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Item MAID ready for primetime?: A survey of SGO members regarding medical aid in dying (MAID)(Elsevier, 2021-07-05) Brown, Alaina J.; duPont, Nefertiti; Alvarez, Ronald D.; Spillman, Monique A.; Landrum, Lisa; Lefkowits, Carolyn; Obstetrics and Gynecology, School of MedicineObjectives: To assess SGO members' knowledge, attitudes, and practice patterns regarding Medical Aid In Dying (MAID). Methods: SGO members were surveyed via online survey. The survey included questions regarding demographics, knowledge, attitudes, and practice patterns relating to MAID. Descriptive statistics were calculated. Associations between sociodemographic factors and attitudes related to MAID were analyzed utilizing logistic regression. Results: Of 1,337 invited members, 225 (17%) responded. Median age was 46. Most were female (58%), white (81%), and in academic practice (64%). Over 50% had heard the term MAID and have had a patient ask about it. Few (20%) reported living in a state where MAID is legal and 61% of these respondents provided MAID. Sixty percent lived in a state that had not legalized MAID and 18% did not know if MAID was legal in their state. 36% of respondents living in a state where MAID was illegal/unknown legality indicated they would provide MAID if it were legal in their state, 30% would not, and 34% were uncertain. The majority (69%) of respondents believed MAID should be legal. Female respondents were more likely to support legalization of MAID (OR 2.44, p=<0.05). Respondents practicing in the southern U.S. were less likely to support legalization of MAID (OR 0.42, p=<0.05). Over 75% of respondents stated an SGO position statement on MAID would be helpful. Conclusions: MAID is a highly relevant topic for gynecologic oncologists. Gaps in MAID-related knowledge exist among SGO members and there is a desire for additional education and guidance regarding MAID.Item A phase II trial of bevacizumab and rucaparib in recurrent carcinoma of the cervix or endometrium(Elsevier, 2022) Jackson, C. G.; Moore, K. N.; Cantrell, L.; Erickson, B. K.; Duska, L. R.; Richardson, D. L.; Landrum, L. M.; Holman, L. L.; Walker, J. L.; Mannel, R. S.; Moxley, K. M.; Queimado, L.; Cohoon, A.; Ding, K.; Dockery, L. E.; Obstetrics and Gynecology, School of MedicineObjective: The aim of this study was to examine the tolerability and efficacy of combination bevacizumab rucaparib therapy in patients with recurrent cervical or endometrial cancer. Patients & methods: Thirty-three patients with recurrent cervical or endometrial cancer were enrolled. Patients were required to have tumor progression after first line treatment for metastatic, or recurrent disease. Rucaparib was given at 600 mg BID twice daily for each 21-day cycle. Bevacizumab was given at 15 mg/kg on day 1 of each 21-day cycle. The primary endpoint was efficacy as determined by objective response rate or 6-month progression free survival. Results: Of the 33 patients enrolled, 28 were evaluable. Patients with endometrial cancer had a response rate of 17% while patients with cervical cancer had a response rate of 14%. Median progression free survival was 3.8 months (95% C·I 2.5 to 5.7 months), and median overall survival was 10.1 months (95% C·I 7.0 to 15.1 months). Patients with ARID1A mutations displayed a better response rate (33%) and 6-month progression free survival (PFS6) rate (67%) than the entire study population. Observed toxicity was similar to that of previous studies with bevacizumab and rucaparib. Conclusions: The combination of bevacizumab with rucaparib did not show significantly increased anti-tumor activity in all patients with recurrent cervical or endometrial cancer. However, patients with ARID1A mutations had a higher response rate and PFS6 suggesting this subgroup may benefit from the combination of bevacizumab and rucaparib. Further study is needed to confirm this observation. No new safety signals were seen.Item A role for zinc transporter gene SLC39A12 in the nervous system and beyond(Elsevier, 2021) Davis, Danielle N.; Strong, Morgan D.; Chambers, Emily; Hart, Matthew D.; Bettaieb, Ahmed; Clarke, Stephen L.; Smith, Brenda J.; Stoecker, Barbara J.; Lucas, Edralin A.; Lin, Dingbo; Chowanadisai, Winyoo; Obstetrics and Gynecology, School of MedicineThe SLC39A12 gene encodes the zinc transporter protein ZIP12, which is expressed across many tissues and is highly abundant in the vertebrate nervous system. As a zinc transporter, ZIP12 