Inhibition of the proline metabolism rate-limiting enzyme P5CS allows proliferation of glutamine-restricted cancer cells.

Glutamine is a critical metabolite for rapidly proliferating cells as it is used for the synthesis of key metabolites necessary for cell growth and proliferation. Glutamine metabolism has been proposed as a therapeutic target in cancer and several chemical inhibitors are in development or in clinical trials. How cells subsist when glutamine is limiting is poorly understood. Here, using an unbiased screen, we identify ALDH18A1, which encodes P5CS, the rate-limiting enzyme in the proline biosynthetic pathway, as a gene that cells can downregulate in response to glutamine starvation. Notably, P5CS downregulation promotes de novo glutamine synthesis, highlighting a previously unrecognized metabolic plasticity of cancer cells. The glutamate conserved from reducing proline synthesis allows cells to produce the key metabolites necessary for cell survival and proliferation under glutamine-restricted conditions. Our findings reveal an adaptive pathway that cancer cells acquire under nutrient stress, identifying proline biosynthesis as a previously unrecognized major consumer of glutamate, a pathway that could be exploited for developing effective metabolism-driven anticancer therapies.

Symmetry Breaking of Human Pluripotent Stem Cells (hPSCs) in Micropattern Generates a Polarized Spinal Cord-Like Organoid (pSCO) with Dorsoventral Organization.

Axis formation and related spatial patterning are initiated by symmetry breaking during development. A geometrically confined culture of human pluripotent stem cells (hPSCs) mimics symmetry breaking and cell patterning. Using this, polarized spinal cord organoids (pSCOs) with a self-organized dorsoventral (DV) organization are generated. The application of caudalization signals promoted regionalized cell differentiation along the radial axis and protrusion morphogenesis in confined hPSC colonies. These detached colonies grew into extended spinal cord-like organoids, which established self-ordered DV patterning along the long axis through the spontaneous expression of polarized DV patterning morphogens. The proportions of dorsal/ventral domains in the pSCOs can be controlled by the changes in the initial size of micropatterns, which altered the ratio of center-edge cells in 2D. In mature pSCOs, highly synchronized neural activity is separately detected in the dorsal and ventral side, indicating functional as well as structural patterning established in the organoids. This study provides a simple and precisely controllable method to generate spatially ordered organoids for the understanding of the biological principles of cell patterning and axis formation during neural development.

Breast arterial calcification is associated with incident atrial fibrillation among older but not younger post-menopausal women.

Aims: The goal of this study was to examine the association of breast arterial calcification (BAC) presence and quantity with incident atrial fibrillation (AF) in a large cohort of post-menopausal women. Methods and results: We conducted a longitudinal cohort study among women free of clinically overt cardiovascular disease and AF at baseline (between October 2012 and February 2015) when they attended mammography screening. Atrial fibrillation incidence was ascertained using diagnostic codes and natural language processing. Among 4908 women, 354 incident cases of AF (7%) were ascertained after a mean (standard deviation) of 7 (2) years of follow-up. In Cox regression adjusting for a propensity score for BAC, BAC presence vs. absence was not significantly associated with AF [hazard ratio (HR) = 1.12; 95% confidence interval (CI), 0.89-1.42; P = 0.34]. However, a significant (a priori hypothesized) age by BAC interaction was found (P = 0.02) such that BAC presence was not associated with incident AF in women aged 60-69 years (HR = 0.83; 95% CI, 0.63-1.15; P = 0.26) but was significantly associated with incident AF in women aged 70-79 years (HR = 1.75; 95% CI, 1.21-2.53; P = 0.003). No evidence of dose-response relationship between BAC gradation and AF was noted in the entire cohort or in age groups separately. Conclusion: Our results demonstrate, for the first time, an independent association between BAC and AF in women over age 70 years.

High-sensitivity troponin I is associated with cardiovascular outcomes but not with breast arterial calcification among postmenopausal women.

