A quality improvement initiative standardizing the antibiotic treatment and feeding practices in patients with medical necrotizing enterocolitis.

OBJECTIVE: Evaluate the impact of a multidisciplinary guideline standardizing antibiotic duration and enteral feeding practices following medical necrotizing enterocolitis (mNEC). STUDY DESIGN: For preterm infants with Bell Stage 2 A mNEC and negative blood culture, antibiotic treatment was standardized to 7 days. Trophic feeds of unfortified human milk began 72 h after resolution of pneumatosis. Feeds were advanced by 20 cc/kg/day starting on the last day of antibiotics. Primary outcomes were antibiotic days and days to full feeds, defined as 120 cc/kg/day of enteral nutrition. Secondary outcomes included central line days and length of stay (LOS). RESULTS: Antibiotic duration decreased 23%. Time to start trophic feeds and time to full feeds decreased 33 and 16% respectively. Central line use dropped (98 to 72% of infants) and central line days were reduced by 59%. CONCLUSION: Implementation of a mNEC QI package reduced antibiotic duration, time to full feeds, central line use and CL days.

Utility of Postnatal Chest X-Ray in Newborns for the Evaluation of Prenatally Suspected Congenital Pulmonary Airway Malformation: A Single-Center Experience.

OBJECTIVE: The aim of the study is to assess the necessity of chest X-ray (CXR) during the newborn hospitalization for all patients with prenatally suspected congenital pulmonary airway malformation (CPAM). STUDY DESIGN: This is a retrospective chart review of all infants delivered with prenatally suspected CPAM at our high-risk delivery hospital from January 2013 through April 2020 (n = 44). Nonparametric tests assessed the association between postnatal CXR findings, prescribed follow-up timeline, and neonatal outcomes. RESULTS: Mean follow-up period recommended was 6.4 weeks regardless of CXR findings in the neonatal period (p = 0.81). Additionally, patients who required respiratory support at or after birth were not more likely to have a lesion identified on chest X-ray (odds ratio [OR] = 0.72, 95% confidence interval [CI], 0.18-2.64, p = 0.71). CONCLUSION: Neonatal hospital course and future follow-up plan of patients with prenatally suspected CPAM were not altered by information from the CXR obtained in the immediate neonatal period, suggesting that this CXR may not be necessary in the asymptomatic patient. KEY POINTS: · Immediate postnatal X-ray of prenatally diagnosed CPAM does not alter planned follow-up interval.. · Immediate postnatal X-ray does not alter surgical plan for CPAM.. · Postnatal X-ray is not absolutely required for asymptomatic newborns with CPAM..

Types and spatial contexts of neighborhood greenery matter in associations with weight status in women across 28 U.S. communities.

Excess body weight is a risk factor for many chronic diseases. Studies have identified neighborhood greenery as supportive of healthy weight. However, few have considered plausible effect pathways for ecosystem services (e.g., heat mitigation, landscape aesthetics, and venues for physical activities) or potential variations by climate. This study examined associations between weight status and neighborhood greenery that capture ecosystem services most relevant to weight status across 28 U.S. communities. Weight status was defined by body mass index (BMI) reported for 6591 women from the U.S. Sister Study cohort. Measures of greenery within street and circular areas at 500 m and 2000 m buffer distances from homes were derived for each participant using 1 m land cover data. Street area was defined as a 25 m-wide zone on both sides of street centerlines multiplied by the buffer distances, and circular area was the area of the circle centered on a home within each of the buffer distances. Measures of street greenery characterized the pedestrian environment to capture physically and visually accessible greenery for shade and aesthetics. Circular greenery was generated for comparison. Greenery types of tree and herbaceous cover were quantified separately, and a combined measure of tree and herbaceous cover (i.e., aggregate greenery) was also included. Mixed models accounting for the clustering at the community level were applied to evaluate the associations between neighborhood greenery and the odds of being overweight or obese (BMI > 25) with adjustment for covariates selected using gradient boosted regression trees. Analyses were stratified by climate zone (arid, continental, and temperate). Tree cover was consistently associated with decreased odds of being overweight or obese. For example, the adjusted odds ratio [AOR] was 0.92, 95% Confidence Interval [CI]: 0.88-0.96, given a 10% increase in street tree cover at the 2000 m buffer across the 28 U.S. communities. These associations held across climate zones, with the lowest AOR in the arid climate (AOR: 0.74, 95% CI: 0.54-1.01). In contrast, associations with herbaceous cover varied by climate zone. For the arid climate, a 10% increase in street herbaceous cover at the 2000 m buffer was associated with lower odds of being overweight or obese (AOR: 0.75, 95% CI: 0.55-1.03), whereas the association was reversed for the temperate climate, the odds increased (AOR: 1.19, 95% CI: 1.05-1.35). Associations between greenery and overweight/obesity varied by type and spatial context of greenery, and climate. Our findings add to a growing body of evidence that greenery design in urban planning can support public health. These findings also justify further defining the mechanism that underlies the observed associations.

