Correlated MR spectroscopic imaging of breast cancer to investigate metabolites and lipids: acceleration and compressed sensing reconstruction.

Objectives: The main objective of this work was to detect novel biomarkers in breast cancer by spreading the MR spectra over two dimensions in multiple spatial locations using an accelerated 5D EP-COSI technology. Methods: The 5D EP-COSI data were non-uniformly undersampled with an acceleration factor of 8 and reconstructed using group sparsity-based compressed sensing reconstruction. Different metabolite and lipid ratios were then quantified and statistically analyzed for significance. Linear discriminant models based on the quantified metabolite and lipid ratios were generated. Spectroscopic images of the quantified metabolite and lipid ratios were also reconstructed. Results: The 2D COSY spectra generated using the 5D EP-COSI technique showed differences among healthy, benign, and malignant tissues in terms of their mean values of metabolite and lipid ratios, especially the ratios of potential novel biomarkers based on unsaturated fatty acids, myo-inositol, and glycine. It is further shown the potential of choline and unsaturated lipid ratio maps, generated from the quantified COSY signals across multiple locations in the breast, to serve as complementary markers of malignancy that can be added to the multiparametric MR protocol. Discriminant models using metabolite and lipid ratios were found to be statistically significant for classifying benign and malignant tumor from healthy tissues. Conclusions: Accelerated 5D EP-COSI technique demonstrates the potential to detect novel biomarkers such as glycine, myo-inositol, and unsaturated fatty acids in addition to commonly reported choline in breast cancer, and facilitates metabolite and lipid ratio maps which have the potential to play a significant role in breast cancer detection. Advances in knowledge: This study presents the first evaluation of a multidimensional MR spectroscopic imaging technique for the detection of potentially novel biomarkers based on glycine, myo-inositol, and unsaturated fatty acids, in addition to commonly reported choline. Spatial mapping of choline and unsaturated fatty acid ratios with respect to water in malignant and benign breast masses are also shown. These metabolic characteristics may serve as additional biomarkers for improving the diagnostic and therapeutic evaluation of breast cancer.

Omega-3 fatty acids increase OXPHOS energy for immune therapy of Alzheimer disease patients.

Sporadic late-onset Alzheimer disease (LOAD) preceded by mild cognitive impairment (MCI) is the most common type of dementia. Long-term studies of immunity to pathogenic amyloid-ß (Aß) in LOAD are lacking. Innate immunity of LOAD patients is malfunctioning in phagocytosis and degradation of Aß and LOAD patients' macrophage transcriptome and metabolome are deregulated. We previously showed omega-3 fatty acid (ω-3)-mediated repair of unfolded protein response and here we show much broader transcriptomic effects. ω-3 treatment in vitro and ω-3 supplementation by the drink Smartfish (SMF) in vivo increased the transcripts of the genes and pathways of immunity, glycolysis, tricarboxylic acid cycle, OX-PHOS, nicotinamide dinucleotide (NAD+ ) synthesis, and reversed the defects in Aß phagocytosis. In both peripheral blood mononuclear cells (PBMC) and macrophages, ω-3 increased ATP-linked oxygen consumption rate (OCR) and ω-3 with carnitine was superior to ω-3. ω-3 treatment in vitro and supplementation by the ω-3 drink SMF in vivo rescued macrophage phagocytosis when glycolysis or glycosylation were blocked. ω-3 provide flexible energy for immune clearance of the brain throughout the diurnal cycle, even in hypo- or hyper-glycemia. In certain LOAD patients, ω-3 may delay progression to dementia.

Omega-3 Fatty Acids Increase Amyloid-ß Immunity, Energy, and Circadian Rhythm for Cognitive Protection of Alzheimer's Disease Patients Beyond Cholinesterase Inhibitors.

BACKGROUND: The cholinesterase inhibitor therapeutics (CI) approved for use in Alzheimer's disease (AD) are palliative for a limited time. OBJECTIVE: To examine the outcome of AD patients with add-on therapy of the omega-3 fatty acid drink Smartfish. METHODS: We performed a prospective study using Mini-Mental State Examination, amyloid-ß (Aß) phagocytosis blood assay, and RNA-seq of peripheral blood mononuclear cells in 28 neurodegenerative patients who had failed their therapies, including 8 subjective cognitive impairment (SCI), 8 mild cognitive impairment (MCI), 2 AD dementia, 1 frontotemporal dementia (FTD), 2 vascular cognitive impairment, and 3 dementia with Lewy bodies (DLB) patients. RESULTS: MCI, FTD, and DLB patients patients volunteered for the addition of a ω-3 fatty acid drink Smartfish protected by anti-oxidants to failing CI therapy. On this therapy, all MCI patients improved in the first year energy transcripts, Aß phagocytosis, cognition, and activities of daily living; in the long term, they remained in MCI status two to 4.5 years. All FTD and DLB patients rapidly progressed to dementia. On in vivo or in vitroω-3 treatments, peripheral blood mononuclear cells of MCI patients upregulated energy enzymes for glycolysis and citric acid cycle, as well as the anti-inflammatory circadian genes CLOCK and ARNTL2. CONCLUSION: Add-on ω-3 therapy to CI may delay dementia in certain patients who had failed single CI therapy.

