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The 9.4T scanner in Maastricht is a whole-body magnet with head gradients and parallel RF transmit capability. At the time of the design, it was conceptualized to be one of the best fMRI scanners in the world, but it has also been used for anatomical and diffusion imaging. 9.4T offers increases in sensitivity and contrast, but the technical ultra-high field (UHF) challenges, such as field inhomogeneities and constraints set by RF power deposition, are exacerbated compared to 7T. This article reviews some of the 9.4T work done in Maastricht. Functional imaging experiments included blood oxygenation level-dependent (BOLD) and blood-volume weighted (VASO) fMRI using different readouts. BOLD benefits from shorter T2* at 9.4T while VASO from longer T1. We show examples of both ex vivo and in vivo anatomical imaging. For many applications, pTx and optimized coils are essential to harness the full potential of 9.4T. Our experience shows that, while considerable effort was required compared to our 7T scanner, we could obtain high-quality anatomical and functional data, which illustrates the potential of MR acquisitions at even higher field strengths. The practical challenges of working with a relatively unique system are also discussed.

When microbes grow in foreign nutritional environments, selection may enrich mutations in unexpected pathways connecting growth and homeostasis. An evolution experiment designed to identify beneficial mutations inBurkholderia cenocepaciacaptured six independent nonsynonymous substitutions in the essential genetilS, which modifies tRNAIle2by adding a lysine to the anticodon for faithful AUA recognition. Further, five additional mutants acquired mutations in tRNAIle2, which strongly suggests that disrupting the TilS:tRNAIle2interaction was subject to strong positive selection. Mutated TilS incurred greatly reduced enzymatic function but retained capacity for tRNAIle2binding. Yet both mutant sets outcompeted wild-type by decreasing lag phase duration by ∼3.5 hours. We hypothesized that lysine demand could underlie fitness in the experimental conditions. As predicted, supplemental lysine complemented the ancestral fitness deficit, but so did additions of several other amino acids. Mutant fitness advantages were also specific to rapid growth on galactose using oxidative overflow metabolism that generates redox imbalance, not resources favoring more balanced metabolism. Remarkably, 13tilSmutations also evolved in the Long-Term Evolution Experiment withE. coli, including four fixed mutations. These results suggest that TilS or unknown binding partners contribute to improved growth under conditions of rapid sugar oxidation at the predicted expense of translational accuracy.

S1. RUNX1 mRNA is decreased during breast cancer progression. S2. RUNX1 does not change cell proliferation. S3. RUNX1 represses tumor growth in mammary fat pad. S4. Gate for MCF10AT1 sorting. S5. CD24high Cells have high RUNX1 expression in MCF10AT1 cells. S6. Loss of RUNX1 promotes stemness in MCF10A and MCF7 cells. S7. Overexpression RUNX1 in MCF10CA1a cells does not change BCSC population. S8. Zeb1 is expressed at low level in MCF10CA1a cells. S9. Schematic diagram of ChIP qPCR primers and amplicons over Zeb1 for ChIP-qPCR. S10. Knockdown Zeb1 in MCF10AT1 ns cells does not change cancer stem cell phenotypes.

Breast cancer remains the most common malignant disease in women worldwide. Despite advances in detection and therapies, studies are still needed to understand the mechanisms underlying this cancer. Cancer stem cells (CSC) play an important role in tumor formation, growth, drug resistance, and recurrence. Here, it is demonstrated that the transcription factor RUNX1, well known as essential for hematopoietic differentiation, represses the breast cancer stem cell (BCSC) phenotype and suppresses tumor growth in vivo. The current studies show that BCSCs sorted from premalignant breast cancer cells exhibit decreased RUNX1 levels, whereas ectopic expression of RUNX1 suppresses tumorsphere formation and reduces the BCSC population. RUNX1 ectopic expression in breast cancer cells reduces migration, invasion, and in vivo tumor growth (57%) in mouse mammary fat pad. Mechanistically, RUNX1 functions to suppress breast cancer tumor growth through repression of CSC activity and direct inhibition of ZEB1 expression. Consistent with these cellular and biochemical results, clinical findings using patient specimens reveal that the highest RUNX1 levels occur in normal mammary epithelial cells and that low RUNX1 expression in tumors is associated with poor patient survival.Implications:The key finding that RUNX1 represses stemness in several breast cancer cell lines points to the importance of RUNX1 in other solid tumors where RUNX1 may regulate CSC properties.

