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Metabolic reprogramming, a hallmark of tumorigenesis, involves alterations in glucose and fatty acid metabolism. Here, we investigate the role of Carnitine palmitoyl transferase 1a (Cpt1a), a key enzyme in long-chain fatty acid (LCFA) oxidation, in ErbB2-driven breast cancers. In ErbB2+ breast cancer models, ablation of Cpt1a delays tumor onset, growth, and metastasis. However, Cpt1a-deficient cells exhibit increased glucose dependency that enables survival and eventual tumor progression. Consequently, these cells exhibit heightened oxidative stress and upregulated nuclear factor erythroid 2-related factor 2 (Nrf2) activity. Inhibiting Nrf2 or silencing its expression reduces proliferation and glucose consumption in Cpt1a-deficient cells. Combining the ketogenic diet, composed of LCFAs, or an anti-ErbB2 monoclonal antibody (mAb) with Cpt1a deficiency significantly perturbs tumor growth, enhances apoptosis, and reduces lung metastasis. Using an immunocompetent model, we show that Cpt1a inhibition promotes an antitumor immune microenvironment, thereby enhancing the efficacy of anti-ErbB2 mAbs. Our findings underscore the importance of targeting fatty acid oxidation alongside HER2-targeted therapies to combat resistance in HER2+ breast cancer patients. Metabolic reprogramming is crucial in tumorigenesis, with alterations in glucose and fatty acid metabolism playing key roles. Here, the authors show that inhibiting fatty acid oxidation in HER2-driven breast cancers delays tumor growth and enhances the effectiveness of HER2-targeted therapies. [ABSTRACT FROM AUTHOR]

Functional oncogenic links between ErbB2 and ERRα in HER2+ breast cancer patients support a therapeutic benefit of co-targeted therapies. However, ErbB2 and ERRα also play key roles in heart physiology, and this approach could pose a potential liability to cardiovascular health. Herein, using integrated phosphoproteomic, transcriptomic and metabolic profiling, we uncovered molecular mechanisms associated with the adverse remodeling of cardiac functions in mice with combined attenuation of ErbB2 and ERRα activity. Genetic disruption of both effectors results in profound effects on cardiomyocyte architecture, inflammatory response and metabolism, the latter leading to a decrease in fatty acyl-carnitine species further increasing the reliance on glucose as a metabolic fuel, a hallmark of failing hearts. Furthermore, integrated omics signatures of ERRα loss-of-function and doxorubicin treatment exhibit common features of chemotherapeutic cardiotoxicity. These findings thus reveal potential cardiovascular risks in discrete combination therapies in the treatment of breast and other cancers. Murine hearts deficient in ErbB2 and/or ERRα are used to profile the adverse cardiac remodeling associated with potential targeted breast cancer treatments by phosphoproteomic, transcriptomic and metabolomic profiling. [ABSTRACT FROM AUTHOR]

Cells interpret cues from and interact with fibrous microenvironments through the body based on the mechanics and organization of these environments and the phenotypic state of the cell. This in turn regulates mechanoactive pathways, such as the localization of mechanosensitive factors. Here, we leverage the microscale heterogeneity inherent to engineered fiber microenvironments to produce a large morphologic data set, across multiple cells types, while simultaneously measuring mechanobiological response (YAP/TAZ nuclear localization) at the single cell level. This dataset describing a large dynamic range of cell morphologies and responses was coupled with a machine learning approach to predict the mechanobiological state of individual cells from multiple lineages. We also noted that certain cells (e.g., invasive cancer cells) or biochemical perturbations (e.g., modulating contractility) can limit the predictability of cells in a universal context. Leveraging this finding, we developed further models that incorporate biochemical cues for single cell prediction or identify individual cells that do not follow the established rules. The models developed here provide a tool for connecting cell morphology and signaling, incorporating biochemical cues in predictive models, and identifying aberrant cell behavior at the single cell level. [ABSTRACT FROM AUTHOR]

Background: The transforaminal posterior approach (TLIF) procedure was first described in 1982. Current literature indicates its equality in outcomes for fusion constructs as other anterior-posterior procedures. As a procedure becomes more popular and is more frequently performed the types and number of complications that occur increase. We report on a two case series that underwent TLIF. Both patients had satisfactory postoperative imaging, but presented later with coronal plane vertebral body fractures in the caudal vertebral body of the TLIF construct. We believe the complication may be related to: (a) unrecognized fracture of the endplate during cage impaction; (b) overloading the endplates by maximizing the lordosis achieved by using the reverse jackknife position on a Jackson table; (c) underlying mineral bone disease in patients. As the TLIF procedure increases in popularity, caution should be exercised to avoid the same potential complications.Purpose: To describe a potential complication with the TLIF procedure.Study Design: Case report.Patient Sample: 2.Outcome Measure: Revision surgery.Methods: Case series.Results: Caudal vertebral body fracture is a potential complication after TLIF.Conclusion: TLIF procedures can result in an unstable vertebral body fracture potentially necessitating revision decompression & stabilization. We recommend extra caution in patients with mineral bone disease, as technical errors can be magnified. [ABSTRACT FROM AUTHOR]

