The histone deacetylase SIRT6 is a tumor suppressor that controls cancer metabolism.

Reprogramming of cellular metabolism is a key event during tumorigenesis. Despite being known for decades (Warburg effect), the molecular mechanisms regulating this switch remained unexplored. Here, we identify SIRT6 as a tumor suppressor that regulates aerobic glycolysis in cancer cells. Importantly, loss of SIRT6 leads to tumor formation without activation of known oncogenes, whereas transformed SIRT6-deficient cells display increased glycolysis and tumor growth, suggesting that SIRT6 plays a role in both establishment and maintenance of cancer. By using a conditional SIRT6 allele, we show that SIRT6 deletion in vivo increases the number, size, and aggressiveness of tumors. SIRT6 also functions as a regulator of ribosome metabolism by corepressing MYC transcriptional activity. Lastly, Sirt6 is selectively downregulated in several human cancers, and expression levels of SIRT6 predict prognosis and tumor-free survival rates, highlighting SIRT6 as a critical modulator of cancer metabolism. Our studies reveal SIRT6 to be a potent tumor suppressor acting to suppress cancer metabolism.

Oncogenic Kras maintains pancreatic tumors through regulation of anabolic glucose metabolism.

Tumor maintenance relies on continued activity of driver oncogenes, although their rate-limiting role is highly context dependent. Oncogenic Kras mutation is the signature event in pancreatic ductal adenocarcinoma (PDAC), serving a critical role in tumor initiation. Here, an inducible Kras(G12D)-driven PDAC mouse model establishes that advanced PDAC remains strictly dependent on Kras(G12D) expression. Transcriptome and metabolomic analyses indicate that Kras(G12D) serves a vital role in controlling tumor metabolism through stimulation of glucose uptake and channeling of glucose intermediates into the hexosamine biosynthesis and pentose phosphate pathways (PPP). These studies also reveal that oncogenic Kras promotes ribose biogenesis. Unlike canonical models, we demonstrate that Kras(G12D) drives glycolysis intermediates into the nonoxidative PPP, thereby decoupling ribose biogenesis from NADP/NADPH-mediated redox control. Together, this work provides in vivo mechanistic insights into how oncogenic Kras promotes metabolic reprogramming in native tumors and illuminates potential metabolic targets that can be exploited for therapeutic benefit in PDAC.

The histone deacetylase Sirt6 regulates glucose homeostasis via Hif1alpha.

SIRT6 is a member of a highly conserved family of NAD(+)-dependent deacetylases with various roles in metabolism, stress resistance, and life span. SIRT6-deficient mice develop normally but succumb to a lethal hypoglycemia early in life; however, the mechanism underlying this hypoglycemia remained unclear. Here, we demonstrate that SIRT6 functions as a histone H3K9 deacetylase to control the expression of multiple glycolytic genes. Specifically, SIRT6 appears to function as a corepressor of the transcription factor Hif1alpha, a critical regulator of nutrient stress responses. Consistent with this notion, SIRT6-deficient cells exhibit increased Hif1alpha activity and show increased glucose uptake with upregulation of glycolysis and diminished mitochondrial respiration. Our studies uncover a role for the chromatin factor SIRT6 as a master regulator of glucose homeostasis and may provide the basis for novel therapeutic approaches against metabolic diseases, such as diabetes and obesity.

Pregnancy and weaning regulate human maternal liver size and function.

During pregnancy, the rodent liver undergoes hepatocyte proliferation and increases in size, followed by weaning-induced involution via hepatocyte cell death and stromal remodeling, creating a prometastatic niche. These data suggest a mechanism for increased liver metastasis in breast cancer patients with recent childbirth. It is unknown whether the human liver changes in size and function during pregnancy and weaning. In this study, abdominal imaging was obtained in healthy women at early and late pregnancy and postwean. During pregnancy time points, glucose production and utilization and circulating bile acids were measured. Independently of weight gain, most women's livers increased in size with pregnancy, then returned to baseline postwean. Putative roles for bile acids in liver growth and regression were observed. Together, the data support the hypothesis that the human liver is regulated by reproductive state with growth during pregnancy and volume loss postwean. These findings have implications for sex-specific liver diseases and for breast cancer outcomes.

3D MR fingerprinting using Seiffert spirals.