Clinical Course for Patients With Trisomy 13 and 18 Pursuing Life-Prolonging Therapies Versus Comfort-Directed Care.

BACKGROUND: Care for infants with Trisomy 13 and 18 is evolving with more children being offered medical and surgical interventions. Parents and clinicians of children diagnosed with trisomy 13 and 18 would benefit from understanding how parental goals of care correlate with the subsequent clinical course of children with these conditions. OBJECTIVE: To describe and compare parental goals of care (GOC) and clinical course in infants with trisomy 13 and 18. DESIGN: Single center, retrospective (2013-19) analysis of electronic health record repository at a birthing center and a tertiary care hospital. MEASUREMENTS: ICD-9/10 codes were used to identify patients with trisomy 13 or 18 born between 2013-2019. Their records were abstracted for their diagnosis, hospitalization days, interventions, GOC, death location and length of life. RESULT: Twenty-eight total patients were identified; trisomy 13, mosaic trisomy 13 and trisomy 18 were diagnosed in 9, 2 and 17 patients respectively. Among the 26 patients with complete trisomy 13 or 18, 8 had life-prolonging and 18 had comfort care goals at birth/diagnosis. Life-prolonging goals were not associated with longer life (p = 0.36) but were associated with more mean hospital days (70 vs. 12, p = 0.01), ICU days (66 vs. 9, p = 0.009), intubation (7/8 vs 7/18, p = 0.04), and death in ICU (7/7 vs. 10/17, p = 0.02). Zero patients underwent cardiac surgery. CONCLUSION: Parental GOC did not affect length of life in children with complete trisomy, but did alter treatment intensity. This may inform decision making for patients with trisomy 13 or 18.

How do natural features in the residential environment influence women's self-reported general health? Results from cross-sectional analyses of a U.S. national cohort.

BACKGROUND: The relationship between health and human interaction with nature is complex. Here we conduct analyses to provide insights into potential health benefits related to residential proximity to nature. OBJECTIVES: We aimed to examine associations between measures of residential nature and self-reported general health (SRGH), and to explore mediation roles of behavioral, social, and air quality factors, and variations in these relationships by urbanicity and regional climate. METHODS: Using residential addresses for 41,127 women from the Sister Study, a U.S.-based national cohort, we derived two nature exposure metrics, canopy and non-gray cover, using Percent Tree Canopy and Percent Developed Imperviousness from the National Land Cover Database. Residential circular buffers of 250 m and 1250 m were considered. Gradient boosted regression trees were used to model the effects of nature exposure on the odds of reporting better SRGH (Excellent/Very Good versus the referent, Good/Fair/Poor). Analyses stratified by urbanicity and regional climate (arid, continental, temperate) and mediation by physical activity, social support, and air quality were conducted. RESULTS: A 10% increase in canopy and non-gray cover within 1250 m buffer was associated with 1.02 (95% CI: 1.00-1.03) and 1.03 (95% CI: 1.01-1.04) times the odds of reporting better SRGH, respectively. Stronger associations were observed for the urban group and for continental climate relative to other strata. Social support and physical activity played a more significant mediation role than air quality for the full study population. DISCUSSION: Findings from this study identified a small but important beneficial association between residential nature and general health. These findings could inform community planning and investments in neighborhood nature for targeted health improvements and potential societal and environmental co-benefits.

