Following unenhanced MRI assessment for local recurrence after surgical resection of mesenchymal soft tissue tumors,do additional gadolinium-enhanced images change reader confidence or diagnosis?

Purpose

Evaluate if gadolinium enhanced MR imaging (GeMRI) improves confidence, changes the final diagnosis, or improves accuracy in the assessment of musculoskeletal (MSK) tumor residual or recurrence following surgical resection. We also assess if different experience levels change the above results.

Methods and materials

Initially, pre-contrast images were independently reviewed by two radiologists, one with 25 years of experience (R1) and one undergoing MSK specialty training (R2). Two questions were answered: (1) Mass present? and (2) Likelihood of malignancy? Subsequently, both pre-contrast and post-contrast images were independently reviewed. The same questions were again answered plus four others including if GeMRI changed mass characterization, better defined cystic versus solid, better defined tumor extent, or improved conspicuity. Lastly, the readers answered whether GeMRI changed confidence, and changed their final diagnosis. Histologic diagnoses were available in 43 cases, with the remaining 44 cases based upon clinical and/or imaging follow-up.

Results

GeMRI definitely improved confidence in 8/7 cases, and slightly improved confidence in 20/29 cases and changed the final diagnosis in 11/8 cases for R1 and R2 respectively. Positive and negative predictive values statistically improved for R2 (positive predictive value 36.4% versus 50%, p = 0.02; negative predictive value 75.4% versus 79.1%, p = 0.04) but not for R1. Reader concordance for malignancy improved with GeMRI (κ = 0.44 pre-contrast and κ = 0.71 post-contrast).

Conclusion

GeMRI improved reader confidence, improved reader concordance and modestly improved accuracy for the less experienced reader. Where possible, GeMRI should be used in the assessment of MSK tumor residual or recurrence.     

Gene expression profiles of the rat brain both immediately and 3 months following acute sarin exposure

We have studied sarin-induced global gene expression patterns at an early time point (15 min; 0.5xLD50) and a later time point (3 months; 1xLD50) using Affymetrix: Rat Neurobiology U34 chips in male, Sprague-Dawley rats and have identified a total of 65 (early) and 38 (late) genes showing statistically significant alterations from control levels at 15 min and 3 months, respectively. At the early time point, those that are classified as ion channel, cytoskeletal and cell adhesion molecules, in addition to neuropeptides and their receptors predominated over all other groups. The other groups included: cholinergic signaling, calcium channel and binding proteins, transporters, chemokines, GABAnergic, glutamatergic, aspartate, catecholaminergic, nitric oxide synthase, purinergic, and serotonergic signaling molecules. At the late time point, genes that are classified as calcium channel and binding proteins, cytoskeletal and cell adhesion molecules and GABAnergic signaling molecules were most prominent. Seven molecules (Ania-9, Arrb-1, CX-3C, Gabab-1d, Nos-2a, Nrxn-1b, PDE2) were identified that showed altered persistent expression in both time points. Selected genes from each of these time points were further validated using semi quantitative RT-PCR approaches. Some of the genes that were identified in the present study have been shown to be involved in organophosphate-induced neurotoxicity by both other groups as well as ours. Principal component analysis (PCA) of the expression data from both time points was used for comparative analysis of the gene expression, which indicated that the changes in gene expression were a function of dose and time of euthanasia after the treatment. Our model also predicts that besides dose and duration of post-treatment period, age and possibly other factors may be playing important roles in the regulation of pathways, leading to the neurotoxicity.     

Mitogen- and stress-activated protein kinase 1: convergence of the ERK and p38 pathways in Alzheimer's disease