PURPOSE: Seiffert spirals were recently explored as an efficient way to traverse 3D k-space compared to traditional 3D techniques. Several studies have shown the ability of 3D MR fingerprinting (MRF) techniques to acquire T1 and T2 relaxation maps in a short period of time. However, these sequences do not sample across a large region of 3D k-space every TR, especially in the way that Seiffert trajectories can. METHODS: A 3D MRF sequence was designed using 8 Seiffert spirals rotated in 3D k-space, with flip angle modulation for T1 and T2 sensitivity. The sequence was compared to an MRF sequence using a 2D spiral rotated in 3D k-space using the tiny golden angle acquisition with similar resolution/readout duration. Both sequences were evaluated using simulations, phantom validation, and in vivo imaging. RESULTS: In all experiments, the Seiffert spiral MRF sequence performed similar to if not better than the multi-axis 2D spiral MRF sequence. Strong intraclass correlation coefficients (> 0.9) were found between conventional and MRF sequences in phantoms, whereas the in vivo results showed slightly less aliasing artifact with the Seiffert trajectory. CONCLUSION: In this study, Seiffert spirals were used within the MRF framework to acquire high-resolution T1 and T2 relaxation time maps in less than 2.5 min. The reduced aliasing artifacts seen with the Seiffert sequence suggests that sampling over 3D k-space evenly each TR can improve quantification or shorten scan times.

Standardization of MRI Screening and Reporting in Individuals With Elevated Risk of Pancreatic Ductal Adenocarcinoma: Consensus Statement of the PRECEDE Consortium.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignancies, with a dismal survival rate. Screening the general population for early detection of PDAC is not recommended, but because early detection improves survival, high-risk individuals, defined as those meeting criteria based on a family history of PDAC and/or the presence of known pathogenic germline variant genes with PDAC risk, are recommended to undergo screening with MRI and/or endoscopic ultrasound at regular intervals. The Pancreatic Cancer Early Detection (PRECEDE) Consortium was formed in 2018 and is composed of gastroenterologists, geneticists, pancreatic surgeons, radiologists, statisticians, and researchers from 40 sites in North America, Europe, and Asia. The overarching goal of the PRECEDE Consortium is to facilitate earlier diagnosis of PDAC for high-risk individuals to increase survival of the disease. A standardized MRI protocol and reporting template are needed to enhance the quality of screening examinations, improve consistency of clinical management, and facilitate multiinstitutional research. We present a consensus statement to standardize MRI screening and reporting for individuals with elevated risk of pancreatic cancer.

Importance of incorporating quantitative imaging biomarker technical performance characteristics when estimating treatment effects.

BACKGROUND/AIMS: Quantitative imaging biomarkers have the potential to detect change in disease early and noninvasively, providing information about the diagnosis and prognosis of a patient, aiding in monitoring disease, and informing when therapy is effective. In clinical trials testing new therapies, there has been a tendency to ignore the variability and bias in quantitative imaging biomarker measurements. Unfortunately, this can lead to underpowered studies and incorrect estimates of the treatment effect. We illustrate the problem when non-constant measurement bias is ignored and show how treatment effect estimates can be corrected. METHODS: Monte Carlo simulation was used to assess the coverage of 95% confidence intervals for the treatment effect when non-constant bias is ignored versus when the bias is corrected for. Three examples are presented to illustrate the methods: doubling times of lung nodules, rates of change in brain atrophy in progressive multiple sclerosis clinical trials, and changes in proton-density fat fraction in trials for patients with nonalcoholic fatty liver disease. RESULTS: Incorrectly assuming that the measurement bias is constant leads to 95% confidence intervals for the treatment effect with reduced coverage (<95%); the coverage is especially reduced when the quantitative imaging biomarker measurements have good precision and/or there is a large treatment effect. Estimates of the measurement bias from technical performance validation studies can be used to correct the confidence intervals for the treatment effect. CONCLUSION: Technical performance validation studies of quantitative imaging biomarkers are needed to supplement clinical trial data to provide unbiased estimates of the treatment effect.

T1ρ magnetic resonance fingerprinting.

T1ρ relaxation imaging is a quantitative imaging technique that has been used to assess cartilage integrity, liver fibrosis, tumors, cardiac infarction, and Alzheimer's disease. T1 , T2 , and T1ρ relaxation time constants have each demonstrated different degrees of sensitivity to several markers of fibrosis and inflammation, allowing for a potential multi-parametric approach to tissue quantification. Traditional magnetic resonance fingerprinting (MRF) has been shown to provide quick, quantitative mapping of T1 and T2 relaxation time constants. In this study, T1ρ relaxation is added to the MRF framework using spin lock preparations. An MRF sequence involving an RF-spoiled sequence with TR , flip angle, T1ρ , and T2 preparation variation is described. The sequence is then calibrated against conventional T1 , T2 , and T1ρ relaxation mapping techniques in agar phantoms and the abdomens of four healthy volunteers. Strong intraclass correlation coefficients (ICC > 0.9) were found between conventional and MRF sequences in phantoms and also in healthy volunteers (ICC > 0.8). The highest ICC correlation values were seen in T1 , followed by T1ρ and then T2 . In this study, T1ρ relaxation has been incorporated into the MRF framework by using spin lock preparations, while still fitting for T1 and T2 relaxation time constants. The acquisition of these parameters within a single breath hold in the abdomen alleviates the issues of movement between breath holds in conventional techniques.