Background and Objectives A key strategy for resolving the antibiotic resistance crisis is the development of new drugs with antimicrobial properties. The engineered cationic antimicrobial peptide WLBU2 (also known as PLG0206) is a promising broad-spectrum antimicrobial compound that has completed Phase I clinical studies. It has activity against Gram-negative and Gram-positive bacteria including infections associated with biofilm. No definitive mechanisms of resistance to WLBU2 have been identified. Methodology Here, we used experimental evolution under different levels of mutation supply and whole genome sequencing (WGS) to detect the genetic pathways and probable mechanisms of resistance to this peptide. We propagated populations of wild-type and hypermutator Pseudomonas aeruginosa in the presence of WLBU2 and performed WGS of evolved populations and clones. Results Populations that survived WLBU2 treatment acquired a minimum of two mutations, making the acquisition of resistance more difficult than for most antibiotics, which can be tolerated by mutation of a single target. Major targets of resistance to WLBU2 included the orfN and pmrB genes, previously described to confer resistance to other cationic peptides. More surprisingly, mutations that increase aggregation such as the wsp pathway were also selected despite the ability of WLBU2 to kill cells growing in a biofilm. Conclusions and implications The results show how experimental evolution and WGS can identify genetic targets and actions of new antimicrobial compounds and predict pathways to resistance of new antibiotics in clinical practice.

Gedeeltelijke of volledige occlusie van het nasolacrimale drainagesysteem (NLDS) is een veelvoorkomend klinisch probleem bij konijnen. Computertomografische dacryocystografie (CTDCG) kan een efficiente techniek zijn voor de behandeling van deze indicatie. In deze prospectieve studie worden de CT-DCG-techniek en het uitzicht van de CT-DCG-beelden van het NLDS bij acht gezonde konijnen beschreven. De kwaliteit van de visualisatie van osseuze structuren in de proximiteit van het NLDS was goed op de pre-contrast computertomografische beelden. Het beenderige lacrimale kanaal had een gladde aflijning, een gelijkmatige diameter en de gemiddelde waarden worden in de voorliggende studie weergegeven. De CT-DCG techniek was makkelijk uitvoerbaar en kon het NLDS goed in beeld brengen, inclusief anatomische vernauwingen en bochten. CT-DCH is een minimaal invasieve en informatieve techniek voor de evaluatie van het NLDS bij konijnen. Zijn diagnostische meerwaarde in het onderzoek naar nasolacrimale aandoeningen dient nog verder gespecificeerd te worden bij deze diersoort.

RUNX1 has recently been shown to play an important role in determination of mammary epithelial cell identity. However, mechanisms by which loss of the RUNX1 transcription factor in mammary epithelial cells leads to epithelial-to-mesenchymal transition (EMT) are not known. Here, we report that interaction between RUNX1 and its heterodimeric partner CBFβ is essential for sustaining mammary epithelial cell identity. Disruption of RUNX1-CBFβ interaction, DNA binding, and association with mitotic chromosomes alters cell morphology, global protein synthesis, and phenotype-related gene expression. During interphase, RUNX1 is organized as punctate, predominantly nuclear, foci that are dynamically redistributed during mitosis, with a subset localized to mitotic chromosomes. Genome-wide RUNX1 occupancy profiles for asynchronous, mitotically enriched, and early G1 breast epithelial cells reveal RUNX1 associates with RNA Pol II-transcribed protein coding and long non-coding RNA genes and RNA Pol I-transcribed ribosomal genes critical for mammary epithelial proliferation, growth, and phenotype maintenance. A subset of these genes remains occupied by the protein during the mitosis to G1 transition. Together, these findings establish that the RUNX1-CBFβ complex is required for maintenance of the normal mammary epithelial phenotype and its disruption leads to EMT. Importantly, our results suggest, for the first time, that RUNX1 mitotic bookmarking of a subset of epithelial-related genes may be an important epigenetic mechanism that contributes to stabilization of the mammary epithelial cell identity.