functions to transport zinc across cellular membranes, including cellular zinc influx across the plasma membrane. Genome-wide association and exome sequencing studies have shown that brain susceptibility-weighted magnetic resonance imaging (MRI) intensity is associated with ZIP12 polymorphisms and rare mutations. ZIP12 is required for neural tube closure and embryonic development in Xenopus tropicalis. Frog embryos depleted of ZIP12 by antisense morpholinos develop an anterior neural tube defect and lack viability. ZIP12 is also necessary for neurite outgrowth and mitochondrial function in mouse neural cells. ZIP12 mRNA is increased in brain regions of schizophrenic patients. Outside of the nervous system, hypoxia induces ZIP12 expression in multiple mammalian species, including humans, which leads to endothelial and smooth muscle thickening in the lung and contributes towards pulmonary hypertension. Other studies have associated ZIP12 with other diseases such as cancer. Given that ZIP12 is highly expressed in the brain and that susceptibility-weighted MRI is associated with brain metal content, ZIP12 may affect neurological diseases and psychiatric illnesses such as Parkinson's disease, Alzheimer's disease, and schizophrenia. Furthermore, the induction of ZIP12 and resultant zinc uptake under pathophysiological conditions may be a critical component of disease pathology, such as in pulmonary hypertension. Drug compounds that bind metals like zinc may be able to treat diseases associated with impaired zinc homeostasis and altered ZIP12 function.Item Long-Term Efficacy and Safety of RNAi-Mediated Virus Resistance in ‘HoneySweet’ Plum(Frontiers Media, 2021-10-12) Singh, Khushwant; Callahan, Ann M.; Smith, Brenda J.; Malinowski, Tadeusz; Scorza, Ralph; Jarošová, Jana; Beoni, Eva; Polák, Jaroslav; Kundu, Jiban Kumar; Dardick, Chris; Obstetrics and Gynecology, School of MedicineInterfering RNA technology has been established as an effective strategy to protect plants against viral infection. Despite this success, interfering RNA (RNAi) has rarely been applied due to the regulatory barriers that confront genetically engineered plants and concerns over possible environmental and health risks posed by non-endogenous small RNAs. 'HoneySweet' was developed as a virus-resistant plum variety that is protected by an RNAi-mediated process against Sharka disease caused by the plum pox virus. 'HoneySweet' has been approved for cultivation in the United States but not in countries where the plum pox virus is endemic. In this study, we evaluated the long-term efficacy of virus resistance in 'HoneySweet,' the nature and stability of its sRNA profile, and the potential health risks of consuming 'HoneySweet' plums. Graft-challenged 'HoneySweet' trees carrying large non-transgenic infected limbs remained virus-free after more than 10 years in the field, and the viral sequences from the non-transgenic infected limbs showed no evidence of adaptation to the RNAi-based resistance. Small RNA profiling revealed that transgene-derived sRNA levels were stable across different environments and, on average, were more than 10 times lower than those present in symptom-less fruits from virus-infected trees. Comprehensive 90-day mouse feeding studies showed no adverse health impacts in mice, and there was no evidence for potential siRNA off-target pathologies predicted by comparisons of the most abundant transgene-derived sRNAs to the mouse genome. Collectively, the data confirmed that RNAi provides a highly effective, stable, and safe strategy to combat virus diseases in crop plants.Item Pulse Supplementation Improves Gut Health and Lowers Total Cholesterol in Postmenopausal Women(Elsevier, 2022) Orphan, Jessica; Alake, Sanmi; Keirns, Bryant; Ice, John; Smith, Brenda; Emerson, Sam; Lucas, Edralin; Obstetrics and Gynecology, School of MedicineObjectives: Menopause is associated with many physiological changes as well as increased risk of obesity, cardiovascular disease, type 2 diabetes, and gut-related diseases (i.e. irritable bowel syndrome, inflammatory bowel disease, colon cancer). Data regarding the use of pulse crops in alleviating health risks associated with menopause are limited. This study investigated the effects of pulse supplementation on markers of gut health and metabolic outcomes in postmenopausal women. Methods: Thirty-five postmenopausal (≥1 year without menstruation) women, ages 45–70 years old, who were not on hormone replacement