ω-3 Supplementation increases amyloid-ß phagocytosis and resolvin D1 in patients with minor cognitive impairment.

We investigated the effects of 4-17 month supplementation with ω-3 fatty acids and antioxidants (Smartfish drink; Smartfish AS, Oslo, Norway) in 12 patients with minor cognitive impairment (MCI) [minimental state examination (MMSE) ≥19], 2 patients with pre-MCI (normal MMSE), and 7 patients with Alzheimer disease (AD) (MMSE <19). We measured the phagocytosis of amyloid-ß 1-42 (Aß) by flow cytometry and microscopy, the transcription of inflammatory genes by RT-PCR, the production of resolvin D1 (RvD1) by enzyme immunoassay, and the cognitive status by MMSE. In patients with MCI and pre-MCI, phagocytosis of Aß by monocytes increased from 530 to 1306 mean fluorescence intensity units (P = 0.016). The increase in patients with AD was not significant (N.S.). The lipidic mediator RvD1, which stimulates Aß phagocytosis in vitro, increased in macrophages in 80% of patients with MCI and pre-MCI (mean increase 9.95 pg/ml) (N.S.). Transcription of inflammatory genes' mRNAs was increased in a subgroup of patients with low transcription at baseline, whereas it was not significantly changed in patients with high transcription at baseline. The mean MMSE score of patients with MCI and pre-MCI was 25.9 at baseline and 25.7 after 4-17 months (N.S.). Our study is the first to show significant immune and biochemical effects of ω-3 fatty acids with antioxidants in patients with MCI. Cognitive benefits of ω-3 supplementation in patients with MCI should be tested in a clinical trial.

MGAT3 mRNA: a biomarker for prognosis and therapy of Alzheimer's disease by vitamin D and curcuminoids.

Practical biomarkers of Alzheimer's disease (AD) prognosis are lacking. Correspondingly, no drugs are known to decrease disease progression, although vitamin D3 has positive effects on cognition in vivo and 1α, 25-dihydroxyvitamin D3 (1,25 D3) on amyloid-ß 1-42 (Aß) phagocytosis in vitro. We have examined in a pilot study a new biomarker in peripheral blood mononuclear cells, the transcription of mRNA of ß-1,4-mannosyl-glycoprotein 4-ß-N-acetylglucosaminyltransferase (MGAT3), the essential gene for Aß phagocytosis. The transcription of MGAT3 stimulated by Aß distinguishes macrophages into Type 0 (very low MGAT3 transcription), Type I (low MGAT3 transcription up regulated by bisdemethoxycurcumin), and Type II (high MGAT3 transcription down regulated by bisdemethoxycurcumin). In this pilot study of 20 AD patients and 20 control subjects, 45% patients, but only 10% control subjects, were Type 0 (p-value = 0.009). Type 0 AD patients had worse 2-year prognosis regarding loss of independence than Type I and Type II patients (p-value = 0.013). Phagocytosis of Aß in Type I and II patients was shown to be dependent on 1,25 D3 using a specific inhibitor of the 1,25 D3-VDR activated nuclear receptor transcription factor. In a Type II patient, recovery from cognitive dysfunction related to surgical anesthesia was preceded by an improvement in phagocytosis of Aß. The results of this pilot study suggest that the MGAT3 Type biomarker may characterize subgroups of AD patients with different disease progression. In vitro results suggest that vitamin D3 supplementation might be beneficial in both Type I and II patients, whereas curcuminoids only in Type I. These results must be investigated in a large prospective study.

High-throughput screening identifies two classes of antibiotics as radioprotectors: tetracyclines and fluoroquinolones.