Background: Prior studies support the utility of high sensitivity troponin I (hsTnI) for cardiovascular disease (CVD) risk stratification among asymptomatic populations; however, only two prior studies examined women separately. The association between hsTnI and breast arterial calcification is unknown. Methods: Cohort study of 2896 women aged 60-79 years recruited after attending mammography screening between 10/2012 and 2/2015. BAC status (presence versus absence) and quantity (calcium mass mg) was determined using digital mammograms. Pre-specified endpoints were incident coronary heart disease (CHD), ischemic stroke, heart failure and its subtypes and all CVD. Results: After 7.4 (SD = 1.7) years of follow-up, 51 CHD, 30 ischemic stroke and 46 heart failure events were ascertained. At a limit of detection of 1.6 ng/L, 98.3 of the cohort had measurable hsTnI concentration. HsTnI in the 4-10 ng/L range were independently associated of CHD (adjusted hazard ratio[aHR] = 2.78; 95% CI, 1.48-5.22; p = 0.002) and all CVD (aHR = 2.06; 95% CI, 1.37-3.09; p = 0.0005) and hsTnI over 10 ng/L was independently associated with CHD (aHR = 4.75; 95% CI, 1.83-12.3; p = 0.001), ischemic stroke (aHR = 3.81; 95% CI, 1.22-11.9; p = 0.02), heart failure (aHR = 3.29; 95% CI, 1.33-8.13; p = 0.01) and all CVD (aHR = 4.78; 95% CI, 2.66-8.59; p < 0.0001). No significant association was found between hsTnI and BAC. Adding hsTnI to a model containing the Pooled Cohorts Equation resulted in significant and clinical important improved calibration, discrimination (Δ Cindex = 6.5; p = 0.02) and reclassification (bias-corrected clinical NRI = 0.18; 95% CI, -0.13-0.49 after adding hsTnI categories). Conclusions: Our results support the consideration of hsTnI as a risk enhancing factor for CVD in asymptomatic women that could drive preventive or therapeutic decisions.

Breast Arterial Calcification: a Novel Cardiovascular Risk Enhancer Among Postmenopausal Women.

BACKGROUND: Breast arterial calcification (BAC), a common incidental finding in mammography, has been shown to be associated with angiographic coronary artery disease and cardiovascular disease (CVD) outcomes. We aimed to (1) examine the association of BAC presence and quantity with hard atherosclerotic CVD (ASCVD) and global CVD; (2) ascertain model calibration, discrimination and reclassification of ASCVD risk; (3) assess the joint effect of BAC presence and 10-year pooled cohorts equations risk on ASCVD. METHODS: A cohort study of 5059 women aged 60-79 years recruited after attending mammography screening between October 2012 and February 2015 was conducted in a large health plan in Northern California, United States. BAC status (presence versus absence) and quantity (calcium mass mg) was determined using digital mammograms. Prespecified end points were incident hard ASCVD and a composite of global CVD. RESULTS: Twenty-six percent of women had BAC >0 mg. After a mean (SD) follow-up of 6.5 (1.6) years, we ascertained 155 (3.0%) ASCVD events and 427 (8.4%) global CVD events. In Cox regression adjusted for traditional CVD risk factors, BAC presence was associated with a 1.51 (95% CI, 1.08-2.11; P=0.02) increased hazard of ASCVD and a 1.23 (95% CI, 1.002-1.52; P=0.04) increased hazard of global CVD. While there was no evidence of dose-response association with ASCVD, a threshold effect was found for global CVD at very high BAC burden (95th percentile when BAC present). BAC status provided additional risk stratification of the pooled cohorts equations risk. We noted improvements in model calibration and reclassification of ASCVD: the overall net reclassification improvement was 0.12 (95% CI, 0.03-0.14; P=0.01) and the bias-corrected clinical-net reclassification improvement was 0.11 (95% CI, 0.01-0.22; P=0.04) after adding BAC status. CONCLUSIONS: Our results indicate that BAC has potential utility for primary CVD prevention and, therefore, support the notion that BAC ought to be considered a risk-enhancing factor for ASCVD among postmenopausal women.

Heat shock protein 60 couples an oxidative stress-responsive p38/MK2 signaling and NF-κB survival machinery in cancer cells.