Background: Pseudomeningoceles most commonly occur due to prior trauma or surgery and are often located in the posterior paraspinous tissues. Here, we report a case of an intraosseous pseudomeningocele that mimicked an intra-osseous T2 hyperintense lesion in the L1 vertebral body.Case Description: A 64-year-old male presented with back, left lateral thigh and left knee pain lasting several months. He had no prior history of trauma or surgery. Radiographs of the lumbar spine showed mild levoscoliotic curvature of the lumbar spine, Baastrup's changes between the spinous processes, multilevel degenerative disc disease and facet arthropathy. Magnetic resonance imaging (MRI) of the lumbar spine performed without intravenous contrast showed severe spinal canal stenosis from L1-L2 to L3-L4 and moderate spinal canal stenosis at L4-L5. MRI also showed a 2.5-cm T2 hyperintense lesion involving the posterior aspect of the L1 vertebral body, with questionable contiguity with cerebrospinal fluid. Computed tomography (CT) myelogram was performed instead of biopsy. CT myelogram showed contiguity of the lesion with the intrathecal contrast and a rent in the posterior longitudinal ligament and anterior dura consistent with an intraosseous pseudomeningocele. The patient opted for non-operative management of the pseudomeningocele and his lumbar stenosis due to medical comorbidities.Conclusions: This case illustrates a rare case of an intra-osseous pseudomeningocele and highlights the importance of CT myelogram for diagnosis. [ABSTRACT FROM AUTHOR]

Emerging evidence has illustrated the importance of epigenomic reprogramming in cancer, with altered post-translational modifications of histones contributing to pathogenesis. However, the contributions of histone modifiers to breast cancer progression are unclear, and how these processes vary between molecular subtypes has yet to be adequately addressed. Here we report that genetic or pharmacological targeting of the epigenetic modifier Ezh2 dramatically hinders metastatic behaviour in both a mouse model of breast cancer and patient-derived xenografts reflective of the Luminal B subtype. We further define a subtype-specific molecular mechanism whereby EZH2 maintains H3K27me3-mediated repression of the FOXC1 gene, thereby inactivating a FOXC1-driven, anti-invasive transcriptional program. We demonstrate that higher FOXC1 is predictive of favourable outcome specifically in Luminal B breast cancer patients and establish the use of EZH2 methyltransferase inhibitors as a viable strategy to block metastasis in Luminal B breast cancer, where options for targeted therapy are limited. [ABSTRACT FROM AUTHOR]

Urokinase-type plasminogen activator receptor (uPAR) expression is elevated during inflammation and tissue remodelling and in many human cancers, in which it frequently indicates poor prognosis. uPAR regulates proteolysis by binding the extracellular protease urokinase-type plasminogen activator (uPA; also known as urokinase) and also activates many intracellular signalling pathways. Coordination of extracellular matrix (ECM) proteolysis and cell signalling by uPAR underlies its important function in cell migration, proliferation and survival and makes it an attractive therapeutic target in cancer and inflammatory diseases. uPAR lacks transmembrane and intracellular domains and so requires transmembrane co-receptors for signalling. Integrins are essential uPAR signalling co-receptors and a second uPAR ligand, the ECM protein vitronectin, is also crucial for this process. [ABSTRACT FROM AUTHOR]

Small mammals are important predators of gypsy moths ( Lymantria dispar L.), which are major defoliators of deciduous forests in the northeastern United States. Abundance and habitat relationships of small mammals were studied during summers 1984 and 1985 on forested sites at Moshannon and Rothrock state forests in two physiographic regions of Pennsylvania (Allegheny High Plateaus Province and Valley and Ridge Province, respectively) that varied in potential susceptibility to defoliation. The white-footed mouse ( Peromyscus leucopus), which is a major vertebrate predator of gypsy moths, was the most common small mammal on all sites. Of the four common species, northern short-tailed shrews ( Blarina brevicauda), southern red-backed voles ( Clethrionomys gapperi), and white-footed mice were more abundant at Moshannon compared to Rothrock State Forest, but masked shrews ( Sorex cinereus) were more abundant at Rothrock. Elevation was a major factor affecting abundance and distribution of small mammals. Because of the greater abundance of small mammals and more suitable physiographic features at Moshannon compared to Rothrock State Forest, small mammals may be more effective as predators on gypsy moths in the Allegheny High Plateaus than the Valley and Ridge Province of Pennsylvania. [ABSTRACT FROM AUTHOR]