Breast cancer stem cells (BCSCs) are competent to initiate tumor formation and growth and refractory to conventional therapies. Consequently BCSCs are implicated in tumor recurrence. Many signaling cascades associated with BCSCs are critical for epithelial-to-mesenchymal transition (EMT). We developed a model system to mechanistically examine BCSCs in basal-like breast cancer using MCF10AT1 FACS sorted for CD24 (negative/low in BCSCs) and CD44 (positive/high in BCSCs). Ingenuity Pathway Analysis comparing RNA-seq on the CD24-/low versus CD24+/high MCF10AT1 indicates that the top activated upstream regulators include TWIST1, TGFβ1, OCT4, and other factors known to be increased in BCSCs and during EMT. The top inhibited upstream regulators include ESR1, TP63, and FAS. Consistent with our results, many genes previously demonstrated to be regulated by RUNX factors are altered in BCSCs. The RUNX2 interaction network is the top significant pathway altered between CD24-/low and CD24+/high MCF10AT1. RUNX1 is higher in expression at the RNA level than RUNX2. RUNX3 is not expressed. While, human-specific quantitative polymerase chain reaction primers demonstrate that RUNX1 and CDH1 decrease in human MCF10CA1a cells that have grown tumors within the murine mammary fat pad microenvironment, RUNX2 and VIM increase. Treatment with an inhibitor of RUNX binding to CBFβ for 5 days followed by a 7-day recovery period results in EMT suggesting that loss of RUNX1, rather than increase in RUNX2, is a driver of EMT in early stage breast cancer. Increased understanding of RUNX regulation on BCSCs and EMT will provide novel insight into therapeutic strategies to prevent recurrence.

Thoracic aortic emergencies reflect a wide range of etiologies, pathologic processes, and clinical presentations. Accurate identification with an appropriate treatment algorithm is best accomplished in a multidisciplinary setting with interventional radiologists, vascular surgeons, and cardiothoracic surgeons. While knowledge of thoracic stent graft equipment and technique is essential in the treatment of thoracic aortic emergencies, many clinical settings may employ alternative treatment techniques. This article will review the most common thoracic aortic emergencies and treatment strategies.

The cell cycle is governed by stringent epigenetic mechanisms that, in response to intrinsic and extrinsic regulatory cues, support fidelity of DNA replication and cell division. We will focus on (1) the complex and interdependent processes that are obligatory for control of proliferation and compromised in cancer, (2) epigenetic and topological domains that are associated with distinct phases of the cell cycle that may be altered in cancer initiation and progression, and (3) the requirement for mitotic bookmarking to maintain intranuclear localization of transcriptional regulatory machinery to reinforce cell identity throughout the cell cycle to prevent malignant transformation.

Spiral galaxies undergo strong ram-pressure effects when they fall into the galaxy cluster potential. As a consequence, their gas is stripped to form extended tails within which star formation can happen, giving them the typical jellyfish appearance. The ultraviolet imaging observations of jellyfish galaxies provide an opportunity to understand ongoing star formation in the stripped tails. We report the ultraviolet observations of the jellyfish galaxies JW39, JO60, JO194 and compare with observations in optical continuum and $\mathrm{H}{\alpha}$. We detect knots of star formation in the disk and tails of the galaxies and find that their UV and H$\alpha$ flux are well correlated. The optical emission line ratio maps of these galaxies are used to identify for every region the emission mechanism, due to either star formation, LINER or a mix of the two phenomena. The star-forming regions in the emission line maps match very well with the regions having significant UV flux. The central regions of two galaxies (JW39, JO194) show a reduction in UV flux which coincides with composite or LINER regions in the emission line maps. The galaxies studied here demonstrate significant star formation in the stripped tails, suppressed star formation in the central regions and present a possible case of accelerated quenching happening in jellyfish galaxies., Comment: Accepted for publication in MNRAS

Epigenetic gene regulatory mechanisms play a central role in the biological control of cell and tissue structure, function, and phenotype. Identification of epigenetic dysregulation in cancer provides mechanistic into tumor initiation and progression and may prove valuable for a variety of clinical applications. We present an overview of epigenetically driven mechanisms that are obligatory for physiological regulation and parameters of epigenetic control that are modified in tumor cells. The interrelationship between nuclear structure and function are not mutually exclusive and are instead synergistic. We explore concepts influencing the maintenance of chromatin structures including phase separation, recognition signals, factors that mediate enhancer-promoter looping and insulation and how these are altered in during the cell cycle and in cancer. Understanding how these processes are altered in cancer provides potential for advancing capabilities for diagnosis and identification of novel therapeutic targets.