Two of the earliest manifestations of the selective neurodegeneration that occurs in Alzheimer's disease (AD) involve the oxidative modification of various biomacromolecules and the reexpression of a multitude of cell cycle-related proteins. Taken together with the proximal and ectopic increases in activated components of the ERK and p38 pathways, involved in mitotic and cellular stress signaling, respectively, there is a clear and important role for mitotic and oxidative insults in the pathogenesis of AD. Despite the mounting evidence, however, for the causal role of mitogenic abnormalities and oxidative stress in AD pathogenesis, the effect of the converging relevant pathways due to chronic stimulation in AD remains largely unknown. To delineate further the mechanism by which mitogenic and stress signaling cascades converge, we focused on one of the downstream effectors of activated ERK and p38, mitogen- and stress-activated kinase 1 (MSK1). Activated MSK1, phosphorylated at residues Ser376 and Thr581, was upregulated in vulnerable neurons in AD when compared to that in age-matched controls, whereas MSK1 phosphorylated at residue Ser360 was not increased in AD. Furthermore, activated MSK1 phosphorylated at Thr581 colocalized strongly with activated p38 but only weakly with activated ERK, whereas MSK1 phosphorylated at Ser376 colocalized strongly with activated ERK but only weakly with activated p38, suggesting potential preferential phosphorylation sites for the two upstream effectors.     

Pathways of TRH degradation in rat brain

We have investigated the TRH degradative enzymes in brain by examining the pattern of metabolites formed . The homogenate and three subcellular fractions of rat brain were separately incubated for 1, 5, and 15 minutes with ³H-TRH (pyro-glu-his-³H-proNH₂) at 37°C. TRH and its metabolites were separated on silica gel thin-layer chromatography plates. The crude homogenate and subcellular fractions each produced a characteristic pattern of metabolism. The homogenate metabolized TRH to TRH-OH, proline, and prolineamide. With the P₁ fraction, prolineamide and proline were the major metabolites. In both the homogenate and P₁ fraction incubations, histidyl-prolineamide appeared as a minor component. The P₂ fraction produced prolineamide and histidyl-prolineamide as the major metabolites while the cytosol metabolized TRH primarily to TRH-OH. Proline was formed during incubation with both cytosol and P₂ fractions.The TRH deamidase is found in the soluble fraction of brain tissue homogenate while the pyroglutamate aminopeptidase and the prolineamide cleaving enzyme are associated with particulate fractions. Histidyl-prolineamide is further degraded in the homogenate and P₁ fractions by a secondary metabolic pathway. Proline salvaging enzymes are present in all subcellular fractions of rat brain.     

Long Head of the Biceps Tendon (LHBT)

Pathology of the long head of the biceps brachii tendon (LHBT) is a common source of shoulder pain. While a careful history and a thorough physical examination are important steps in the assessment of LHBT pathology, it is still difficult to differentiate the type and severity of the pathology. Currently, the gold standard for confirming a diagnosis of LHBT pathologies is arthroscopic examination. Additionally, MRI is commonly ordered for diagnosis. Since an accurate diagnosis of pathology is critical for treatment success, musculoskeletal ultrasound (MSK US) is an attractive adjunct to the diagnostic process for long head of the biceps pathology due to it being safe, inexpensive and non-invasive. When used in combination with clinical special tests, MSK US can drastically increase the diagnostic accuracy of the clinical examination.     

Perfusion MR imaging at 3-Tesla: Can it predict tumor grade and histologic necrosis rate of musculoskeletal sarcoma?

Purpose

To identify quantitative perfusion parameters that are best associated with tumor grade and tumor necrosis at magnetic resonance (MR) imaging at 3-Tesla.

Angiopoietin2 enhances doxorubin resistance in HepG2 cells by upregulating survivin and Ref-1 via MSK1 activation

Angiopoietin2 (Ang2) and its Tie2 receptor have extensive effects on tumor malignancy including angiogenesis and metastasis. In this study, we evaluated the protective effect of Ang2 on doxorubicin-induced apoptosis in HepG2 cells. Ang2 (400 ng/ml) attenuated doxorubicin-mediated cytotoxicity by upregulating the expression of Survivin and Ref-1, which was reversed by a soluble extracellular domain of Tie2. Mechanistic study showed Ang2 activated ERK–MSK cascade to induce histone H3 phosphorylation and inducible gene expression. The stimulatory effect of Ang2 on anti-apoptotic genes was attenuated by either MSK inhibitor (H89) or by overexpression of a kinase-deficient MSK1. Activated MSK1 phosphorylated the CREB at Ser133 and phosho-CREB was recruited to Ref-1 promoter rapidly to initiate the gene expression. Moreover, knockdown of MSK1 by specific siRNA also attenuated the pro-survival activity of Ang2 and CREB phosphorylation. Hence, our study suggests the existence of an Ang2−ERK−MSK signaling axis mediating survival responses and drug resistance of tumor cells.