Multiomic analysis of homologous recombination-deficient end-stage high-grade serous ovarian cancer.

High-grade serous ovarian cancer (HGSC) is frequently characterized by homologous recombination (HR) DNA repair deficiency and, while most such tumors are sensitive to initial treatment, acquired resistance is common. We undertook a multiomics approach to interrogate molecular diversity in end-stage disease, using multiple autopsy samples collected from 15 women with HR-deficient HGSC. Patients had polyclonal disease, and several resistance mechanisms were identified within most patients, including reversion mutations and HR restoration by other means. We also observed frequent whole-genome duplication and global changes in immune composition with evidence of immune escape. This analysis highlights diverse evolutionary changes within HGSC that evade therapy and ultimately overwhelm individual patients.

TRACEBACK: Testing of Historical Tubo-Ovarian Cancer Patients for Hereditary Risk Genes as a Cancer Prevention Strategy in Family Members.

PURPOSE: Tubo-ovarian cancer (TOC) is a sentinel cancer for BRCA1 and BRCA2 pathogenic variants (PVs). Identification of a PV in the first member of a family at increased genetic risk (the proband) provides opportunities for cancer prevention in other at-risk family members. Although Australian testing rates are now high, PVs in patients with TOC whose diagnosis predated revised testing guidelines might have been missed. We assessed the feasibility of detecting PVs in this population to enable genetic risk reduction in relatives. PATIENTS AND METHODS: In this pilot study, deceased probands were ascertained from research cohort studies, identification by a relative, and gynecologic oncology clinics. DNA was extracted from archival tissue or stored blood for panel sequencing of 10 risk-associated genes. Testing of deceased probands ascertained through clinic records was performed with a consent waiver. RESULTS: We identified 85 PVs in 84 of 787 (11%) probands. Familial contacts of 39 of 60 (65%) deceased probands with an identified recipient (60 of 84; 71%) have received a written notification of results, with follow-up verbal contact made in 85% (33 of 39). A minority of families (n = 4) were already aware of the PV. For many (29 of 33; 88%), the genetic result provided new information and referral to a genetic service was accepted in most cases (66%; 19 of 29). Those who declined referral (4 of 29) were all male next of kin whose family member had died more than 10 years before. CONCLUSION: We overcame ethical and logistic challenges to demonstrate that retrospective genetic testing to identify PVs in previously untested deceased probands with TOC is feasible. Understanding reasons for a family member's decision to accept or decline a referral will be important for guiding future TRACEBACK projects.

Impact of Medicaid expansion on women with gynecologic cancer: a difference-in-difference analysis.

BACKGROUND: Women with gynecologic cancer face socioeconomic disparities in care that affect survival outcomes. The Affordable Care Act offered states the option to expand Medicaid enrollment eligibility criteria as a means of improving timely and affordable access to care for the most vulnerable. The variable uptake of expansion by states created a natural experiment, allowing for quasi-experimental methods that offer more unbiased estimates of treatment effects from retrospective data than the traditional regression adjustment. OBJECTIVE: To use a quasi-experimental, difference-in-difference framework to create unbiased estimates of impact of Medicaid expansion on women with gynecologic cancer. STUDY DESIGN: We performed a quasi-experimental retrospective cohort study from the National Cancer Database files for women with invasive cancers of the uterus, ovary and fallopian tube, cervix, vagina, and vulva diagnosed from 2008 to 2016. Using a marker for state Medicaid expansion status, we created difference-in-difference models to assess the impact of Medicaid expansion on the outcomes of access to and timeliness of care. We excluded women aged <40 years owing to the suppression of the state Medicaid expansions status in the data and women aged ≥65 years owing to the universal Medicare coverage availability. Our primary outcome was the rate of uninsurance at diagnosis. Secondary outcomes included Medicaid coverage, early-stage diagnosis, treatment at an academic facility, and any treatment or surgery within 30 days of diagnosis. Models were run within multiple subgroups and on a propensity-matched cohort to assess the robustness of the treatment estimates. The assumption of parallel trends was assessed with event study time plots. RESULTS: Our sample included 335,063 women. Among this cohort, 121,449 were from nonexpansion states and 213,614 were from expansion states, with 79,886 posttreatment cases diagnosed after the expansion took full effect in expansion states. The groups had minor differences in demographics, and we found occasional preperiod event study coefficients diverging from the mean, but the outcome trends were generally similar between the expansion and nonexpansion states in the preperiod, satisfying the necessary assumption for the difference-in-difference analysis. In a basic difference-in-difference model, the Medicaid expansion in January 2014 was associated with significant increases in insurance at diagnosis, treatment at an academic facility, and treatment within 30 days of diagnosis (P<.001 for all). In an adjusted model including all states and accounting for variable expansion implementation time, there was a significant treatment effect of Medicaid expansion on the reduction in uninsurance at diagnosis (-2.00%; 95% confidence interval, -2.3 to -1.7; P<.001), increases in early-stage diagnosis (0.80%; 95% confidence interval, 0.2-1.4; P=.02), treatment at an academic facility (0.83%; 95% confidence interval, 0.1-1.5; P=.02), treatment within 30 days (1.62%; 95% confidence interval, 1.0-2.3; P<.001), and surgery within 30 days (1.54%; 95% confidence interval, 0.8-2.3; P<.001). In particular, large gains were estimated for women living in low-income zip codes, Hispanic women, and women with cervical cancer. Estimates from the subgroup and propensity-matched cohorts were generally consistent for all outcomes besides early-stage diagnosis and treatment within 30 days. CONCLUSION: Medicaid expansion was significantly associated with gains in the access and timeliness of treatment for nonelderly women with gynecologic cancer. The implementation of Medicaid expansion could greatly benefit women in nonexpansion states. Gynecologists and gynecologic oncologists should advocate for Medicaid expansion as a means of improving outcomes and reducing socioeconomic and racial disparities.