Corn earworm, Helicoverpa zea (Boddie) (Lepidoptera: Noctuidae), has emerged as an injurious insect pest to hemp, Cannabis sativa L., a crop newly reintroduced to the United States. Growing hemp presents a potential alternative economic opportunity for farmers but can be challenging with a market that is unstable and just developing. One of the most notable production challenges is managing corn earworm, an insect pest that is particularly damaging when it feeds on flower buds produced in cannabinoid varieties, creating extensive bud tunneling and wounds that allow entry of pathogens that can aid development and presence of bud rot. Damage to seeds is of lesser concern in hemp cultivars grown for grain and minimal risk is associated with hemp grown for fiber. Our ability to research hemp has only recently been allowed as production was largely suspended following World War II and, as such, there has been limited opportunity to develop information for empirically-based pest management recommendations. Further complicating development of integrated pest management (IPM) strategies are regulatory challenges associated with providing registration support to add hemp to pesticide labels, as it was not formally recognized as a crop by U.S. regulatory agencies until late 2019. Research needs and challenges to develop effective IPM programs for corn earworm on hemp are discussed here.

Een twee jaar oude labrador retriever uit de Franse Alpen werd aangeboden omwille van een opgezet abdomen, lethargie en gewichtsverlies. Op computertomografisch onderzoek werd een grote, cavitaire levermassa vastgesteld die de vena cava caudalis in groeide en die geassocieerd was met multipele gelijkaardige laesies ter hoogte van de lever, alsook met longnodulen en lymfadenopathie. Initieel werd deze aandoening verkeerdelijk aanzien als een maligne neoplasie, maar cytologisch en histologisch onderzoek van de grootste levermassa was compatibel met een cestodeninfectie. Een PCR-test bevestigde een infestatie met Echinococcus multilocularis. Medicamenteuze therapie met albendazole werd opgestart. De hond bleef klinisch goed gedurende tien maanden na de diagnose, maar moest worden geeuthanaseerd omdat de eigenaars terug moesten keren naar Groot-Brittannie en ze niet legaal kon geimporteerd worden. Volgens de auteurs is dit de eerste casereport waarin een langetermijnopvolging wordt beschreven van een Echinococcus sp.-infectie bij een hond, die medicamenteus behandeld werd. Dit geval toont ook aan dat medicamenteuze therapie een bruikbare optie is als chirurgie niet haalbaar is.

Cells establish and sustain structural and functional integrity of the genome to support cellular identity and prevent malignant transformation. In this review, we present a strategic overview of epigenetic regulatory mechanisms including histone modifications and higher order chromatin organization (HCO) that are perturbed in breast cancer onset and progression. Implications for dysfunctions that occur in hormone regulation, cell cycle control, and mitotic bookmarking in breast cancer are considered, with an emphasis on epithelial-to-mesenchymal transition and cancer stem cell activities. The architectural organization of regulatory machinery is addressed within the contexts of translating cancer-compromised genomic organization to advances in breast cancer risk assessment, diagnosis, prognosis, and identification of novel therapeutic targets with high specificity and minimal off target effects.