Implementing a comprehensive translational oncology platform: from molecular testing to actionability.

BACKGROUND: In order to establish the workflows required to implement a real-time process involving multi-omic analysis of patient samples to support precision-guided therapeutic intervention, a tissue acquisition and analysis trial was implemented. This report describes our findings to date, including the frequency with which mutational testing led to precision-guided therapy and outcome for those patients. METHODS: Eligible patients presenting to Oregon Health and Science University Knight Cancer Institute were enrolled on the study. Patients with biopsy proven metastatic or locally advanced unresectable prostate cancer, breast cancer, pancreatic adenocarcinoma, or refractory acute myelogenous leukemia receiving standard of care therapy were eligible. Metastatic site biopsies were collected and analyzed using the Knight Diagnostic Lab GeneTrails comprehensive solid tumor panel (124 genes). CLIA certified genomic information was made available to the treating physician. RESULTS: Between 1/26/2017 and 5/30/2018, 38 patients were enrolled, with 28 successfully undergoing biopsy. Of these, 25 samples yielded sufficient tumor for analysis. The median biopsy cellularity and number of cores collected were 70% (15-90%) and 5 (2-20), respectively. No procedure-related complications occurred. GeneTrails analysis revealed that 22 of 25 (88%) tumor samples harbored at least one potentially actionable mutation, and 18 (72%) samples harbored 2 or more potentially actionable mutations. The most common genetic alterations identified involved: DNA damage repair genes, cell cycle regulating genes, PIK3CA/Akt/mTOR pathway, and FGF gene family. To date, CLIA certified genomic results were used by treating physicians for precision-guided therapy in 5 (23%) patients. CONCLUSION: We report the feasibility of real-time tissue acquisition and analysis to support a successful translational oncology platform. The workflow will provide the foundation to improve access and accrual to biomarker driven precision oncology trials.

Multi-parametric T2 * magnetic resonance fingerprinting using variable echo times.

The use of quantitative imaging biomarkers in the imaging of various disease states, including cancer and neurodegenerative disease, has increased in recent years. T1 , T2 , and T2 * relaxation time constants have been shown to be affected by tissue structure or contrast infusion. Acquiring these biomarkers simultaneously in a multi-parametric acquisition could provide more robust detection of tissue changes in various disease states including neurodegeneration and cancer. Traditional magnetic resonance fingerprinting (MRF) has been shown to provide quick, quantitative mapping of T1 and T2 relaxation time constants. In this study, T2 * relaxation is added to the MRF framework using variable echo times (TE). To demonstrate the feasibility of the method and compare incremental and golden angle spiral rotations, simulated phantom data was fit using the proposed method. Additionally, T1 /T2 /T2 */δf MRF as well as conventional T1 , T2 , and T2 * acquisitions were acquired in agar phantoms and the brains of three healthy volunteers. Golden angle spiral rotation was found to reduce inaccuracy resulting from off resonance effects. Strong correlations were found between conventional and MRF values in the T1 , T2 , and T2 * relaxation time constants of the agar phantoms and healthy volunteers. In this study, T2 * relaxation has been incorporated into the MRF framework by using variable echo times, while still fitting for T1 and T2 relaxation time constants. In addition to fitting these relaxation time constants, a novel method for fitting and correcting off resonance effects has been developed.

Current and potential imaging applications of ferumoxytol for magnetic resonance imaging.

Contrast-enhanced magnetic resonance imaging is a commonly used diagnostic tool. Compared with standard gadolinium-based contrast agents, ferumoxytol (Feraheme, AMAG Pharmaceuticals, Waltham, MA), used as an alternative contrast medium, is feasible in patients with impaired renal function. Other attractive imaging features of i.v. ferumoxytol include a prolonged blood pool phase and delayed intracellular uptake. With its unique pharmacologic, metabolic, and imaging properties, ferumoxytol may play a crucial role in future magnetic resonance imaging of the central nervous system, various organs outside the central nervous system, and the cardiovascular system. Preclinical and clinical studies have demonstrated the overall safety and effectiveness of this novel contrast agent, with rarely occurring anaphylactoid reactions. The purpose of this review is to describe the general and organ-specific properties of ferumoxytol, as well as the advantages and potential pitfalls associated with its use in magnetic resonance imaging. To more fully demonstrate the applications of ferumoxytol throughout the body, an imaging atlas was created and is available online as supplementary material.