Associations between types of greenery along neighborhood roads and weight status in different climates.

Obesity is a major international health concern. Neighborhood greenery has been identified as a critical factor for promoting health in urban areas, due in part to its apparent role in facilitating healthy weight by promoting physical activity. However, studies have used diverse greenery measures and spatial analysis units to ascertain this relationship. This study examined associations between street greenery and weight status at the residential address level across 500 to 2000m buffers in two climatically distinct communities, Phoenix, AZ, and Portland, OR. Greenery was measured using one-meter landcover data. Street greenery measures were designed to quantify the pedestrian environment along a gradient of suitability for promoting physical exercise. Weight status was defined by body mass index (BMI) calculated from weight and height information on driver's license records. BMI values were dichotomized at 25 into overweight or obese vs. neither. Approximately 500,000 BMI values in Phoenix and 225,000 in Portland were modelled by community using logistic regression. Street tree cover was consistently protective for healthy weight status across all buffer sizes after adjusting for potential confounders. Herbaceous street cover showed protective associations in Phoenix but harmful associations in Portland. Every 10% increase in street tree cover within 2000m was associated with 18% lower odds of being overweight or obese (adjusted odds ratio [AOR]: 0.82, 95% CI: 0.81 - 0.84 in Phoenix; 0.82, 95% CI: 0.81 - 0.83 in Portland). When compared to residents with less than 10% street tree cover within 2000m, those with greater than 10% tree cover had at least 13% (AOR for Portland: 0.87, 95% CI: 0.81 - 0.92) lower odds of being overweight or obese. Findings support the importance of urban street trees in very different climates for facilitating healthy weight status. They can inform greenery management to prioritize vegetation type and allocation decisions in limited urban spaces.

Myc and ChREBP transcription factors cooperatively regulate normal and neoplastic hepatocyte proliferation in mice.

Analogous to the c-Myc (Myc)/Max family of bHLH-ZIP transcription factors, there exists a parallel regulatory network of structurally and functionally related proteins with Myc-like functions. Two related Myc-like paralogs, termed MondoA and MondoB/carbohydrate response element-binding protein (ChREBP), up-regulate gene expression in heterodimeric association with the bHLH-ZIP Max-like factor Mlx. Myc is necessary to support liver cancer growth, but not for normal hepatocyte proliferation. Here, we investigated ChREBP's role in these processes and its relationship to Myc. Unlike Myc loss, ChREBP loss conferred a proliferative disadvantage to normal murine hepatocytes, as did the combined loss of ChREBP and Myc. Moreover, hepatoblastomas (HBs) originating in myc-/-, chrebp-/-, or myc-/-/chrebp-/- backgrounds grew significantly more slowly. Metabolic studies on livers and HBs in all three genetic backgrounds revealed marked differences in oxidative phosphorylation, fatty acid ß-oxidation (FAO), and pyruvate dehydrogenase activity. RNA-Seq of livers and HBs suggested seven distinct mechanisms of Myc-ChREBP target gene regulation. Gene ontology analysis indicated that many transcripts deregulated in the chrebp-/- background encode enzymes functioning in glycolysis, the TCA cycle, and ß- and ω-FAO, whereas those dysregulated in the myc-/- background encode enzymes functioning in glycolysis, glutaminolysis, and sterol biosynthesis. In the myc-/-/chrebp-/- background, additional deregulated transcripts included those involved in peroxisomal ß- and α-FAO. Finally, we observed that Myc and ChREBP cooperatively up-regulated virtually all ribosomal protein genes. Our findings define the individual and cooperative proliferative, metabolic, and transcriptional roles for the "Extended Myc Network" under both normal and neoplastic conditions.

