The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Abstract: Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PALB2, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and p.Arg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM−/− patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

Transforming the Muncie Mall into a Community Sustainability Hub

Students in this course have worked to develop proposals to transform the Muncie Mall into a sustainability center for the Muncie community. Interdisciplinary student teams used specialized disciplinary knowledge and skills to plan projects that they have presented and discussed with local business and government leaders

Body-composition changes in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE)-2 study: A 2-y randomized controlled trial of calorie restriction in nonobese humans

Background: Calorie restriction (CR) retards aging and increases longevity in many animal models. However, it is unclear whether CR can be implemented in humans without adverse effects on body composition.Objective: We evaluated the effect of a 2-y CR regimen on body composition including the influence of sex and body mass index (BMI; in kg/m2) among participants enrolled in CALERIE-2 (Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy), a multicenter, randomized controlled trial.Design: Participants were 218 nonobese (BMI: 21.9-28.0) adults aged 21-51 y who were randomly assigned to 25% CR (CR, n = 143) or ad libitum control (AL, n = 75) in a 2:1 ratio. Measures at baseline and 12 and 24 mo included body weight, waist circumference, fat mass (FM), fat-free mass (FFM), and appendicular mass by dual-energy X-ray absorptiometry; activity-related energy expenditure (AREE) by doubly labeled water; and dietary protein intake by self-report. Values are expressed as means ± SDs.Results: The CR group achieved 11.9% ± 0.7% CR over 2-y and had significant decreases in weight (-7.6 ± 0.3 compared with 0.4 ± 0.5 kg), waist circumference (-6.2 ± 0.4 compared with 0.9 ± 0.5 cm), FM (-5.4 ± 0.3 compared with 0.5 ± 0.4 kg), and FFM (-2.0 ± 0.2 compared with -0.0 ± 0.2 kg) at 24 mo relative to the AL group (all between-group P < 0.001). Moreover, FFM as a percentage of body weight at 24 mo was higher, and percentage of FM was lower in the CR group than in the AL. AREE, but not protein intake, predicted preservation of FFM during CR (P < 0.01). Men in the CR group lost significantly more trunk fat (P = 0.03) and FFM expressed as a percentage of weight loss (P < 0.001) than women in the CR group.Conclusions: Two years of CR had broadly favorable effects on both whole-body and regional adiposity that could facilitate health span in humans. The decrements in FFM were commensurate with the reduced body mass; although men in the CR group lost more FFM than the women did, the percentage of FFM in the men in the CR group was higher than at baseline. CALERIE was registered at clinicaltrials.gov as NCT00427193

The FANCM:p.Arg658* truncating variant is associated with risk of triple-negative breast cancer

Breast cancer is a common disease partially caused by genetic risk factors. Germline pathogenic variants in DNA repair genes BRCA1, BRCA2, PAM, ATM, and CHEK2 are associated with breast cancer risk. FANCM, which encodes for a DNA translocase, has been proposed as a breast cancer predisposition gene, with greater effects for the ER-negative and triple-negative breast cancer (TNBC) subtypes. We tested the three recurrent protein-truncating variants FANCM:p.Arg658*, p.Gln1701*, and pArg1931* for association with breast cancer risk in 67,112 cases, 53,766 controls, and 26,662 carriers of pathogenic variants of BRCA1 or BRCA2. These three variants were also studied functionally by measuring survival and chromosome fragility in FANCM(-/-) patient-derived immortalized fibroblasts treated with diepoxybutane or olaparib. We observed that FANCM:p.Arg658* was associated with increased risk of ER-negative disease and TNBC (OR = 2.44, P = 0.034 and OR = 3.79; P = 0.009, respectively). In a country-restricted analysis, we confirmed the associations detected for FANCM:p.Arg658* and found that also FANCM:p.Arg1931* was associated with ER-negative breast cancer risk (OR = 1.96; P = 0.006). The functional results indicated that all three variants were deleterious affecting cell survival and chromosome stability with FANCM:p.Arg658* causing more severe phenotypes. In conclusion, we confirmed that the two rare FANCM deleterious variants p.Arg658* and p.Arg1931* are risk factors for ER-negative and TNBC subtypes. Overall our data suggest that the effect of truncating variants on breast cancer risk may depend on their position in the gene. Cell sensitivity to olaparib exposure, identifies a possible therapeutic option to treat FANCM-associated tumors