Evaluation of antitumor activity and cardiac toxicity of a bone-targeted ph-sensitive liposomal formulation in a bone metastasis tumor model in mice.

Chemotherapy for bone tumors is a major challenge because of the inability of therapeutics to penetrate dense bone mineral. We hypothesize that a nanostructured formulation with high affinity for bone could deliver drug to the tumor while minimizing off-target toxicity. Here, we evaluated the efficacy and toxicity of a novel bone-targeted, pH-sensitive liposomal formulation containing doxorubicin in an animal model of bone metastasis. Biodistribution studies with the liposome showed good uptake in tumor, but low accumulation of doxorubicin in the heart. Mice treated with the bone-targeted liposome formulation showed a 70% reduction in tumor volume, compared to 35% reduction for free doxorubicin at the same dose. Both cardiac toxicity and overall mortality were significantly lower for animals treated with the bone-targeted liposomes compared to free drug. Bone-targeted, pH-sensitive, doxorubicin containing liposomes represent a promising approach to selectively delivering doxorubicin to bone tumors while minimizing cardiac toxicity.

Metrology Standards for Quantitative Imaging Biomarkers.

Although investigators in the imaging community have been active in developing and evaluating quantitative imaging biomarkers (QIBs), the development and implementation of QIBs have been hampered by the inconsistent or incorrect use of terminology or methods for technical performance and statistical concepts. Technical performance is an assessment of how a test performs in reference objects or subjects under controlled conditions. In this article, some of the relevant statistical concepts are reviewed, methods that can be used for evaluating and comparing QIBs are described, and some of the technical performance issues related to imaging biomarkers are discussed. More consistent and correct use of terminology and study design principles will improve clinical research, advance regulatory science, and foster better care for patients who undergo imaging studies.

Image-guided Treatment in the Hepatobiliary System: Role of Imaging in Treatment Planning and Posttreatment Evaluation.

In the past decade, image-guided targeted treatments such as percutaneous ablation, intra-arterial embolic therapies, and targeted radiation therapy have shown substantial promise in management of hepatobiliary malignancies. Imaging is integral to patient selection, treatment delivery, and assessment of treatment effectiveness. Preprocedural imaging is crucial and allows local tumor staging, evaluation of surrounding structures, and selection of suitable therapeutic options and strategies for treatment delivery. Postprocedural imaging is required to monitor therapeutic success, detect residual or recurrent disease, and identify procedure-related complications to guide appropriate future therapy. Technical innovations in cross-sectional imaging techniques such as computed tomography (CT) and magnetic resonance (MR) imaging, combined with advances in image postprocessing and new types of contrast agents, allow precise morphologic assessment and functional evaluation of hepatobiliary tumors. Advanced postprocessing techniques such as image fusion and volumetric assessment not only facilitate procedural planning and treatment delivery but also enhance posttreatment imaging surveillance. In addition, molecular imaging techniques such as fluorodeoxyglucose positron emission tomography (PET), PET/CT, and PET/MR imaging offer opportunities to evaluate various physiologic properties of tumors.

Body MR Imaging: Artifacts, k-Space, and Solutions.

Body magnetic resonance (MR) imaging is challenging because of the complex interaction of multiple factors, including motion arising from respiration and bowel peristalsis, susceptibility effects secondary to bowel gas, and the need to cover a large field of view. The combination of these factors makes body MR imaging more prone to artifacts, compared with imaging of other anatomic regions. Understanding the basic MR physics underlying artifacts is crucial to recognizing the trade-offs involved in mitigating artifacts and improving image quality. Artifacts can be classified into three main groups: (a) artifacts related to magnetic field imperfections, including the static magnetic field, the radiofrequency (RF) field, and gradient fields; (b) artifacts related to motion; and (c) artifacts arising from methods used to sample the MR signal. Static magnetic field homogeneity is essential for many MR techniques, such as fat saturation and balanced steady-state free precession. Susceptibility effects become more pronounced at higher field strengths and can be ameliorated by using spin-echo sequences when possible, increasing the receiver bandwidth, and aligning the phase-encoding gradient with the strongest susceptibility gradients, among other strategies. Nonuniformities in the RF transmit field, including dielectric effects, can be minimized by applying dielectric pads or imaging at lower field strength. Motion artifacts can be overcome through respiratory synchronization, alternative k-space sampling schemes, and parallel imaging. Aliasing and truncation artifacts derive from limitations in digital sampling of the MR signal and can be rectified by adjusting the sampling parameters. Understanding the causes of artifacts and their possible solutions will enable practitioners of body MR imaging to meet the challenges of novel pulse sequence design, parallel imaging, and increasing field strength.