Exploring links between greenspace and sudden unexpected death: A spatial analysis.

Greenspace has been increasingly recognized as having numerous health benefits. However, its effects are unknown concerning sudden unexpected death (SUD), commonly referred to as sudden cardiac death, which constitutes a large proportion of mortality in the United States. Because greenspace can promote physical activity, reduce stress and buffer air pollutants, it may have beneficial effects for people at risk of SUD, such as those with heart disease, hypertension, and diabetes mellitus. Using several spatial techniques, this study explored the relationship between SUD and greenspace. We adjudicated 396 SUD cases that occurred from March 2013 to February 2015 among reports from emergency medical services (EMS) that attended out-of-hospital deaths in Wake County (central North Carolina, USA). We measured multiple greenspace metrics in each census tract, including the percentages of forest, grassland, average tree canopy, tree canopy diversity, near-road tree canopy and greenway density. The associations between SUD incidence and these greenspace metrics were examined using Poisson regression (non-spatial) and Bayesian spatial models. The results from both models indicated that SUD incidence was inversely associated with both greenway density (adjusted risk ratio [RR] = 0.82, 95% credible/ confidence interval [CI]: 0.69-0.97) and the percentage of forest (adjusted RR = 0.90, 95% CI: 0.81-0.99). These results suggest that increases in greenway density by 1 km/km2 and in forest by 10% were associated with a decrease in SUD risk of 18% and 10%, respectively. The inverse relationship was not observed between SUD incidence and other metrics, including grassland, average tree canopy, near-road tree canopy and tree canopy diversity. This study implies that greenspace, specifically greenways and forest, may have beneficial effects for people at risk of SUD. Further studies are needed to investigate potential causal relationships between greenspace and SUD, and potential mechanisms such as promoting physical activity and reducing stress.

Genetic Dissociation of Glycolysis and the TCA Cycle Affects Neither Normal nor Neoplastic Proliferation.

Rapidly proliferating cells increase glycolysis at the expense of oxidative phosphorylation (oxphos) to generate sufficient levels of glycolytic intermediates for use as anabolic substrates. The pyruvate dehydrogenase complex (PDC) is a critical mitochondrial enzyme that catalyzes pyruvate's conversion to acetyl coenzyme A (AcCoA), thereby connecting these two pathways in response to complex energetic, enzymatic, and metabolic cues. Here we utilized a mouse model of hepatocyte-specific PDC inactivation to determine the need for this metabolic link during normal hepatocyte regeneration and malignant transformation. In PDC "knockout" (KO) animals, the long-term regenerative potential of hepatocytes was unimpaired, and growth of aggressive experimental hepatoblastomas was only modestly slowed in the face of 80%-90% reductions in AcCoA and significant alterations in the levels of key tricarboxylic acid (TCA) cycle intermediates and amino acids. Overall, oxphos activity in KO livers and hepatoblastoma was comparable with that of control counterparts, with evidence that metabolic substrate abnormalities were compensated for by increased mitochondrial mass. These findings demonstrate that the biochemical link between glycolysis and the TCA cycle can be completely severed without affecting normal or neoplastic proliferation, even under the most demanding circumstances. Cancer Res; 77(21); 5795-807. ©2017 AACR.

Vegetated land cover near residence is associated with reduced allostatic load and improved biomarkers of neuroendocrine, metabolic and immune functions.