There is an increasing interest in quantitative imaging of T1, T2 and diffusion contrast in the brain due to greater robustness against bias fields and artifacts, as well as better biophysical interpretability in terms of microstructure. However, acquisition time constraints are a challenge, particularly when multiple quantitative contrasts are desired and when extensive sampling of diffusion directions, high b-values or long diffusion times are needed for multi-compartment microstructure modeling. Although ultra-high fields of 7 T and above have desirable properties for many MR modalities, the shortening T2 and the high specific absorption rate (SAR) of inversion and refocusing pulses bring great challenges to quantitative T1, T2 and diffusion imaging. Here, we present the MESMERISED sequence (Multiplexed Echo Shifted Multiband Excited and Recalled Imaging of STEAM Encoded Diffusion). MESMERISED removes the dead time in Stimulated Echo Acquisition Mode (STEAM) imaging by an echo-shifting mechanism. The echo-shift (ES) factor is independent of multiband (MB) acceleration and allows for very high multiplicative (ESxMB) acceleration factors, particularly under moderate and long mixing times. This results in super-acceleration and high time efficiency at 7 T for quantitative T1 and diffusion imaging, while also retaining the capacity to perform quantitative T2 and B1 mapping. We demonstrate the super-acceleration of MESMERISED for whole-brain T1 relaxometry with total acceleration factors up to 36 at 1.8 mm isotropic resolution, and up to 54 at 1.25 mm resolution qT1 imaging, corresponding to a 6x and 9x speedup, respectively, compared to MB-only accelerated acquisitions. We then demonstrate highly efficient diffusion MRI with high b-values and long diffusion times in two separate cases. First, we show that super-accelerated multi-shell diffusion acquisitions with 370 whole-brain diffusion volumes over 8 b-value shells up to b = 7000 s/mm2 can be generated at 2 mm isotropic in under 8 minutes, a data rate of almost a volume per second, or at 1.8 mm isotropic in under 11 minutes, achieving up to 3.4x speedup compared to MB-only. A comparison of b = 7000 s/mm2 MESMERISED against standard MB pulsed gradient spin echo (PGSE) diffusion imaging shows 70% higher SNR efficiency and greater effectiveness in supporting complex diffusion signal modeling. Second, we demonstrate time-efficient sampling of different diffusion times with 1.8 mm isotropic diffusion data acquired at four diffusion times up to 290 ms, which supports both Diffusion Tensor Imaging (DTI) and Diffusion Kurtosis Imaging (DKI) at each diffusion time. Finally, we demonstrate how adding quantitative T2 and B1+ mapping to super-accelerated qT1 and diffusion imaging enables efficient quantitative multi-contrast mapping with the same MESMERISED sequence and the same readout train. MESMERISED extends possibilities to efficiently probe T1, T2 and diffusion contrast for multi-component modeling of tissue microstructure.

There is an increasing interest in quantitative imaging of T

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Despite recent advances in targeted therapies, the molecular mechanisms driving breast cancer initiation, progression, and metastasis are minimally understood. Growing evidence indicate that transfer RNA (tRNA)-derived small RNAs (tsRNA) contribute to biological control and aberrations associated with cancer development and progression. The runt-related transcription factor 1 (RUNX1) transcription factor is a tumor suppressor in the mammary epithelium whereas RUNX1 downregulation is functionally associated with breast cancer initiation and progression. We identified four tsRNA (ts-19, ts-29, ts-46, and ts-112) that are selectively responsive to expression of the RUNX1 tumor suppressor. Our finding that ts-112 and RUNX1 anticorrelate in normal-like mammary epithelial and breast cancer lines is consistent with tumor-related activity of ts-112 and tumor suppressor activity of RUNX1. Inhibition of ts-112 in MCF10CA1a aggressive breast cancer cells significantly reduced proliferation. Ectopic expression of a ts-112 mimic in normal-like mammary epithelial MCF10A cells significantly increased proliferation. These findings support an oncogenic potential for ts-112. Moreover, RUNX1 may repress ts-112 to prevent overactive proliferation in breast epithelial cells to augment its established roles in maintaining the mammary epithelium.

Significant research conducted over the last 20 years has shown that engineered clay barriers for chemical containment applications can behave as semipermeable membranes that restrict the m...

We present the results of a VLA HI imaging survey aimed at understanding why some galaxies develop long extraplanar H$\alpha$ tails, becoming extreme jellyfish galaxies. The observations are centered on five extreme jellyfish galaxies, optically selected from the WINGS and OmegaWINGS surveys and confirmed to have long H$\alpha$ tails through MUSE observations. Each galaxy is located in a different cluster. In the observations there are in total 88 other spiral galaxies within the field of view (40'x40') and observed bandwidth (6500 km s$^{-1}$). We detect 13 of these 88 spirals, plus one uncatalogued spiral, with HI masses ranging from 1 to 7 $\times$ 10${^9}$ M$_{\odot}$. Many of these detections have extended HI disks, two show direct evidence for ram pressure stripping, while others are possibly affected by tidal forces and/or ram-pressure stripping. We stack the 75 non-detected spiral galaxies and find an average HI mass of 1.9 $\times$ 10$^{8}$ M$_{\odot}$, which given their average stellar mass, implies they are very HI deficient. Comparing the extreme jellyfish galaxies to the other disk galaxies, we find that they have a larger stellar mass than almost all disk galaxies and than all HI detected galaxies, they are at smaller projected distance from the cluster center and at higher relative velocity to the cluster mean than all HI detections and most non-detections. We conclude that the high stellar mass allows extreme jellyfish galaxies to fall deeply into the cluster before being stripped and the surrounding ICM pressure gives rise to their spectacular star-forming tails., Comment: 25 pages, 13 figures, accepted to ApJ