therapy, probiotics, antibiotics, multiple supplements, or medications that affect lipids or glucose, were recruited for this clinical study. Study participants were asked to consume 100 g of pulses (alternate between chickpeas, kidney beans, pinto beans, black-eyed peas, and lentils) daily for 12 wks, and to maintain their normal diet and lifestyle. Anthropometric measures including body composition by dual-energy X-ray absorptiometry, plasma lipids and glucose, fecal short chain fatty acids (SCFAs), and stool characteristics (Bristol Stool Chart and the Cleveland Clinic Constipation Scoring System) were assessed before and at the end of 12-wk supplementation. P < 0.05 was considered statistically significant. Results: There were no differences in anthropometric measures and plasma glucose at the end of the 12-wk supplementation compared to baseline. However, a reduction in plasma total cholesterol (p = 0.039) and LDL-C (p = 0.026), but an increase in both VLDL-C (p = 0.031) and triglycerides (p = 0.033) were observed with pulse supplementation. Constipation score significantly improved (p = 0.003) but no change in stool quality were observed with pulse supplementation. Fecal acetic acid (p< 0.001), n-butyric (p = 0.038), n-caproic (p = 0.004) and total SCFAs (p = 0.001) were also significantly increased with pulse supplementation. Conclusions: Our findings demonstrate that 12 wks of pulse supplementation improved markers of gut health and lowers total- and LDL-cholesterol in postmenopausal women. This population who are at an increased risk for cardiovascular and gut-related diseases can benefit from regularly consuming pulses.Item Understanding How Sex Influences the Impact of IL-10 on Bone Microarchitecture and Bone Metabolism Over Time(Elsevier, 2021) Price, Payton; Perez, Leo; Hatter, Bethany; Robinson, Kara; Islam, Proapa; Alake, Sanmi; Ice, John; Lucas, Edralin; Smith, Brenda; Obstetrics and Gynecology, School of MedicineObjectives: Dietary interventions with pre- and probiotics favorably affect the gut-bone axis, mediated in part by the anti-inflammatory cytokine, interleukin (IL)-10. This study sought to understand how IL-10’s impact on bone metabolism and microarchitecture differs with sex and time. Methods: Six-week-old B6.129P2-Il10tm1Cgn/J (KO) and C57BL/6 (WT) mice were assigned in a 2 × 2 × 2 factorial design with strain (WT & KO), sex, and time (3 & 6 m) as factors. Mice were fed AIN-93G diet for 3 m followed by AIN-93 M for the study duration. Dual-energy x-ray absorptiometry was used to assess bone mineral content (BMC) and density (BMD). Micro-computed tomography was used to assess femur and lumbar vertebrae trabecular and cortical bone. Serum procollagen 1 intact N-terminal propeptide (P1NP) and C-terminal telopeptide of type I collagen (CTX-1), bone formation and resorption markers respectively, were assessed by ELISA. Data were analyzed using ANOVA; p < 0.05 was considered significant. Results: Reductions in BMC and BMD (P < 0.05) in KO vs WT and at 3 vs 6 m were observed; a sex effect was found with reductions in BMC in KO females compared to KO males. Femoral trabecular bone volume (BV/TV) was lower (P < 0.05) in KO vs WT, females vs males, and at 6 vs 3 m. Trabecular thickness (TbTh) decreased (P < 0.05) in KO vs WT and increased from 3 to 6 m, while decreases in trabecular number (TbN) were greater (P < 0.05) in KO mice, females, and at 6 m compared to counterparts. Cortical area and thickness were decreased (P < 0.05) in KO vs WT and in females vs males, which was greater at 6 m, while cortical bone porosity was higher in KO vs WT and increased at 6 mo. Vertebral trabecular BV/TV was lower (P < 0.05) in KO vs WT at 3 and 6 m, with KO females showing reduced BV/TV (P < 0.05) from 3 to 6 m. Reduced TbTh and TbN were observed in KO vs WT, and females had increased (P < 0.05) TbTh and trabecular separation and reduced TbN. P1NP showed a time effect (P < 0.05) with reductions in WT females and males at 6 m compared to 3 m KO females (P < 0.05). CTX-1 shows a sex effect (P < 0.05) and a trending strain effect (P = 0.059), with elevated serum CTX-1 in 3 m KO males compared to WT and KO females at 6 m (P < 0.05). Conclusions: While IL-10 plays an important role in maintaining both trabecular and cortical bone, it may have a more protective effect on the cortical bone of female mice over time.Item Loss of Interleukin (IL)-10 Is Associated With Increased Vascular Inflammation and Sex-Differences in Metabolic Outcomes of