BACKGROUND: Greater exposure to urban green spaces has been linked to reduced risks of depression, cardiovascular disease, diabetes and premature death. Alleviation of chronic stress is a hypothesized pathway to improved health. Previous studies linked chronic stress with a biomarker-based composite measure of physiological dysregulation known as allostatic load. OBJECTIVE: This study's objective was to assess the relationship between vegetated land cover near residences and allostatic load. METHODS: This cross-sectional population-based study involved 206 adult residents of the Durham-Chapel Hill, North Carolina metropolitan area. Exposure was quantified using high-resolution metrics of trees and herbaceous vegetation within 500m of each residence derived from the U.S. Environmental Protection Agency's EnviroAtlas land cover dataset. Eighteen biomarkers of immune, neuroendocrine, and metabolic functions were measured in serum or saliva samples. Allostatic load was defined as a sum of potentially unhealthy biomarker values dichotomized at 10th or 90th percentile of sample distribution. Regression analysis was conducted using generalized additive models with two-dimensional spline smoothing function of geographic coordinates, weighted measures of vegetated land cover allowing decay of effects with distance, and geographic and demographic covariates. RESULTS: An inter-quartile range increase in distance-weighted vegetated land cover was associated with 37% (95% Confidence Limits 46%; 27%) reduced allostatic load; significantly reduced adjusted odds of having low level of norepinephrine, dopamine, and dehydroepiandrosterone, and high level of epinephrine, fibrinogen, vascular cell adhesion molecule-1, and interleukin-8 in serum, and α-amylase in saliva; and reduced odds of previously diagnosed depression. CONCLUSIONS: The observed effects of vegetated land cover on allostatic load and individual biomarkers are consistent with prevention of depression, cardiovascular disease and premature mortality.

Rethinking Environmental Protection: Meeting the Challenges of a Changing World.

SUMMARY: From climate change to hydraulic fracturing, and from drinking water safety to wildfires, environmental challenges are changing. The United States has made substantial environmental protection progress based on media-specific and single pollutant risk-based frameworks. However, today's environmental problems are increasingly complex and new scientific approaches and tools are needed to achieve sustainable solutions to protect the environment and public health. In this article, we present examples of today's environmental challenges and offer an integrated systems approach to address them. We provide a strategic framework and recommendations for advancing the application of science for protecting the environment and public health. We posit that addressing 21st century challenges requires transdisciplinary and systems approaches, new data sources, and stakeholder partnerships. To address these challenges, we outline a process driven by problem formulation with the following steps: a) formulate the problem holistically, b) gather and synthesize diverse information, c) develop and assess options, and d) implement sustainable solutions. This process will require new skills and education in systems science, with an emphasis on science translation. A systems-based approach can transcend media- and receptor-specific bounds, integrate diverse information, and recognize the inextricable link between ecology and human health.

Evidence that Subanesthetic Doses of Ketamine Cause Sustained Disruptions of NMDA and AMPA-Mediated Frontoparietal Connectivity in Humans.

Following the discovery of the antidepressant properties of ketamine, there has been a recent resurgence in the interest in this NMDA receptor antagonist. Although detailed animal models of the molecular mechanisms underlying ketamine's effects have emerged, there are few MEG/EEG studies examining the acute subanesthetic effects of ketamine infusion in man. We recorded 275 channel MEG in two experiments (n = 25 human males) examining the effects of subanesthetic ketamine infusion. MEG power spectra revealed a rich set of significant oscillatory changes compared with placebo sessions, including decreases in occipital, parietal, and anterior cingulate alpha power, increases in medial frontal theta power, and increases in parietal and cingulate cortex high gamma power. Each of these spectral effects demonstrated their own set of temporal dynamics. Dynamic causal modeling of frontoparietal connectivity changes with ketamine indicated a decrease in NMDA and AMPA-mediated frontal-to-parietal connectivity. AMPA-mediated connectivity changes were sustained for up to 50 min after ketamine infusion had ceased, by which time perceptual distortions were absent. The results also indicated a decrease in gain of parietal pyramidal cells, which was correlated with participants' self-reports of blissful state. Based on these results, we suggest that the antidepressant effects of ketamine may depend on its ability to change the balance of frontoparietal connectivity patterns. SIGNIFICANCE STATEMENT: In this paper, we found that subanesthetic doses of ketamine, similar to those used in antidepressant studies, increase anterior theta and gamma power but decrease posterior theta, delta, and alpha power, as revealed by magnetoencephalographic recordings. Dynamic causal modeling of frontoparietal connectivity changes with ketamine indicated a decrease in NMDA and AMPA-mediated frontal-to-parietal connectivity. AMPA-mediated connectivity changes were sustained for up to 50 min after ketamine infusion had ceased, by which time perceptual distortions were absent. The results also indicated a decrease in gain of parietal pyramidal cells, which was correlated with participants' self-reports of blissful state. The alterations in frontoparietal connectivity patterns we observe here may be important in generating the antidepressant response to ketamine.

