by measuring gamma emission of the 125Iodine radiolabel. The hyperbranched PAMAM dendrimer, hydroxyl terminated, generation 5 (G5.0-OH) was retained in the kidney over one week while the linear HPMA copolymer of comparable molecular weight was excreted into the urine and did not show persistent renal accumulation. PAMAM dendrimer, hydroxyl terminated, generation 6.0 (G6.0-OH) was taken up by the liver to a higher extent while the HPMA copolymer of comparable molecular weight was observed to have a plasma exposure three times that of this dendrimer. Tumor accumulation and plasma exposure were correlated with the hydrodynamic sizes of the polymers. PAMAM dendrimer, hydroxyl terminated, generation 7.0 (G7.0-OH) showed extended plasma circulation, enhanced tumor accumulation and prolonged retention with the highest tumor/blood ratio for the polymers under study. Head-to-head comparative study of HPMA copolymers and PAMAM dendrimers can guide the rational design and development of carriers based on these systems for delivery of bioactive and imaging agents.
doi:10.1021/bm101046d
PMCID: PMC3476841  PMID: 21128624
PAMAM dendrimers; N-(2-hydroxypropyl)methacrylamide copolymers; enhanced permeability and retention effect; drug delivery; polymer architecture; ovarian tumor
24.  VcR-CVAD induction chemotherapy followed by maintenance rituximab in mantle cell lymphoma: a Wisconsin Oncology Network study 
British journal of haematology  2011;155(2):190-197.
Intensive chemotherapy regimens are not feasible in many adults with mantle cell lymphoma (MCL). We sought to build upon our previous experience with a non-intensive regimen, modified R-hyperCVAD chemotherapy (rituximab, cyclophosphamide, vincristine, doxorubicin, dexamethasone) with maintenance rituximab (MR), by the incorporation of bortezomib (VcR-CVAD) and the extension of MR beyond 2 years. Patients with previously untreated MCL received VcR-CVAD chemotherapy every 21 days for 6 cycles. Patients achieving at least a partial response to induction chemotherapy received rituximab consolidation (375 mg/m2 × 4 weekly doses) and MR (375 mg/m2 every 12 weeks × 20 doses). The primary end points were overall and complete response (CR), and secondary endpoints were progression-free (PFS) and overall survival (OS). Thirty patients were enrolled, with a median age of 61 years. All patients had advanced stage disease, and 60% had medium/high MCL International Prognostic Index risk factors. A CR or unconfirmed CR was achieved in 77% of patients. After a median follow-up of 42 months, the 3-year PFS and OS were 63% and 86%, respectively. The observed 3-year PFS and OS with VcR-CVAD in MCL were comparable to reported outcomes with more intensive regimens. A cooperative group trial (E1405) is attempting to replicate these promising results.
doi:10.1111/j.1365-2141.2011.08820.x
PMCID: PMC3188692  PMID: 21848883
bortezomib; chemotherapy; mantle cell lymphoma; non-Hodgkin lymphoma; rituximab
25.  Incidence of endometriosis by study population and diagnostic method: the ENDO Study 
Fertility and sterility  2011;96(2):360-365.
Study Objective
To estimate the incidence of endometriosis in an operative cohort of women seeking clinical care and in a matched population cohort to delineate more fully the scope and magnitude of endometriosis in the context of and beyond clinical care.
Design
Matched exposure cohort design.
Setting
Surgical centers in the Salt Lake City, Utah and San Francisco, California areas.
Patients
The operative cohort comprised 495 women undergoing laparoscopy/laparotomy between 2007–2009, while the population cohort comprised 131 women from the surgical centers’ catchment areas.
Interventions
None
Main Outcome Measure(s)
Incidence of endometriosis by diagnostic method in the operative cohort and by pelvic magnetic resonance imaged (MRI) disease in the population cohort.
Results
Endometriosis incidence in the operative cohort ranged by two orders of magnitude by diagnostic method: 0.7% for only histology, 7% for only MRI and 41% for visualized disease. Endometriosis staging was skewed toward minimal (58%) and mild disease (15%). The incidence of MRI-diagnosed endometriosis was 11% in the population cohort.
Conclusions
Endometriosis incidence is dependent upon the diagnostic method and choice of sampling framework. Conservatively, 11% of women have undiagnosed endometriosis at the population level with implications for the design and interpretation of etiologic research.
doi:10.1016/j.fertnstert.2011.05.087
PMCID: PMC3143230  PMID: 21719000
Endometriosis; epidemiology; histology; incidence; laparoscopy; magnetic resonance imaging

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