Mitochondria communicate with other cellular compartments via the secretion of protein factors. Here, we report an unexpected messenger role for heat shock protein 60 (HSP60) as a mitochondrial-releasing protein factor that couples stress-sensing signaling and cell survival machineries. We show that mild oxidative stress predominantly activates the p38/MK2 complex, which phosphorylates mitochondrial fission factor 1 (MFF1) at the S155 site. Such phosphorylated MFF1 leads to the oligomerization of voltage anion-selective channel 1, thereby triggering the formation of a mitochondrial membrane pore through which the matrix protein HSP60 passes. The liberated HSP60 associates with and activates the IκB kinase (IKK) complex in the cytosol, which consequently induces the NF-κB-dependent expression of survival genes in nucleus. Indeed, inhibition of the HSP60 release or HSP60-IKK interaction sensitizes the cancer cells to mild oxidative stress and regresses the tumorigenic growth of cancer cells in the mouse xenograft model. Thus, this study reveals a novel mitonuclear survival axis responding to oxidative stress.

Cell position within human pluripotent stem cell colonies determines apical specialization via an actin cytoskeleton-based mechanism.

Human pluripotent stem cells (hPSCs) grow as colonies with epithelial-like features including cell polarity and position-dependent features that contribute to symmetry breaking during development. Our study provides evidence that hPSC colonies exhibit position-dependent differences in apical structures and functions. With this apical difference, edge cells were preferentially labeled with amphipathic dyes, which enabled separation of edge and center cells by fluorescence-activated cell sorting. Transcriptome comparison between center and edge cells showed differential expression of genes related to apicobasal polarization, cell migration, and endocytosis. Accordingly, different kinematics and mechanical dynamics were found between center and edge cells, and perturbed actin dynamics disrupted the position-dependent apical polarity. In addition, our dye-labeling approach could be utilized to sort out a certain cell population in differentiated micropatterned colonies. In summary, hPSC colonies have position-dependent differences in apical structures and properties, and actin dynamics appear to play an important role in the establishment of this position-dependent cell polarity.

Ultra-Low-Dose Spectral CT Based on a Multi-level Wavelet Convolutional Neural Network.

Spectral computed tomography (CT) based on a photon-counting detector (PCD) is a promising technique with the potential to improve lesion detection, tissue characterization, and material decomposition. PCD-based scanners have several technical issues including operation in the step-and-scan mode and long data acquisition time. One straightforward solution to these issues is to reduce the number of projection views. However, if the projection data are under-sampled or noisy, it would be challenging to produce a correct solution without precise prior information. Recently, deep-learning approaches have demonstrated impressive performance for under-sampled CT reconstruction. In this work, the authors present a multilevel wavelet convolutional neural network (MWCNN) to address the limitations of PCD-based scanners. Data properties of the proposed method in under-sampled spectral CT are analyzed with respect to the proposed deep-running-network-based image reconstruction using two measures: sampling density and data incoherence. This work presents the proposed method and four different methods to restore sparse sampling. We investigate and compare these methods through a simulation and real experiments. In addition, data properties are quantitatively analyzed and compared for the effect of sparse sampling on the image quality. Our results indicate that both sampling density and data incoherence affect the image quality in the studied methods. Among the different methods, the proposed MWCNN shows promising results. Our method shows the highest performance in terms of various evaluation parameters such as the structural similarity, root mean square error, and resolution. Based on the results of imaging and quantitative evaluation, this study confirms that the proposed deep-running network structure shows excellent image reconstruction in sparse-view PCD-based CT. These results demonstrate the feasibility of sparse-view PCD-based CT using the MWCNN. The advantage of sparse view CT is that it can significantly reduce the radiation dose and obtain images with several energy bands by fusing PCDs. These results indicate that the MWCNN possesses great potential for sparse-view PCD-based CT.

Development of length standard phantom for length measurement correction in x-ray image.