Normal Diet-Fed Mice(Elsevier, 2021) Alake, Sanmi; Ojo, Babajide; Kaur, Amritpal; Hermann, Evan; Ice, John; Chowanadisai, Winyoo; Lin, Dingbo; Smith, Brenda; Lucas, Edralin; Obstetrics and Gynecology, School of MedicineObjectives: The anti-inflammatory cytokine, IL-10, plays an important role in reducing the risk of many inflammatory diseases. This study investigated the time and sex effects of IL-10 gene deletion on metabolic risk factors that contribute to the development of cardiovascular disease. Methods: Six-wk-old male and female B6.129P2-Il10tm1Cgn/J (IL-10–/–) and C57BL/6 (WT) mice (n = 12–16/group) were randomly assigned to 12- or 24-wk time points and were fed growth (AIN-93G) diet up to 3 m of age and then maintenance diet (AIN-93M) for the remainder of the study. Monthly fasting glucose was assessed as well as intraperitoneal glucose tolerance test (ipGTT), body composition, and serum metabolic parameters at each study end point. Cardiac and vascular adhesion molecules, macrophage marker F4/80, and sterol metabolism genes were assessed using qPCR. Data were analyzed using t-test and 2-way ANOVA with strain and gender as factors, and α = 0.05. Results: IL-10 deletion resulted in weight loss (p < 0.05) coinciding with reduced fat mass and % fat (P < 0.05) in both sexes of IL-10–/–. Loss of IL-10 had no effect on fasting glucose at any time point in either sex; however, a delayed response to glucose challenge and increased AUC with the ipGTT (P < 0.05) occurred in male IL-10–/– vs WT mice. No strain effect was observed on serum lipids at 12 wks, but cholesterol and high-density lipoprotein (HDL)-C were reduced (P < 0.05) in IL-10–/– vs WT mice at 24 wks. Only male IL-10–/– mice exhibited elevated (P < 0.05) non-HDL cholesterol and tended (P = 0.072) to have elevated triglycerides vs WT mice at 24 wks. In conjunction with serum lipid changes, male IL-10–/– mice increased (P < 0.05) hepatic transcription of β-hydroxy β-methylglutaryl-CoA (HMG-CoA), whereas HMGCoA transcript tended to be repressed (≥ –53.5%; P = 0.08) in female IL-10–/– vs WT mice. At 12 and 24 wks, IL-10–/– exhibited increased (P < 0.05) circulating c-reactive protein and aortic and cardiac gene expression of VCAM-1, ICAM-1, and iNOS. The only increase in the F4/80 macrophage marker occurred in male IL-10–/– mice vs WT at 24 wks. Conclusions: Loss of IL-10 was associated with different metabolic responses in male and female mice and could be detrimental to cholesterol-mediated metabolic processes in female mice on a control diet.Item Dietary Supplementation With Montmorency Tart Cherries and Exercise Improves Lean Mass in Older C57BL/6 Mice(Elsevier, 2021) Robinson, Kara; Hatter, Bethany; Washburn, Karley; Bothwell, James; Anderson, Kendall; Lin, Dingbo; Lucas, Edralin; Smith, Brenda; Obstetrics and Gynecology, School of MedicineObjectives: Sarcopenia, the progressive loss of muscle mass and strength, accelerates with age. Current recommendations to prevent sarcopenia focus on exercise and protein intake. Tart cherry (TC) has shown beneficial effects on muscle recovery following exercise. In this study, we investigated the effects of TC alone and in combination with exercise on lean mass, mitochondrial biogenesis, and oxidative stress in young compared to older mice. Methods: In two cohorts (6 & 52 wk-old), female C57BL/6 mice were randomly assigned to 4 groups in a 2 × 2 factorial design with diet (AIN-93 control or TC supplemented at 10% w/w) and exercise as factors. Exercise consisted of treadmill running for 30 min, 5 d/wk, at 12 m/min and a 5° incline. Food intake was recorded daily and body weights weekly. After 8 wks, body composition was assessed using dual-energy x-ray absorptiometry. The gastrocnemius muscle was collected for protein analysis. Western blotting techniques were used to probe for superoxide dismutase 2 (SOD2) and peroxisome proliferator-activated receptor-gamma coactivator 1-alpha (PGC1a), indicators of oxidative stress and mitochondrial biogenesis. Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was used as loading control. Data were analyzed using 2-way ANOVA with α = 0.05. Results: In young mice, TC had no effect on body weight and % lean mass, but led to decreased (P < 0.05) % fat mass compared to controls. Exercise decreased (P < 0.05) body weight and % fat, and tended to increase (P = 0.069) % lean mass. In contrast, TC and exercise independently decreased body weight and % fat, and increased % lean mass in older mice compared to controls. The combination of TC and exercise tended to have a synergistic effect on % lean mass (P = 0.056). Preliminary results show that TC significantly up-regulated SOD2 protein expression in young mice, but no effect was observed with exercise or combined treatments. PGC1α expression tended to be suppressed (P = 0.064) in young animals fed TC. To date, we have been unable to detect changes in SOD2 and PGC1α in older mice. Conclusions: TC had a protective effect on lean tissue in older mice, preliminary analyses revealed no alterations in oxidative stress or mitochondrial biogenesis. Further investigation is warranted to understand the benefits of TC on lean muscle mass in older mice.Item Zeaxanthin Drives Dynamic Changes in the Mouse Metabolome Through Gut Microbiome Shift(Elsevier, 2021) Lu, Peiran; Wong, Siau Yen; Chai, Jianmin; Jasbi, Paniz; Wu, Lei; Lyu, Yi; Tang, Minghua; Smith, Brenda; Lucas, Edralin; Clarke, Stephen L.; Chowanadisai, Winyoo; Shen, Xinchun; He, Hui; Zhao, Jiangchao; Gu, Haiwei; Conway, Tyrrell; Wyss, Adrian; Lin, Dingbo; Obstetrics and Gynecology, School of MedicineObjectives: Zeaxanthin, an oxygenized carotenoid, exerts antioxidant properties in human nutrition and metabolism. Like other carotenoids, zeaxanthin is poorly absorbed in the small intestine. The large portion of zeaxanthin reaches the colon and is not fully recovered in the colon. In this study, we aimed to investigate the association of zeaxanthin intake with the gut microbiome homeostasis and metabolomic responses in mice. Methods: Six-week-old male and female C57BL/6J wild type (WT), beta-carotene oxygenase 2 (BCO2) knockout mice were fed with AIN93M chow diets supplemented with or without zeaxanthin (0.02% w/w) for 10 weeks. At the termination of the study, mice were fasted for 3 hrs prior to euthanization. Cecal contents, colon, serum, feces, and other tissues were collected for laboratory assessments.16S rRNA sequencing and LC-MS/MS were performed for gut microbiota profiling and serum and fecal metabolomics analysis, respectively. Results: Significant zeaxanthin accumulation occurred in BCO2 KO, but not WT mice. Zeaxanthin accumulation was associated with the alteration of colonic gut microbiota composition, for example, zeaxanthin-increased abundance in Lachnospiraceae, Proteobacteria, and Parabacteroides, indicating enhanced short-chain production, improved intestinal integrity, and anaerobic bacterial colonization. The results of fecal and serum metabolomics revealed that zeaxanthin significantly altered tyrosine metabolism, branched-chain fatty acid oxidation, fatty acid biosynthesis, and phospholipid biosynthesis, and suppressed levels of kynurenine and trimethylamine N-oxide (TMAO). Conclusions: The results suggested that zeaxanthin accumulation promotes gut microbiome homeostasis and alters the gut microbial metabolites as signals in stimulating the host-gut microbe interplay.Item Transversus abdominis plane (TAP) blocks for prevention of postoperative pain in women undergoing laparoscopic and robotic gynaecological surgery(Cochrane Library, 2022-11-21) Pickett, Charlotte; Patanwala, Insiyyah; Kasper, Kelly; Haas, David M.; Obstetrics and Gynecology, School of MedicineObjective: We sought to determine the effect of a subcostal transversus abdominis plane (TAP) block with liposomal bupivacaine on postoperative maximal pain score and length of hospital stay among women undergoing robotic-assisted hysterectomy. Methods: This was a retrospective study comparing patients before and after consistent implementation of TAP blocks with liposomal bupivacaine during robotic-assisted hysterectomies at a single academic institution. Analysis compared patient demographic and operative characteristics by TAP block use, along with outcomes of interest, including postoperative pain and length of hospital stay. Results: There was a statistically significant decrease in maximal numerical rating scale pain scores, presence of nausea and vomiting, and length of hospital stay in those who had a TAP block with liposomal bupivacaine compared with those who did not receive a TAP block. These differences remained even after adjustment for potential confounders. Conclusions: In this retrospective study, liposomal bupivacaine used in a TAP block was a useful method to provide postoperative pain control in patients undergoing robotic-assisted hysterectomy and was associated with lower postoperative maximal pain scores and length of hospital stay.