A Bayesian reanalysis of the Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial

Background Timing of initiation of kidney-replacement therapy (KRT) in critically ill patients remains controversial. The Standard versus Accelerated Initiation of Renal-Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial compared two strategies of KRT initiation (accelerated versus standard) in critically ill patients with acute kidney injury and found neutral results for 90-day all-cause mortality. Probabilistic exploration of the trial endpoints may enable greater understanding of the trial findings. We aimed to perform a reanalysis using a Bayesian framework. Methods We performed a secondary analysis of all 2927 patients randomized in multi-national STARRT-AKI trial, performed at 168 centers in 15 countries. The primary endpoint, 90-day all-cause mortality, was evaluated using hierarchical Bayesian logistic regression. A spectrum of priors includes optimistic, neutral, and pessimistic priors, along with priors informed from earlier clinical trials. Secondary endpoints (KRT-free days and hospital-free days) were assessed using zero–one inflated beta regression. Results The posterior probability of benefit comparing an accelerated versus a standard KRT initiation strategy for the primary endpoint suggested no important difference, regardless of the prior used (absolute difference of 0.13% [95% credible interval [CrI] − 3.30%; 3.40%], − 0.39% [95% CrI − 3.46%; 3.00%], and 0.64% [95% CrI − 2.53%; 3.88%] for neutral, optimistic, and pessimistic priors, respectively). There was a very low probability that the effect size was equal or larger than a consensus-defined minimal clinically important difference. Patients allocated to the accelerated strategy had a lower number of KRT-free days (median absolute difference of − 3.55 days [95% CrI − 6.38; − 0.48]), with a probability that the accelerated strategy was associated with more KRT-free days of 0.008. Hospital-free days were similar between strategies, with the accelerated strategy having a median absolute difference of 0.48 more hospital-free days (95% CrI − 1.87; 2.72) compared with the standard strategy and the probability that the accelerated strategy had more hospital-free days was 0.66. Conclusions In a Bayesian reanalysis of the STARRT-AKI trial, we found very low probability that an accelerated strategy has clinically important benefits compared with the standard strategy. Patients receiving the accelerated strategy probably have fewer days alive and KRT-free. These findings do not support the adoption of an accelerated strategy of KRT initiation

Regional Practice Variation and Outcomes in the Standard Versus Accelerated Initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) Trial: A Post Hoc Secondary Analysis.

ObjectivesAmong patients with severe acute kidney injury (AKI) admitted to the ICU in high-income countries, regional practice variations for fluid balance (FB) management, timing, and choice of renal replacement therapy (RRT) modality may be significant.DesignSecondary post hoc analysis of the STandard vs. Accelerated initiation of Renal Replacement Therapy in Acute Kidney Injury (STARRT-AKI) trial (ClinicalTrials.gov number NCT02568722).SettingOne hundred-fifty-three ICUs in 13 countries.PatientsAltogether 2693 critically ill patients with AKI, of whom 994 were North American, 1143 European, and 556 from Australia and New Zealand (ANZ).InterventionsNone.Measurements and main resultsTotal mean FB to a maximum of 14 days was +7199 mL in North America, +5641 mL in Europe, and +2211 mL in ANZ (p p p p p p p p = 0.007).ConclusionsAmong STARRT-AKI trial centers, significant regional practice variation exists regarding FB, timing of initiation of RRT, and initial use of continuous RRT. After adjustment, such practice variation was associated with lower ICU and hospital stay and 90-day mortality among ANZ patients compared with other regions