Specific tissue lengths or volumes in x-ray images are measured for diagnostic and therapeutic purposes. Measurements are used to make clinical decisions; however, the accuracy of these measurements has not been studied. In this study, based on the sources of uncertainty, an SI-traceable length standard phantom and an x-ray imaging system calibration method are proposed. The uncertainty in the length of the fabricated standard phantom is determined using a toolmaker's microscope. The sources of uncertainty in an x-ray imaging system, such as magnification, pixel-to-millimeter unit conversion, and penumbra effect, are considered, and the lengths of the phantom before and after imaging system calibration were compared. The maximum deviation of length measurements with and without calibration is (-0.11 ± 0.10) and (-3.37 ± 0.15) mm (k = 2, 95% level of confidence), respectively. The proposed phantom and calibration method can be used for calibrating x-ray images and obtaining their length correction values. Furthermore, length correction values are expected to be useful for diagnosis and treatment planning, where precise length measurements are essential.

Visualization of gross anatomy for ultrasound scanning planes using a virtual dissection table / Visualización de la anatomía macroscópica para planos de escaneo de ultrasonido utilizando una mesa de disección virtual

SUMMARY: There is a lack of visualization on gross anatomy planes for the non-orthogonal sections, such as subcostal and intercostal oblique scanning planes of ultrasound imaging. The aim of the present study was to visualize the anatomical image of corresponding plane for the oblique ultrasound scanning using a virtual dissection system. the oblique gross anatomy plane was constructed by appropriate segmentation using a virtual dissection table. A suitable cutting of the body plane was accomplished by turning on and off the organ systems, particularly the skeletal system, category, and structure. The right hepatic vein (RHV), middle hepatic vein (MHV), and left hepatic vein (LHV) for the right subcostal oblique plane appeared in the single slice plane. The location of the liver, gallbladder, and kidneys differently appeared in the oblique anatomical plane and body position. The results of this study suggest that using a virtual anatomy system contributes to improving the sonographer's ability to understand anatomy.

RESUMEN: Existe una falta de visualización en los planos de anatomía macroscópica para las secciones no ortogonales, tal como los planos de exploración oblicuos subcostales e intercostales en las imágenes de ultrasonido. El objetivo del presente estudio fue visualizar la imagen anatómica del plano correspondiente para la ecografía oblicua mediante un sistema de disección virtual. El plano de anatomía macroscópica oblicua se construyó mediante una adecuada segmentación utilizando una mesa de disección virtual. Se logró un corte correcto del plano corporal al encender y apagar los sistemas de órganos, particularmente el sistema esquelético, la categoría y la estructura. La vena hepática derecha, la vena hepática media y la vena hepática izquierda para el plano oblicuo subcostal derecho aparecieron en el plano de corte único. La ubicación del hígado, la vesícula biliar y los riñones aparecieron de manera diferente en el plano anatómico oblicuo y en la posición del cuerpo. Los resultados de este estudio sugieren que el uso de un sistema de anatomía virtual ayuda a mejorar la capacidad del ecografista para comprender la anatomía humana.

Quantification of water and lipid density with dual-energy mammography: validation in postmortem breasts.

OBJECTIVES: Breast cancer is the most common cancer in women and the second leading cause of cancer death. It is well known that breast density is an important risk factor for breast cancer and also can be used to personalize screening and for assessment of treatment response. Breast density has previously been correlated to volumetric water density. The purpose of this study is to validate the accuracy and precision of dual-energy mammography in measuring water density in postmortem breasts. METHODS: Twenty pairs of postmortem breasts were imaged using dual-energy mammography with energy-sensitive photon-counting detectors. Chemical analysis was used as the reference standard to assess the accuracy of dual-energy mammography in measuring volumetric water and lipid density. Images from different views and contralateral breasts were used to assess estimate of precision for water and lipid volumetric density measurements. RESULTS: The measured volumetric water and lipid density from dual-energy mammography and chemical analysis were in good agreement, where the standard errors of estimates (SEE) of both were calculated to be 2.1%. Volumetric water and lipid density measurements from different views were also in good agreement, with a SEE of 1.3% and 1.1%, respectively. CONCLUSIONS: The results indicate that dual-energy mammography can be used to accurately measure volumetric water and lipid density in breast tissue. Accurate quantification of volumetric water density is expected to enhance its utility as a risk factor for breast cancer and for assessment of response to therapy. KEY POINTS: • Dual-energy mammography can be used to accurately measure water and lipid volumetric density in breast tissue. • Improved quantification of volumetric water density is expected to enhance its utility for assessment of response to therapy and as a risk factor for breast cancer.