The effects of chronic betaine supplementation on body composition and performance in collegiate females: a double-blind, randomized, placebo controlled trial.

BACKGROUND: Betaine supplementation has been shown to improve body composition and some metrics of muscular performance in young men; but, whether betaine enhances body composition or performance in female subjects is currently unknown. Therefore, the purpose of this study was to investigate the interaction between resistance training adaptation and chronic betaine supplementation in females. METHODS: Twenty-three young women (21.0 ± 1.4 years, 165.9 ± 6.4 cm, 68.6 ± 11.8 kg) without prior structured resistance training experience volunteered for this study. Body composition (BodPod), rectus femoris muscle thickness (B-mode Ultrasound), vertical jump, back squat 1RM and bench press 1RM were assessed pre- and post-training. Following 1 week of familiarization training, subjects were matched for body composition and squat strength, and randomly assigned to either a betaine (2.5 g/day; n = 11) or placebo (n = 12) group that completed 3 sets of 6-7 exercises per day performed to momentary muscular failure. Training was divided into two lower and one upper body training sessions per week performed on non-consecutive days for 8 weeks, and weekly volume load was used to analyze work capacity. RESULTS: Significant main effects of time were found for changes in lean mass (2.4 ± 1.8 kg), muscle thickness (0.13 ± 0.08 cm), vertical jump (1.8 ± 1.6 cm), squat 1RM (39.8 ± 14.0 kg), and bench press 1 RM (9.1 ± 7.3 kg); however, there were no significant interactions. A trend (p = .056) was found for greater weekly training volumes for betaine versus placebo. Significant interactions were found for changes in body fat percentage and fat mass: body fat percentage and fat mass decreased significantly more in betaine (- 3.3 ± 1.7%; - 2.0 ± 1.1 kg) compared to placebo (- 1.7 ± 1.6%; - 0.8 ± 1.3 kg), respectively. CONCLUSIONS: The results of this study indicated that betaine supplementation may enhance reductions in fat mass, but not absolute strength, that accompany a resistance training program in untrained collegiate females.

Genomic characterisation of Eµ-Myc mouse lymphomas identifies Bcor as a Myc co-operative tumour-suppressor gene.

The Eµ-Myc mouse is an extensively used model of MYC driven malignancy; however to date there has only been partial characterization of MYC co-operative mutations leading to spontaneous lymphomagenesis. Here we sequence spontaneously arising Eµ-Myc lymphomas to define transgene architecture, somatic mutations, and structural alterations. We identify frequent disruptive mutations in the PRC1-like component and BCL6-corepressor gene Bcor. Moreover, we find unexpected concomitant multigenic lesions involving Cdkn2a loss and other cancer genes including Nras, Kras and Bcor. These findings challenge the assumed two-hit model of Eµ-Myc lymphoma and demonstrate a functional in vivo role for Bcor in suppressing tumorigenesis.

