SUMMARY Deregulated Myc transcriptionally reprograms cell metabolism to promote neoplasia. Here we show that oncogenic Myc requires the Myc superfamily member MondoA, a nutrient-sensing transcription factor, for tumorigenesis. Knockdown of MondoA, or its dimerization partner Mlx, blocks Myc-induced reprogramming of multiple metabolic pathways resulting in apoptosis. Identification, and knockdown, of genes co-regulated by Myc and MondoA has allowed us to define metabolic functions required by deregulated Myc and demonstrate a critical role for lipid biosynthesis in survival of Myc-driven cancer. Furthermore, overexpression of a subset of Myc and MondoA co-regulated genes correlates with poor outcome of patients with diverse cancers. Co-regulation of cancer metabolism by Myc and MondoA provides the potential for therapeutics aimed at inhibiting MondoA and its target genes.

BackgroundLeft ventricular noncompaction (LVNC) is a myocardial disorder characterized by excessive left ventricular (LV) trabeculae. Current methods for quantification of LV trabeculae have limitations. The aim of this study is to describe a novel technique for quantifying LV trabeculation using cardiovascular magnetic resonance (CMR) and fractal geometry. Observing that trabeculae appear complex and irregular, we hypothesize that measuring the fractal dimension (FD) of the endocardial border provides a quantitative parameter that can be used to distinguish normal from abnormal trabecular patterns.MethodsFractal analysis is a method of quantifying complex geometric patterns in biological structures. The resulting FD is a unitless measure index of how completely the object fills space. FD increases with increased structural complexity. LV FD was measured using a box-counting method on CMR short-axis cine stacks. Three groups were studied: LVNC (defined by Jenni criteria), n=30(age 41±13; men, 16); healthy whites, n=75(age, 46±16; men, 36); healthy blacks, n=30(age, 40±11; men, 15).ResultsIn healthy volunteers FD varied in a characteristic pattern from base to apex along the LV. This pattern was altered in LVNC where apical FD were abnormally elevated. In healthy volunteers, blacks had higher FD than whites in the apical third of the LV (maximal apical FD: 1.253±0.005 vs. 1.235±0.004, p<0.01) (mean±s.e.m.). Comparing LVNC with healthy volunteers, maximal apical FD was higher in LVNC (1.392±0.010, p<0.00001). The fractal method was more accurate and reproducible (ICC, 0.97 and 0.96 for intra and inter-observer readings) than two other CMR criteria for LVNC (Petersen and Jacquier).ConclusionsFD is higher in LVNC patients compared to healthy volunteers and is higher in healthy blacks than in whites. Fractal analysis provides a quantitative measure of trabeculation and has high reproducibility and accuracy for LVNC diagnosis when compared to current CMR criteria.

BackgroundCardiovascular magnetic resonance (CMR) derived native myocardial T1 is decreased in patients with Fabry disease even before left ventricular hypertrophy (LVH) occurs and may be the first non-invasive measure of myocyte sphingolipid storage. The relationship of native T1 lowering prior to hypertrophy and other candidate early phenotype markers are unknown. Furthermore, the reproducibility of T1 mapping has never been assessed in Fabry disease.MethodsSixty-three patients, 34 (54%) female, mean age 48 ± 15 years with confirmed (genotyped) Fabry disease underwent CMR, ECG and echocardiographic assessment. LVH was absent in 25 (40%) patients. Native T1 mapping was performed with both Modified Look-Locker Inversion recovery (MOLLI) sequences and a shortened version (ShMOLLI) at 1.5 Tesla. Twenty-one patients underwent a second scan within 24 hours to assess inter-study reproducibility. Results were compared with 63 healthy age and gender-matched volunteers.ResultsMean native T1 in Fabry disease (LVH positive), (LVH negative) and healthy volunteers was 853 ± 50 ms, 904 ± 46 ms and 968 ± 32 ms (for all p < 0.0001) by ShMOLLI sequences. Native T1 showed high inter-study, intra-observer and inter-observer agreement with intra-class correlation coefficients (ICC) of 0.99, 0.98, 0.97 (ShMOLLI) and 0.98, 0.98, 0.98 (MOLLI). In Fabry disease LVH negative individuals, low native T1 was associated with reduced echocardiographic-based global longitudinal speckle tracking strain (−18 ± 2% vs −22 ± 2%, p = 0.001) and early diastolic function impairment (E/E’ = 7 [6–8] vs 5 [5–6], p = 0.028).ConclusionNative T1 mapping in Fabry disease is a reproducible technique. T1 reduction prior to the onset of LVH is associated with early diastolic and systolic changes measured by echocardiography.