Breast Arterial Calcification Is Not Associated with Mild Cognitive Impairment or Incident All-Cause Dementia Among Postmenopausal Women: The MINERVA Study.

Background: Since vascular risk factors are implicated in cognitive decline, and breast arterial calcification (BAC) is related to vascular risk, we postulated that BAC may be associated with cognitive impairment and dementia. Methods: We used a multiethnic cohort of 3,913 asymptomatic women 60-79 years of age recruited after mammography screening at a large health plan in 2012-2015. A BAC mass score (mg) was derived from digital mammograms. Cognitive function was measured at baseline using the Montreal Cognitive Assessment (MoCA) and incident all-cause dementia (n = 49 events; median follow-up = 5.6 years) were ascertained with validated ICD-9 and ICD-10 codes. We used cross-sectional linear regression of MoCA scores on BAC, then multinomial logistic regression predicting mild cognitive impairment not progressing to dementia and incident all-cause dementia and, finally, Cox regression of incident all-cause dementia. Results: No association by linear regression was found between MoCA scores and BAC presence in unadjusted or adjusted analysis. Women with severe (upper tertile) BAC had a MoCA score lower by 0.58 points (standard error [SE] = 0.18) relative to women with no BAC. However, this difference disappeared after multivariate adjustment. No significant associations were found in multinomial logistic regression for either BAC presence or gradation in unadjusted or adjusted analysis. No significant associations were found between BAC presence with incident all-cause dementia (fully adjusted hazard ratio = 0.74; 95% confidence interval: 0.39-1.39). Likewise, no significant association with incident all-cause dementia was noted for BAC gradation. Conclusions: Our results do not support the hypothesis that BAC presence or gradation may contribute to cognitive impairment or development of all-cause dementia.

LEGO-compatible modular mapping phantom for magnetic resonance imaging.

Physical phantoms have been widely used for performance evaluation of magnetic resonance imaging (MRI). Although there are many kinds of physical phantoms, most MRI phantoms use fixed configurations with specific sizes that may fit one or a few different types of radio frequency (RF) coils. Therefore, it has limitations for various image quality assessments of scanning areas. In this article, we report a novel design for a truly customizable MRI phantom called the LEGO-compatible Modular Mapping (MOMA) phantom, which not only serves as a general quality assurance phantom for a wide range of RF coils, but also a flexible calibration phantom for quantitative imaging. The MOMA phantom has a modular architecture which includes individual assessment functionality of the modules and LEGO-type assembly compatibility. We demonstrated the feasibility of the MOMA phantom for quantitative evaluation of image quality using customized module assembly compatible with head, breast, spine, knee, and body coil features. This unique approach allows comprehensive image quality evaluation with wide versatility. In addition, we provide detailed MOMA phantom development and imaging characteristics of the modules.

Molecular cross talk among the components of the regulatory machinery of mitochondrial structure and quality control.

Mitochondrial dysfunction critically impairs cellular health and often causes or affects the progression of several diseases, including neurodegenerative diseases and cancer. Thus, cells must have several ways to monitor the condition of mitochondrial quality and maintain mitochondrial health. Accumulating evidence suggests that the molecular machinery responding to spontaneous changes in mitochondrial morphology is associated with the routine mitochondrial quality control system. In this short review, we discuss recent progress made in linking mitochondrial structural dynamics and the quality control system.

No Association Between Bone Mineral Density and Breast Arterial Calcification Among Postmenopausal Women.