Betaine supplementation enhances anabolic endocrine and Akt signaling in response to acute bouts of exercise.

Our aim was to examine the effect of betaine supplementation on selected circulating hormonal measures and Akt muscle signaling proteins after an acute exercise session. Twelve trained men (age 19.7 ± 1.23 years) underwent 2 weeks of supplementation with either betaine (B) (1.25 g BID) or placebo (P). Following a 2-week washout period, subjects underwent supplementation with the other treatment (B or P). Before and after each 2-week period, subjects performed an acute exercise session (AES). Circulating GH, IGF-1, cortisol, and insulin were measured. Vastus lateralis samples were analyzed for signaling proteins (Akt, p70 S6k, AMPK). B (vs. P) supplementation approached a significant increase in GH (mean ± SD (Area under the curve, AUC), B: 40.72 ± 6.14, P: 38.28 ± 5.54, p = 0.060) and significantly increased IGF-1 (mean ± SD (AUC), B: 106.19 ± 13.45, P: 95.10 ± 14.23, p = 0.010), but significantly decreased cortisol (mean ± SD (AUC), B: 1,079.18 ± 110.02, P: 1,228.53 ± 130.32, p = 0.007). There was no difference in insulin (AUC). B increased resting Total muscle Akt (p = 0.003). B potentiated phosphorylation (relative to P) of Akt (Ser(473)) and p70 S6 k (Thr(389)) (p = 0.016 and p = 0.005, respectively). Phosphorylation of AMPK (Thr(172)) decreased during both treatments (both p = 0.001). Betaine (vs. placebo) supplementation enhanced both the anabolic endocrine profile and the corresponding anabolic signaling environment, suggesting increased protein synthesis.

The effects of chronic betaine supplementation on exercise performance, skeletal muscle oxygen saturation and associated biochemical parameters in resistance trained men.

Trepanowski, JF, Farney, TM, McCarthy, CG, Schilling, BK, Craig, SA, and Bloomer, RJ. The effects of chronic betaine supplementation on exercise performance, skeletal muscle oxygen saturation, and associated biochemical parameters in resistance trained men. J Strength Cond Res 25(12): 3461-3471, 2011-We examined the effects of chronic betaine supplementation on exercise performance and associated parameters in resistance trained men. Men were randomly assigned in a double-blind manner using a crossover design to consume betaine (2.5 g of betaine mixed in 500 ml of Gatorade®) or a placebo (500 ml of Gatorade®) for 14 days, with a 21-day washout period. Before and after each treatment period, tests of lower- and upper-body muscular power and isometric force were conducted, including a test of upper-body muscular endurance (10 sets of bench press exercise to failure). Muscle tissue oxygen saturation (StO2) during the bench press protocol was measured via near infrared spectroscopy. Blood samples were collected before and after the exercise test protocol for analysis of lactate, nitrate/nitrite (NOx), and malondialdehyde (MDA). When analyzed using a repeated measures analysis of variance, no significant differences were noted between conditions for exercise performance variables (p > 0.05). However, an increase in total repetitions (p = 0.01) and total volume load (p = 0.02) in the 10-set bench press protocol was noted with betaine supplementation (paired t-tests), with values increasing approximately 6.5% from preintervention to postintervention. Although not of statistical significance (p = 0.14), postexercise blood lactate increased to a lesser extent with betaine supplementation (210%) compared with placebo administration (270%). NOx was lower postintervention as compared with preintervention (p = 0.06), and MDA was relatively unchanged. The decrease in StO2 during the bench press protocol was greater with betaine vs. placebo (p = 0.01), possibly suggesting enhanced muscle oxygen consumption. These findings indicate that betaine supplementation results in a moderate increase in total repetitions and volume load in the bench press exercise, without favorably impacting other performance measures.

Effect of 15 days of betaine ingestion on concentric and eccentric force outputs during isokinetic exercise.