Human SERPINB12 Is an Abundant Intracellular Serpin Expressed in Most Surface and Glandular Epithelia.

The intracellular serine protease inhibitors (serpins) are an important family of proteins that protect cells form proteinase-mediated injury. Understanding the tissue and cellular expression pattern of this protein family can provide important insights into their physiologic roles. For example, high expression in epithelial tissues, such as lung, may suggest a biologic function in cellular defense, secretion, or selective absorption. Although the expression pattern of many of the intracellular serpins has been well described, one member of this class, SERPINB12, has not been carefully examined. We generated a mouse monoclonal antibody directed against human SERPINB12 and delineated its specificity and tissue and cell type distribution pattern through immunoblotting and immunohistochemistry, respectively. This monoclonal antibody was human specific and did not cross-react with other human intracellular serpins or mouse Serpinb12. SERPINB12 was found in nearly all the tissues investigated. In addition, this serpin was found in multiple cell types within individual tissues but primarily the epithelium. These data suggest that SERPINB12, like some other intracellular serpins, may play a vital role in barrier function by providing protection of epithelial cells.

Landscape risk factors for Lyme disease in the eastern broadleaf forest province of the Hudson River valley and the effect of explanatory data classification resolution.

This study assessed how landcover classification affects associations between landscape characteristics and Lyme disease rate. Landscape variables were derived from the National Land Cover Database (NLCD), including native classes (e.g., deciduous forest, developed low intensity) and aggregate classes (e.g., forest, developed). Percent of each landcover type, median income, and centroid coordinates were calculated by census tract. Regression results from individual and aggregate variable models were compared with the dispersion parameter-based R(2) (Rα(2)) and AIC. The maximum Rα(2) was 0.82 and 0.83 for the best aggregate and individual model, respectively. The AICs for the best models differed by less than 0.5%. The aggregate model variables included forest, developed, agriculture, agriculture-squared, y-coordinate, y-coordinate-squared, income and income-squared. The individual model variables included deciduous forest, deciduous forest-squared, developed low intensity, pasture, y-coordinate, y-coordinate-squared, income, and income-squared. Results indicate that regional landscape models for Lyme disease rate are robust to NLCD landcover classification resolution.

Skewed X chromosome inactivation and female preponderance in autoimmune thyroid disease: an association study and meta-analysis.

CONTEXT: A number of small data sets have suggested a potential role for skewed X chromosome activation (XCI), away from the expected 50:50 parent of origin ratio, as an explanation for the strong female preponderance seen in the common autoimmune thyroid diseases (AITD), Graves' disease (GD), and Hashimoto's thyroiditis (HT). OBJECTIVE: The objective of the study was to confirm a role for XCI skewing as a potential explanation for the strong female preponderance seen in AITD. DESIGN: The design of the study was to screen XCI in the largest GD, HT, and control case-control cohort and family cohort to date and undertake a meta-analysis of previous AITD XCI reports. SETTING: The study was conducted at a research laboratory. PATIENTS: Three hundred and nine GD, 490 HT, and 325 female UK Caucasians controls, 273 UK Caucasian GD families, and a meta-analysis of 454 GD, 673 HT, and 643 female Caucasian controls were included in the study. MAIN OUTCOME MEASURES: Case-control and family-based association studies and meta-analysis were measured. RESULTS: Skewed XCI was observed with GD [odds ratio (OR) 2.17 [95% confidence interval (CI) 1.43-3.30], P=2.1×10(-4)] and a trend toward skewing with HT (P=.08) compared with the control cohort. A meta-analysis of our UK data and that of four previous non-UK Caucasian studies confirmed significant skewing of XCI with GD [OR 2.54 (95% CI 1.58-4.10), P=1.0×10(-4), I2=30.2%] and HT [OR 2.40 (95% CI 1.10-5.26), P=.03, I2=74.3%]. CONCLUSIONS: Convincing evidence exists to support a role for skewed XCI in female subjects with AITD, which may, in part, explain the strong female preponderance observed in this disease.