CONTEXT: The association between bone mineral density (BMD) and breast arterial calcification (BAC) remains poorly understood and controversial. OBJECTIVE: The objective of this article is to examine the association between BMD and BAC in a large cohort of postmenopausal women undergoing routine mammography. DESIGN: A cross-sectional analysis of baseline data from a multiethnic cohort was performed. SETTING: The setting for this analysis is an integrated health care delivery system in Northern California in the United States. PATIENTS: A total of 1273 women age 60 to 79 years (mean age, 67 years) were recruited within 12 months of screening mammography. MAIN OUTCOME MEASURE: A BAC score (mg) was obtained from digital mammograms using a novel densitometry method. BAC presence was defined as a BAC score greater than 0 mg, and severe BAC as a BAC score greater than 20 mg. RESULTS: Overall, 53% of women had osteopenia and 21% had osteoporosis. The prevalence of BAC greater than 0 mg was 29%, 30%, and 29% among women with normal BMD, osteopenia, and osteoporosis, respectively (P = 0.98). The prevalence of BAC greater than 20 mg was 5%, 3%, and 5% among women with normal BMD, osteopenia and osteoporosis, respectively (P = .65). The odds ratios (ORs) of BAC greater than 0 mg vs BAC = 0 mg after multivariable adjustment were 1.09 (95% CI, 0.81-1.48; P = .54) for osteopenia and 0.99 (95% CI, 0.69-1.48; P = .98) for osteoporosis. The adjusted ORs for BAC greater than 20 mg vs BAC 20 mg or less were 1.03 (95% CI, 0.52-2.01; P = .93) for osteopenia and 1.89 (95 CI, 0.81-4.47; P = .14) for osteoporosis. CONCLUSION: Our findings do not support an association of either osteopenia or osteoporosis with BAC presence or severity among postmenopausal women.

The coordinated regulation of mitochondrial structure and function by Drp1 for mitochondrial quality surveillance.

Mitochondrial morphology is known to be continuously changing via fusion and fission, but it is unclear what the biological importance of this energy-consuming process is and how it develops. Several data have suggested that mitochondrial fission executed by Drp1 is necessary to select out a damaged spot from the interconnected mitochondrial network, but the precise mechanism for the recognition and isolation of a damaged sub-mitochondrial region during mitochondrial fission is yet unclear. Recently, Cho et al. found that the mitochondrial membrane potential (MMP) is transiently reduced by the physical interaction of Drp1 and mitochondrial Zinc transporter, Zip1, at the fission site prior to the typical mitochondrial division, and we found that this event is essential for a mitochondrial quality surveillance. In this review, Cho et al. discuss the role of a mitochondrial fission in the mitochondrial quality surveillance system. [BMB Reports 2019; 52(2): 109-110].

A monitoring system for axonal growth dynamics using micropatterns of permissive and Semaphorin 3F chemorepulsive signals.

Neurons reach their correct targets by directional outgrowth of axons, which is mediated by attractive or repulsive cues. Growing axons occasionally cross a field of repulsive cues and stop at intermediate targets on the journey to their final destination. However, it is not well-understood how individual growth cones make decisions, and pass through repulsive territory to reach their permissive target regions. We developed a microcontact printing culture system that could trap individual axonal tips in a permissive dot area surrounded by the repulsive signal, semaphorin 3F (Sema3F). Axons of rat hippocampal neurons on the Sema3F/PLL dot array extended in the checkboard pattern with a significantly slow growth rate. The detailed analysis of the behaviors of axonal growth cones revealed the saccadic dynamics in the dot array system. The trapped axonal tips in the permissive area underwent growth cone enlargement with remarkably spiky filopodia, promoting their escape from the Sema3F constraints with straight extension of axons. This structured axonal growth on the dot pattern was disrupted by increased inter-dot distance, or perturbing intracellular signaling machineries. These data indicate that axons grow against repulsive signals by jumping over the repulsive cues, depending on contact signals and intracellular milieu. Our study suggests that our dot array culture system can be used as a screening system to easily and efficiently evaluate ECM or small molecule inhibitors interfering growth cone dynamics leading to controlling axonal growth.

Drp1-Zip1 Interaction Regulates Mitochondrial Quality Surveillance System.