Breast cancer remains the most common malignant disease in women worldwide. Despite advances in detection and therapies, studies are still needed to understand the mechanisms underlying this cancer. Cancer stem cells (CSC) play an important role in tumor formation, growth, drug resistance, and recurrence. Here, it is demonstrated that the transcription factor RUNX1, well known as essential for hematopoietic differentiation, represses the breast cancer stem cell (BCSC) phenotype and suppresses tumor growth in vivo. The current studies show that BCSCs sorted from premalignant breast cancer cells exhibit decreased RUNX1 levels, whereas ectopic expression of RUNX1 suppresses tumorsphere formation and reduces the BCSC population. RUNX1 ectopic expression in breast cancer cells reduces migration, invasion, and in vivo tumor growth (57%) in mouse mammary fat pad. Mechanistically, RUNX1 functions to suppress breast cancer tumor growth through repression of CSC activity and direct inhibition of ZEB1 expression. Consistent with these cellular and biochemical results, clinical findings using patient specimens reveal that the highest RUNX1 levels occur in normal mammary epithelial cells and that low RUNX1 expression in tumors is associated with poor patient survival. Implications: The key finding that RUNX1 represses stemness in several breast cancer cell lines points to the importance of RUNX1 in other solid tumors where RUNX1 may regulate CSC properties.

There is an increasing interest in quantitative imaging of T1, T2 and diffusion contrast in the brain due to greater robustness against bias fields and artifacts, as well as better biophysical interpretability in terms of microstructure. However, acquisition time constraints are a challenge, particularly when multiple quantitative contrasts are desired and when extensive sampling of diffusion directions, high b-values or long diffusion times are needed for multi-compartment microstructure modeling. Although ultra-high fields of 7 T and above have desirable properties for many MR modalities, the shortening T2 and the high specific absorption rate (SAR) of inversion and refocusing pulses bring great challenges to quantitative T1, T2 and diffusion imaging. Here, we present the MESMERISED sequence (Multiplexed Echo Shifted Multiband Excited and Recalled Imaging of STEAM Encoded Diffusion). MESMERISED removes the dead time in Stimulated Echo Acquisition Mode (STEAM) imaging by an echo-shifting mechanism. The echo-shift (ES) factor is independent of multiband (MB) acceleration and allows for very high multiplicative (ESxMB) acceleration factors, particularly under moderate and long mixing times. This results in super-acceleration and high time efficiency at 7 T for quantitative T1 and diffusion imaging, while also retaining the capacity to perform quantitative T2 and B1 mapping. We demonstrate the super-acceleration of MESMERISED for whole-brain T1 relaxometry with total acceleration factors up to 36 at 1.8 mm isotropic resolution, and up to 54 at 1.25 mm resolution qT1 imaging, corresponding to a 6x and 9x speedup, respectively, compared to MB-only accelerated acquisitions. We then demonstrate highly efficient diffusion MRI with high b-values and long diffusion times in two separate cases. First, we show that super-accelerated multi-shell diffusion acquisitions with 370 whole-brain diffusion volumes over 8 b-value shells up to b = 7000 s/mm2 can be generated at 2 mm isotropic in under 8 minutes, a data rate of almost a volume per second, or at 1.8 mm isotropic in under 11 minutes, achieving up to 3.4x speedup compared to MB-only. A comparison of b = 7000 s/mm2 MESMERISED against standard MB pulsed gradient spin echo (PGSE) diffusion imaging shows 70% higher SNR efficiency and greater effectiveness in supporting complex diffusion signal modeling. Second, we demonstrate time-efficient sampling of different diffusion times with 1.8 mm isotropic diffusion data acquired at four diffusion times up to 290 ms, which supports both Diffusion Tensor Imaging (DTI) and Diffusion Kurtosis Imaging (DKI) at each diffusion time. Finally, we demonstrate how adding quantitative T2 and B1+ mapping to super-accelerated qT1 and diffusion imaging enables efficient quantitative multi-contrast mapping with the same MESMERISED sequence and the same readout train. MESMERISED extends possibilities to efficiently probe T1, T2 and diffusion contrast for multi-component modeling of tissue microstructure.