Whole-body FDG PET-MR oncologic imaging: pitfalls in clinical interpretation related to inaccurate MR-based attenuation correction.

Simultaneous data collection for positron emission tomography and magnetic resonance imaging (PET/MR) is now a reality. While the full benefits of concurrently acquiring PET and MR data and the potential added clinical value are still being evaluated, initial studies have identified several important potential pitfalls in the interpretation of fluorodeoxyglucose (FDG) PET/MRI in oncologic whole-body imaging, the majority of which being related to the errors in the attenuation maps created from the MR data. The purpose of this article was to present such pitfalls and artifacts using case examples, describe their etiology, and discuss strategies to overcome them. Using a case-based approach, we will illustrate artifacts related to (1) Inaccurate bone tissue segmentation; (2) Inaccurate air cavities segmentation; (3) Motion-induced misregistration; (4) RF coils in the PET field of view; (5) B0 field inhomogeneity; (6) B1 field inhomogeneity; (7) Metallic implants; (8) MR contrast agents.

Hawaii state legislator views on e-cigarettes and likelihood of legislative action.

OBJECTIVE: To examine perspectives on e-cigarette use and regulations in Hawaii through key informant interviews with state legislators. BACKGROUND: E-cigarette use is rapidly increasing, with sales in 2013 topping $1 billion in the United States, but e-cigarettes are still a largely unregulated industry. Although e-cigarettes are thought by most to be a healthier alternative to traditional cigarettes, long-term health effects are not yet known. METHODS: Semistructured key informant interviews were conducted with Hawaii state legislators (n = 15). RESULTS: We found a lack of consensus among legislators, which suggests that substantial legislative action is unlikely in the upcoming session. However, most legislators believe that some type of incremental legislation will pass, such as enactment of a small tax, limitations on advertising to protect adolescents, or regulations concerning where people can use e-cigarettes. CONCLUSION: Legislators eagerly await further research to clarify the overall benefits and harms of e-cigarettes at both the individual and population levels.

First D1-like receptor PET imaging of the rat and primate kidney: implications for human disease monitoring.

The intrarenal dopamine system is important for signaling and natriuresis, and significant dysfunction is associated with hypertension and kidney disease in ex vivo studies. Dopamine receptors also modulate and are modulated by the renin-angiotensin-aldosterone system. Here, we show the first in vivo measurement of D1-like receptors in the renal cortex of Sprague-Dawley rat and Papio anubis baboon using [(11)C]NNC 112, a positron emission tomography radioligand for D1-like receptors. In addition, we show a D1-like binding potential response to angiotensin II blockade in rats using losartan. Demonstration of self-saturable binding in the rat as well as specific and saturable binding in Papio anubis validate the use of [(11)C]NNC 112 in the first in vivo measurement of renal dopamine D1-like receptors. Furthermore, [(11)C]NNC 112 is a radioligand tool already validated for use in probing human central nervous system (CNS) D1-like receptors. Our work demonstrates specific and saturable non-CNS binding in higher animals and the ability to quantify physiological response to drug treatment and provides a clear path to extend use of [(11)C]NNC 112 to study renal dopamine in humans.

Oncologic applications of dual-energy CT in the abdomen.

Dual-energy computed tomographic (DECT) technology offers enhanced capabilities that may benefit oncologic imaging in the abdomen. By using two different energies, dual-energy CT allows material decomposition on the basis of energy-dependent attenuation profiles of specific materials. Although image acquisition with dual-energy CT is similar to that with single-energy CT, comprehensive postprocessing is able to generate not only images that are similar to single-energy CT (SECT) images, but a variety of other images, such as virtual unenhanced (VUE), virtual monochromatic (VMC), and material-specific iodine images. An increase in the conspicuity of iodine on low-energy VMC images and material-specific iodine images may aid detection and characterization of tumors. Use of VMC images of a desired energy level (40-140 keV) improves lesion-to-background contrast and the quality of vascular imaging for preoperative planning. Material-specific iodine images enable differentiation of hypoattenuating tumors from hypo- or hyperattenuating cysts and facilitate detection of isoattenuating tumors, such as pancreatic masses and peritoneal disease, thereby defining tumor targets for imaging-guided therapy. Moreover, quantitative iodine mapping may serve as a surrogate biomarker for monitoring effects of the treatment. Dual-energy CT is an innovative imaging technique that enhances the capabilities of CT in evaluating oncology patients.