Mitophagy, a mitochondrial quality control process for eliminating dysfunctional mitochondria, can be induced by a response of dynamin-related protein 1 (Drp1) to a reduction in mitochondrial membrane potential (MMP) and mitochondrial division. However, the coordination between MMP and mitochondrial division for selecting the damaged portion of the mitochondrial network is less understood. Here, we found that MMP is reduced focally at a fission site by the Drp1 recruitment, which is initiated by the interaction of Drp1 with mitochondrial zinc transporter Zip1 and Zn2+ entry through the Zip1-MCU complex. After division, healthy mitochondria restore MMP levels and participate in the fusion-fission cycle again, but mitochondria that fail to restore MMP undergo mitophagy. Thus, interfering with the interaction between Drp1 and Zip1 blocks the reduction of MMP and the subsequent mitophagic selection of damaged mitochondria. These results suggest that Drp1-dependent fission provides selective pressure for eliminating "bad sectors" in the mitochondrial network, serving as a mitochondrial quality surveillance system.

Association of Breast Arterial Calcification Presence and Gradation with the Ankle-Brachial Index among Postmenopausal Women.

OBJECTIVE: To examine the association of breast arterial calcification (BAC) with the ankle brachial index (ABI), a sensitive metric of peripheral arterial disease (PAD), among postmenopausal women. Background: BAC is an emerging risk marker of cardiovascular disease (CVD). METHODS: MINERVA (MultIethNic study of brEast aRterial calcium gradation and cardioVAscular disease) is a cohort of women aged 60 to 79 at baseline (10/24/2012 - 2/13/2015) who were free of symptomatic CVD at baseline. The analytical sample comprised 3,800 women with available ABI, BAC assessment and covariates. We performed cross-sectional logistic regression analysis. RESULTS: 203 women (5.3%) had an ABI < 0.90 indicative of PAD, 26 (0.7%) had an ABI > 1.3 and 94% (n=3,571) had an ABI within normal limits. After adjustment for age, race/ethnicity, body mass index, smoking status, diabetes, hypertension, LDL-C, HDL-C, hs-CRP, estimated-GFR, urinary albumin/creatinine ratio, serum calcium, serum vitamin D and serum PTH, BAC presence remained significantly associated with ABI < 0.90 (OR=1.37; 95% CI, 1.01-1.87; p=0.04). After further adjustment for menopausal hormone therapy, parity and history of breast feeding, the association became marginally significant (OR=1.36; 95% CI, 0.99-1.85; p=0.05). No clear pattern of association was observed for increased gradation of BAC and ABI<0.9, and no significant associations were noted between BAC presence vs. absence or BAC gradation with ABI > 1.3. CONCLUSIONS: Among asymptomatic postmenopausal women, presence of BAC was associated with PAD independently of traditional risk factors. Additional prospective studies are required to establish the value of BAC for prediction of incident PAD in the general population.

MultIethNic Study of BrEast ARterial Calcium Gradation and CardioVAscular Disease: cohort recruitment and baseline characteristics.

PURPOSE: MultIethNic Study of BrEast ARterial Calcium Gradation and CardioVAscular Disease (MINERVA) was designed to answer the question of whether a novel continuous breast arterial calcification (BAC) mass score improves cardiovascular risk stratification among asymptomatic postmenopausal women. This article describes recruitment and baseline characteristics. METHODS: MINERVA is a multiethnic longitudinal cohort study. The phenotype data include BAC mass by densitometry applied to digital mammograms, sociodemographic factors, self-reported medical history, medications, parental history, reproductive history, smoking, alcohol consumption, physical activity, anthropometry, ankle-brachial index, blood pressure, laboratory panel, breast volumes, cognitive function, bioelectrical impedance, habitual diet, dietary supplements, sleep, psychosocial factors, and sun exposure. RESULTS: A total of 5145 women aged 60 to 79 years with available digital, uncompressed mammograms were recruited from the membership of Kaiser Permanente of Northern California between October 24, 2012 and February 13, 2015 and completed a baseline clinic visit or an abbreviated phone questionnaire. Of those, 4153 underwent phlebotomy and have blood biomarkers. Overall prevalence of BAC was 26%, and it varied by age and race. The mean (SD) BAC mass was 12 (23) mg and the range 0-342 mg. CONCLUSIONS: MINERVA is the first cohort with a continuous measure of BAC. The cohort is large, ethnically diverse, and deeply phenotyped in terms of socioeconomic, behavioral, and clinical factors, and blood biomarkers.