// Deli Hong 1, 2 , Terri L. Messier 1 , Coralee E. Tye 1 , Jason R. Dobson 2 , Andrew J. Fritz 1 , Kenneth R. Sikora 1 , Gillian Browne 1 , Janet L. Stein 1 , Jane B. Lian 1 , Gary S. Stein 1 1 Department of Biochemistry and University of Vermont Cancer Center, University of Vermont College of Medicine, Burlington, VT, USA 2 Department of Cell and Developmental Biology, University of Massachusetts Medical School, Worcester, MA, USA Correspondence to: Gary S. Stein, email: gary.stein@uvm.edu Keywords: Runx1, epithelial to mesenchymal transition, epithelial Integrity, patient survival, breast cancer Received: November 17, 2016 Accepted: January 16, 2017 Published: February 16, 2017 ABSTRACT Runx1 is a well characterized transcription factor essential for hematopoietic differentiation and Runx1 mutations are the cause of leukemias. Runx1 is highly expressed in normal epithelium of most glands and recently has been associated with solid tumors. Notably, the function of Runx1 in the mammary gland and how it is involved in initiation and progression of breast cancer is still unclear. Here we demonstrate the consequences of Runx1 loss in normal mammary epithelial and breast cancer cells. We first observed that Runx1 is decreased in tumorigenic and metastatic breast cancer cells. We also observed loss of Runx1 expression upon induction of epithelial-mesenchymal transition (EMT) in MCF10A (normal-like) cells. Furthermore depletion of Runx1 in MCF10A cells resulted in striking changes in cell shape, leading to mesenchymal cell morphology. The epithelial phenotype could be restored in breast cancer cells by re-expressing Runx1. Analyses of breast tumors and patient data revealed that low Runx1 expression is associated with poor prognosis and decreased survival. We addressed mechanisms for the function of Runx1 in maintaining the epithelial phenotype and find Runx1 directly regulates E-cadherin; and serves as a downstream transcription factor mediating TGFβ signaling. We also observed through global gene expression profiling of growth factor depleted cells that induction of EMT and loss of Runx1 is associated with activation of TGFβ and WNT pathways. Thus these findings have identified a novel function for Runx1 in sustaining normal epithelial morphology and preventing EMT and suggest Runx1 levels could be a prognostic indicator of tumor progression.