Summary Background Reoperation rates are high after surgery for hip fractures. We investigated the effect of a sliding hip screw versus cancellous screws on the risk of reoperation and other key outcomes. Methods For this international, multicentre, allocation concealed randomised controlled trial, we enrolled patients aged 50 years or older with a low-energy hip fracture requiring fracture fixation from 81 clinical centres in eight countries. Patients were assigned by minimisation with a centralised computer system to receive a single large-diameter screw with a side-plate (sliding hip screw) or the present standard of care, multiple small-diameter cancellous screws. Surgeons and patients were not blinded but the data analyst, while doing the analyses, remained blinded to treatment groups. The primary outcome was hip reoperation within 24 months after initial surgery to promote fracture healing, relieve pain, treat infection, or improve function. Analyses followed the intention-to-treat principle. This study was registered with ClinicalTrials.gov, number NCT00761813. Findings Between March 3, 2008, and March 31, 2014, we randomly assigned 1108 patients to receive a sliding hip screw (n=557) or cancellous screws (n=551). Reoperations within 24 months did not differ by type of surgical fixation in those included in the primary analysis: 107 (20%) of 542 patients in the sliding hip screw group versus 117 (22%) of 537 patients in the cancellous screws group (hazard ratio [HR] 0.83, 95% CI 0.63–1.09; p=0.18). Avascular necrosis was more common in the sliding hip screw group than in the cancellous screws group (50 patients [9%] vs 28 patients [5%]; HR 1.91, 1.06–3.44; p=0.0319). However, no significant difference was found between the number of medically related adverse events between groups (p=0.82; appendix); these events included pulmonary embolism (two patients [<1%] vs four [1%] patients; p=0.41) and sepsis (seven [1%] vs six [1%]; p=0.79). Interpretation In terms of reoperation rates the sliding hip screw shows no advantage, but some groups of patients (smokers and those with displaced or base of neck fractures) might do better with a sliding hip screw than with cancellous screws. Funding National Institutes of Health, Canadian Institutes of Health Research, Stichting NutsOhra, Netherlands Organisation for Health Research and Development, Physicians’ Services Incorporated.

Evasion of apoptosis is critical in Myc-induced tumor progression. Here we report that cancer cells evade death under stress by activating calpain-mediated proteolysis of Myc. This generates Myc-nick, a cytoplasmic, transcriptionally inactive cleavage product of Myc. We found conversion of Myc into Myc-nick in cell lines and tissues derived from multiple cancers. In colon cancer, the production of Myc-nick is enhanced under stress conditions such as hypoxia and nutrient deprivation. Under these conditions, ectopic expression of Myc-nick promotes anchorage-independent growth and cell survival at least in part by promoting autophagy. Myc-nick also delays colon cancer cell death after treatment with chemotherapeutic drugs such as etoposide, cisplatin, and imatinib. Furthermore, colon cancer cells expressing a cleavage-resistant form of Myc undergo extensive apoptosis but are rescued by overexpression of Myc-nick. We also found that ectopic expression of Myc-nick results in the induction of the actin-bundling protein fascin, formation of filopodia, and increased cell motility-all mediators of tumor metastasis. Myc-nick-induced survival, autophagy, and motility require Myc box II (MBII), a region of Myc-nick that recruits acetyltransferases that in turn modify cytoplasmic proteins, including a-tubulin and ATG3. Our results suggest that Myc-nick-induced survival and motility contribute to colon cancer progression and metastasis.