Linking ecosystem services and human health: the Eco-Health Relationship Browser.

OBJECTIVES: Ecosystems provide multiple services, many of which are linked to positive health outcomes. Review objectives were to identify the set of literature related to this research topic, and to design an interactive, web-based tool highlighting the weight of evidence, thus making the information more accessible. METHODS: A systematic review was conducted to create the Eco-Health Relationship Browser ( http://www.epa.gov/research/healthscience/browser/introduction.html ). The search was conducted in four stages utilizing Google Scholar, PubMed and Science Direct, targeted journals, and targeted keywords; search results were limited to peer-reviewed journal articles published in English from 1 January 1990 to 31 December 2012. RESULTS: The review identified 344 relevant articles; a subset of 169 articles was included in the Browser. Articles retrieved during the search focused on the buffering and health-promotional aspects of ecosystem services. Landscape and Urban Planning, Urban Forestry and Urban Greening, and Health and Place yielded the most articles relevant to this search. CONCLUSIONS: Results from the systematic review were used to populate the Browser, which organizes the diverse literature and allows users to visualize the numerous connections between ecosystem services and human health.

Effects of HSP90 inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) on NEU/HER2 overexpressing mammary tumours in MMTV-NEU-NT mice monitored by Magnetic Resonance Spectroscopy.

BACKGROUND: The importance of ERBB2/NEU/HER2 in the response of breast tumours to the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG; tanespimycin) has been demonstrated in the clinic. ERBB2 is an oncoprotein client that is highly dependent on HSP90. This and other oncogenic client proteins (e.g. B-RAF, C-RAF, ALK and CDK4) are depleted by 17-AAG in both animal tumours and patients. Here we investigate by Magnetic Resonance Spectroscopy (MRS) the metabolic response of 17-AAG in spontaneous, NEU/HER2 driven mammary tumours in transgenic MMTV-NEU-NT mice and in cells isolated and cultured from these tumours. METHODS: Mammary tumours were monitored by 31P MRS in vivo and in tumour extracts, comparing control and 17-AAG treated mice. A cell line derived from NEU/HER2 mammary tumours was also cultured and the effect of 17-AAG was measured by 31P MRS in cell extracts. Molecular biomarkers were assessed by immunoblotting in extracts from cells and tumours. For comparison of tumour volume, metabolite concentrations and Western blot band intensities, two-tailed unpaired t-tests were used. RESULTS: The NEU/HER2 mammary tumours were very sensitive to 17-AAG and responded in a dose-dependent manner to 3 daily doses of 20, 40 and 80mg/kg of 17-AAG, all of which caused significant regression. At the higher doses, 31P MRS of tumour extracts showed significant decreases in phosphocholine (PC) and phosphoethanolamine (PE) whereas no significant changes were seen at the 20mg/kg dose. Extracts of isolated cells cultured from the mammary carcinomas showed a significant decrease in viable cell number and total PME after 17-AAG treatment. Western blots confirmed the expected action of 17-AAG in inducing HSP72 and significantly depleting HSP90 client proteins, including NEU/HER2 both in tumours and in isolated cells. CONCLUSIONS: The data demonstrate the high degree of sensitivity of this clinically relevant NEU/HER2-driven tumour model to HSP90 inhibition by 17-AAG, consistent with the clinical data, and suggest that the metabolic signature of choline phospholipids obtained by MRS could be useful both as a preclinical and clinical tool for investigating surrogate markers of response to treatment.