Introduction: Thrombotic thrombocytopenic purpura (TTP) is a hematologic emergency where timely plasmapheresis reduces mortality. There are a few cases where benign etiologies mimic TTP and patients may receive unnecessary plasma exchange. Interdisciplinary decision-making is invaluable to avoid expenses and complications of more invasive treatments. Case Presentation: A 38-year-old male with self-reported history of asthma presented with generalized weakness and syncope. He endorses 2-week of bilateral leg pain with numbness, loss of taste, and nausea. Vital signs were remarkable for tachycardia in 110s and hypotension at 101/52. Labs showed hemoglobin 3.3, WBC 3.6, platelet 83, MCV 93.9, reticulocyte 1.1%, total bilirubin 1.4, haptoglobin 2000, however value was drawn near the time of administration of intramuscular vitamin B12. There was concern for TTP due to an intermediate PLASMIC score of 5. However, given that presentation was more consistent with vitamin B12 deficiency, plasmapheresis was deferred after a discussion with pathology. Peripheral blood smear showed anisocytosis, macrocytes, schistocytes, and hypersegmented neutrophils. ADAMTS13 activity returned 62%. Pernicious anemia was diagnosed with labs revealed homocysteine >50, methylmalonic acid 41.97, positive anti-parietal cell antibody, and positive intrinsic factor antibody. Hemoglobin stabilized at around 8 after transfusions. Lab showed haptoglobin 13 and LDH 1211 on discharged after daily vitamin B12 injections. Patient was discharged with weekly injections and last gastric biopsy reveal atrophic gastritis. Discussion: The decision to closely monitor our patient versus initiation of plasmapheresis was based on clinical symptoms of neuropathy and reduced taste consistent with vitamin B12 deficiency. Our patient's lab values and peripheral smear were also more reassuring of a nutritional deficiency. Severe vitamin B12 deficiency is thought to cause both intramedullary and extramedullary hemolysis. Intramedullary hemolysis caused by destruction of erythrocytes leading to ineffective erythropoiesis is more common. Conversely, the mechanism of extramedullary hemolysis is not well established. It is thought that the pro-oxidative qualities of homocysteine can promote thrombosis and endothelial dysfunction and subsequent microangiopathy. This phenomenon, commonly called pseudothrombotic microangiopathy, mimics TTP. Few laboratory values can help distinguish between TTP and an intramedullary process. First, reduced reticulocyte count suggests defective DNA synthesis and destruction of megaloblastic cells by bone marrow macrophages. A high MCV in the setting of low reticulocyte count is suggestive of vitamin B12 deficiency. Blood smear may also show multiple hypersegmented polymorphonuclear cells and macrocytosis in addition to schistocytes. Additionally, LDH tends to be more substantially elevated in intramedullary hemolytic processes like vitamin B12 deficiency. This is attributed to high LDH content of nucleated erythrocytes when compared to mature red blood cells. Immature erythrocytes contain less hemoglobin than mature red blood cells and bilirubin is relatively less elevated in vitamin B12 deficiency. Lastly, platelet counts tend to be higher in vitamin B12 deficiency than in TTP. Disclosures No relevant conflicts of interest to declare.

Diffusion MRI (dMRI) in ex vivo human brain specimens is an important research tool for neuroanatomical investigations and the validation of dMRI techniques. Many ex vivo dMRI applications have benefited from very high dMRI resolutions achievable on small-bore preclinical or animal MRI scanners for small tissue samples. However, the investigation of entire human brains post mortem provides the important context of entire white matter (WM) network systems and entire gray matter (GM) areas connected through these systems. The investigation of intact ex vivo human brains in large bore systems creates challenges due to the limited gradient performance and transmit radio-frequency (B1+) inhomogeneities, specially at ultra-high field (UHF, 7T and higher). To overcome these issues, it is necessary to tailor ex vivo diffusion-weighted sequences specifically for high resolution and high diffusion-weighting. Here, we present kT-dSTEAM, which achieves B1+ homogenization across whole human brain specimens using parallel transmit (pTx) on a 9.4T MR system. We use kT-dSTEAM to obtain multi-shell high b-value and high resolution diffusion-weighted data in ex vivo whole human brains. Isotropic whole brain data can be acquired at high b-value (6000-8000 s/mm2) at high resolution (1000 μm) and at moderate b-value (3000 s/mm2) at ultra-high isotropic resolution (400 μm). As an illustration of the advantages of the ultra-high resolution, tractography across the WM/GM border shows less of the unwanted gyral crown bias, and more high-curvature paths connecting the sulcal wall than at lower resolution. The kT-dSTEAM also allows for acquisition of T1 and T2 weighted images suitable for estimating quantitative T1 and T2 maps. Finally, multi-shell analysis of kT-dSTEAM data at variable mixing time (TM) is shown as an approach for ex vivo data analysis which is adapted to the strengths of STEAM diffusion-weighting. Here, we use this gain for multi-orientation modelling and crossing-fiber tractography. We show that multi-shell data allows superior multiple orientation tractography of known crossing fiber structures in the brain stem.

Diffusion MRI (dMRI) in ex vivo human brain specimens is an important research tool for neuroanatomical investigations and the validation of dMRI techniques. Many ex vivo dMRI applications have benefited from very high dMRI resolutions achievable on small-bore preclinical or animal MRI scanners for small tissue samples. However, the investigation of entire human brains post mortem provides the important context of entire white matter (WM) network systems and entire gray matter (GM) areas connected through these systems. The investigation of intact ex vivo human brains in large bore systems creates challenges due to the limited gradient performance and transmit radio-frequency (B