Dysregulation of histone modifications promotes carcinogenesis by altering transcription. Breast cancers frequently overexpress the histone methyltransferase EZH2, the catalytic subunit of Polycomb Repressor Complex 2 (PRC2). However, the role of EZH2 in this setting is unclear due to the context-dependent functions of PRC2 and the heterogeneity of breast cancer. Moreover, the mechanisms underlying PRC2 overexpression in cancer are obscure. Here, using multiple models of breast cancer driven by the oncogene ErbB2, we show that the tyrosine kinase c-Src links energy sufficiency with PRC2 overexpression via control of mRNA translation. By stimulating mitochondrial ATP production, c-Src suppresses energy stress, permitting sustained activation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), which increases the translation of mRNAs encoding the PRC2 subunits Ezh2 and Suz12. We show that Ezh2 overexpression and activity are pivotal in ErbB2-mediated mammary tumourigenesis. These results reveal the hitherto unknown c-Src/mTORC1/PRC2 axis, which is essential for ErbB2-driven carcinogenesis. Polycomb Repressor Complex 2 (PRC2) is frequently up-regulated in cancers. Here, the authors show that the tyrosine kinase c-Src stimulates mitochondrial function to signal energy sufficiency to mTORC1, increasing translation of the PRC2 subunits EZH2 and SUZ12 to support ErbB2-dependent tumours. [ABSTRACT FROM AUTHOR]

We have previously shown that lipoma preferred partner (LPP) mediates TGFβ-induced breast cancer cell migration and invasion. Herein, we demonstrate that diminished LPP expression reduces circulating tumour cell numbers, impairs cancer cell extravasation and diminishes lung metastasis. LPP localizes to invadopodia, along with Tks5/actin, at sites of matrix degradation and at the tips of extravasating breast cancer cells as revealed by intravital imaging of the chick chorioallantoic membrane (CAM). Invadopodia formation, breast cancer cell extravasation and metastasis require an intact LPP LIM domain and the ability of LPP to interact with α-actinin. Finally, we show that Src-mediated LPP phosphorylation at specific tyrosine residues (Y245/301/302) is critical for invadopodia formation, breast cancer cell invasion and metastasis. Together, these data define a previously unknown function for LPP in the formation of invadopodia and reveal a requirement for LPP in mediating the metastatic ability of breast cancer cells. [ABSTRACT FROM AUTHOR]

Purpose: Cervical spines previously posteriorly instrumented and fused with a kyphotic deformity represent a surgical challenge. Current treatment strategies include C7 pedicle subtraction osteotomy or a posterior-anterior-posterior approach, which carry the risk of significant complications. The objective of this study was to attempt to achieve lordosis with multiple anterior cervical discectomy and fusion (ACDF) cages to overpower the posterior instrumentation., Methods: Four adult cadaveric specimens were selected and underwent C3-C7 posterior laminectomy with posterior instrumentation in a kyphotic alignment using a 3.5-mm titanium screw-rod system. Next, ACDF from C3 to C7 was performed with 15° lordotic cages to restore cervical lordosis. Posterior instrumentation was then inspected for failure. Fluoroscopic images were obtained to calculate total construct lordosis and change in segmental lordosis. CT scans were obtained after ACDF to assess for loosening, instrumentation failure, endplate damage, or impaction. Bone mineral density was calculated on CT scans., Results: Age ranged from 59 to 82, and all specimens were male. No gross instrumentation failure was observed. Mean pre-ACDF lordosis between C3 and C7 was 0° (-5° to 5°). Post-ACDF lordosis increased to 37° (35°-38°). Mean segmental lordosis achieved with no endplate destruction was 13.1° (8°-17°). T scores for the cadavers were -0.5, -0.5, -3.2, and -5.1. Two levels of impaction were observed (12.5%). Failure of bone screw interface occurred in the cadaver, with a T score of -5.1 in the middle of the construct., Conclusion: Our study demonstrates the validity of overpowering posterior instrumentation through multiple level ACDF with lordotic cages. This may obviate the need to perform posterior-anterior-posterior procedures., Level of Evidence: Level III., (Copyright © 2018 Scoliosis Research Society. Published by Elsevier Inc. All rights reserved.)