The purpose of this study was to examine the efficacy of 15 days of betaine supplementation on peak concentric (CON) and eccentric (ECC) force during isokinetic exercise in active college-aged men. Eleven men volunteered for this study (21.7 ± 5.1 years; height: 178.5 ± 6.4 cm; body mass: 79.8 ± 10.3 kg). Subjects were randomly assigned to either a supplement (BET) or placebo (PL) group. Supplementation occurred for 15 days. Subjects reported to the Human Performance Laboratory on 5 occasions during this period, separated by 72 hours, for a testing and exercise session on an isokinetic chest press device. After each exercise protocol, subjects rated their fatigue and muscle soreness on a 15-cm visual analog scale. Subjects then consumed no daily BET for 4 weeks but maintained familiarity with the exercise device once per week. After the washout period, subjects resumed the BET protocol using the opposite drink and repeated the same 15-day protocol. No differences were noted in maximum CON force output between pre (335.9 ± 78.3 and 321.6 ± 63.6 N) and post (330.3 ± 74.8 and 330.2 ± 71.6 N) workouts in both BET and PL, respectively. In addition, no differences were noted in maximum ECC force output between pre (352.0 ± 90.6 and 324.4 ± 85.2 N) and post (353.2 ± 98.2 and 366.9 ± 128.5 N) workouts in BET and PL, respectively. No differences in subjective measures of soreness and fatigue were seen, but a significant reduction in Δ fatigue was observed in BET compared to PL. In conclusion, 15 days of betaine supplementation did not increase peak CON or ECC force outputs during an isokinetic chest press but did appear to reduce subjective measures of fatigue to the exercise protocol.

Influence of betaine consumption on strenuous running and sprinting in a hot environment.

This investigation evaluated the effects of a nutritional supplement (the organic osmolyte betaine) in rehydration solutions, with and without carbohydrate and electrolytes. Ten male runners ((mean +/- SD) age, 20 +/- 2 years; weight, 70.6 +/- 6.8 kg; maximal aerobic power, 63.5 +/- 4.1 mL O2 x kg(-1) x min(-1)) dehydrated to -2.7% of body weight. They next rehydrated to -1.4% of body weight by consuming 1 L fluid during each of four experiments (double-blind, randomized, cross-over design): flavored, non-caloric water (W); W + 5 g x L(-1) betaine (W+B); 6% carbohydrate-electrolyte fluid (C); or C + 5 g x L(-1) betaine (C+B). Subjects then performed prolonged treadmill running (75 minutes at 65%Vo2max) plus a performance sprint to volitional exhaustion (3.1-3.8 minutes at 84%Vo2max) in an environmental chamber (31.1 degrees C, 88.0 degrees F). Only W versus W+B and C versus C+B statistical comparisons were germane to the research questions. Observations indicated that rehydration with fluids containing betaine resulted in significant differences (p < 0.05) of plasma volume, oxygen consumption, plasma lactate concentration, and thermal sensation. The present experiments did not support the use of betaine to improve sprint duration, but nonsignificant trends occurred when betaine trials were compared with non-betaine trials (mean C+B > C by 32 seconds, +16%; mean W+B > W by 38 seconds, +21%). We interpret the increases of both aerobic and anaerobic metabolism (C+B > C) to mean that further investigation of betaine as a nutritional supplement, using other types of exercise, is warranted.

Betaine in human nutrition.

Betaine is distributed widely in animals, plants, and microorganisms, and rich dietary sources include seafood, especially marine invertebrates ( approximately 1%); wheat germ or bran ( approximately 1%); and spinach ( approximately 0.7%). The principal physiologic role of betaine is as an osmolyte and methyl donor (transmethylation). As an osmolyte, betaine protects cells, proteins, and enzymes from environmental stress (eg, low water, high salinity, or extreme temperature). As a methyl donor, betaine participates in the methionine cycle-primarily in the human liver and kidneys. Inadequate dietary intake of methyl groups leads to hypomethylation in many important pathways, including 1) disturbed hepatic protein (methionine) metabolism as determined by elevated plasma homocysteine concentrations and decreased S-adenosylmethionine concentrations, and 2) inadequate hepatic fat metabolism, which leads to steatosis (fatty accumulation) and subsequent plasma dyslipidemia. This alteration in liver metabolism may contribute to various diseases, including coronary, cerebral, hepatic, and vascular diseases. Betaine has been shown to protect internal organs, improve vascular risk factors, and enhance performance. Databases of betaine content in food are being developed for correlation with population health studies. The growing body of evidence shows that betaine is an important nutrient for the prevention of chronic disease.