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BackgroundReported polybrominated diphenyl ether (PBDE) concentrations in human samples in the United States have been higher than in Europe and Asia. Little is known about factors that contribute to individual variability in body burden.ObjectiveIn this large study we measured PBDE concentrations in human milk from the United States during 2004–2006. We assessed characteristics associated with concentrations in milk and change in milk concentration between 3 and 12 months postpartum.MethodsWe analyzed 303 milk samples obtained 3 months postpartum for PBDEs. A second sample was analyzed for 83 women still lactating 12 months postpartum. PBDE concentrations in milk and variability by individual characteristics such as age, parity, and prepregnancy body mass index (BMI) were evaluated using generalized linear models.ResultsPBDE congeners BDEs 28, 47, 99, 100, and 153 were detected in > 70% of samples. BDE-47 concentrations were the highest, ranging from below the limit of detection to 1,430 ng/g lipid, with a median of 28 ng/g lipid. Concentrations of most individual PBDE congeners and the sum of BDEs 28, 47, 99, 100, and 153 (∑PBDE) were lower among mothers > 34 years of age compared with those 25–29 years of age and higher among mothers with high compared with normal BMI, after adjustment for other covariates. Parity was not associated with PBDE concentration. The change in ∑PBDE concentration in milk between 3 and 12 months postpartum was highly variable (median increase, 14%; interquartile range, −26% to 50%).ConclusionsPBDEs were detected in nearly all human milk samples, varying by maternal weight and age and over the course of breast-feeding.

The ability to map the functional connectivity of discrete cell types in the intact mammalian brain during behavior is crucial for advancing our understanding of brain function in normal and disease states. We combined designer receptor exclusively activated by designer drug (DREADD) technology and behavioral imaging with μPET and [ 18 F]fluorodeoxyglucose (FDG) to generate whole-brain metabolic maps of cell-specific functional circuits during the awake, freely moving state. We have termed this approach DREADD-assisted metabolic mapping (DREAMM) and documented its ability in rats to map whole-brain functional anatomy. We applied this strategy to evaluating changes in the brain associated with inhibition of prodynorphin-expressing (Pdyn-expressing) and of proenkephalin-expressing (Penk-expressing) medium spiny neurons (MSNs) of the nucleus accumbens shell (NAcSh), which have been implicated in neuropsychiatric disorders. DREAMM revealed discrete behavioral manifestations and concurrent engagement of distinct corticolimbic networks associated with dysregulation of Pdyn and Penk in MSNs of the NAcSh. Furthermore, distinct neuronal networks were recruited in awake versus anesthetized conditions. These data demonstrate that DREAMM is a highly sensitive, molecular, high-resolution quantitative imaging approach. IntroductionThe mammalian brain is a complex organ with billions of heterogeneous cells whose local and long-range functional connections regulate behavior and physiology. Traditional approaches used for mapping functional brain anatomy do not provide information on long-range, global (i.e., intact whole brain) circuits. Recently, optogenetics was coupled with in vivo functional MRI (fMRI) and allowed, for what we believe is the first time, assessment of functional anatomy of discrete cell types in living animals (1, 2). fMRI technology, however, relies on nonmolecular, indirect measures of neuronal activity (i.e., neurovascular coupling) and is limited in its applicability to anesthetized or immobilized animals. Importantly, a recent study showed that light delivery in the absence of optogenetic stimulation induced strong local fMRI responses in the stimulated site (3). To overcome these limitations, we combined designer receptor exclusively activated by designer drug (DREADD) technology (4), which allows remote in vivo control of cell-specific firing (5), together with behavioral imaging using μPET and [ 18 F]fluorodeoxyglucose (FDG) to measure regional brain glucose metabolism, which is a direct marker of brain function (6-9). This approach, termed DREADD-assisted metabolic mapping (DREAMM), was used to map functional brain anatomy associated with inhibiting the activity of prodynorphin-expressing (Pdyn-expressing) and of proenkephalin-expressing (Penk-expressing) medium spiny neurons (MSNs) in the medial nucleus accum-