PURPOSE: Discovery of agents that protect or mitigate normal tissue from radiation injury during radiotherapy, accidents, or terrorist attacks is of importance. Specifically, bone marrow insufficiency, with possible infection due to immunosuppression, can occur after total body irradiation (TBI) or regional irradiation and is a major component of the acute radiation syndrome. The purpose of this study was to identify novel radioprotectors and mitigators of the hematopoietic system. EXPERIMENTAL DESIGN: High-throughput screening of small-molecule libraries was done using viability of a murine lymphocyte line as a readout with further validation in human lymphoblastoid cells. The selected compounds were then tested for their ability to counter TBI lethality in mice. RESULTS: All of two major classes of antibiotics, tetracyclines and fluoroquinolones, which share a common planar ring moiety, were radioprotective. Furthermore, tetracycline protected murine hematopoietic stem/progenitor cell populations from radiation damage and allowed 87.5% of mice to survive when given before and 35% when given 24 h after lethal TBI. Interestingly, tetracycline did not alter the radiosensitivity of Lewis lung cancer cells. Tetracycline and ciprofloxacine also protected human lymphoblastoid cells, reducing radiation-induced DNA double-strand breaks by 33% and 21%, respectively. The effects of these agents on radiation lethality are not due to the classic mechanism of free radical scavenging but potentially through activation of the Tip60 histone acetyltransferase and altered chromatin structure. CONCLUSIONS: Tetracyclines and fluoroquinolones can be robust radioprotectors and mitigators of the hematopoietic system with potential utility in anticancer radiotherapy and radiation emergencies.

Hepatic encephalopathy: a neurochemical, neuroanatomical, and neuropsychological study.

Hepatic encephalopathy (HE) is normally diagnosed by neuropsychological (NP) tests, which are not very specific and do not reveal the underlying pathology. Magnetic resonance imaging (MRI) and spectroscopy (MRS) of the brain offer alternative and possibly more specific markers for HE. These methods were applied in conjunction with NP testing in order to determine their usefulness in the identification of HE and to understand the pathogenesis of HE more clearly. MR imaging and spectroscopy examinations, in addition to a battery of 15 NP tests, were administered to investigate 31 patients awaiting liver transplantation and 23 healthy controls. MR image intensities from the globus pallidus region were calculated and normalized to those of the thalamus. Absolute concentrations and ratios with respect to creatine (Cr) of several metabolites were computed from MR spectra. The MR data were correlated with the results of NP tests. The patients showed impairment in NP tests of attention and visuospatial and verbal fluency. In T1-weighted MRI, the relative intensity of the globus pallidus with respect to that of the thalamus region was significantly elevated in patients and correlated(negatively) with three NP tests (Hooper, FAS, and Trails B). The absolute concentrations of myo-inositol (mI) and choline (Ch) were significantly reduced in three brain regions. In addition, the absolute concentrations of glutamine (Gln) and combined glutamate and glutamine (Glx) were increased in all three locations, with Gln increase being significant in all areas while that of Glx only in the occipital white matter. In summary, this study partially confirms a hypothesized mechanism of HE pathogenesis, an increased synthesis of glutamine by brain glutamate in astrocytes due to excessive blood ammonia, followed by a compensatory loss of myo-inositol to maintain astrocyte volume homeostasis. It also indicates that the hyperintensity observed in globus pallidus could be used as complementary to the NP test scores in evaluating the mental health of HE patients.

Breast core-needle biopsy: clinical trial of relaxation technique versus medication versus no intervention for anxiety reduction.

PURPOSE: To evaluate effectiveness of oral anxiolytic medication versus relaxation technique for anxiety reduction in women undergoing breast core-needle biopsy (CNB). MATERIALS AND METHODS: The institutional review board reviewed and approved the study. Informed consent was obtained from 143 consecutive women scheduled for breast CNB. Women were randomized as follows: no anxiety intervention (usual care group), relaxation therapy with an audiotape of classical music and ocean sounds during CNB (relaxation group), and 0.5-mg of alprazolam administered orally 15 minutes before CNB (medication group). Anxiety before, during, and 24 hours after the procedure was assessed with State-Trait Anxiety Inventory and self-reported visual analog scale from 0 (no anxiety) to 10 (worst anxiety). Data analysis was performed with statistical software. Descriptive statistics were computed for all variables. Group differences were determined with analysis of variance. Differences in mean values were assessed with Bonferroni multiple comparison procedure. Categorical demographic differences were assessed with chi(2) statistic. RESULTS: Preprocedural State-Trait Anxiety Inventory scores indicated that women were not inherently anxious: usual care group, score of 44.63; relaxation group, 45.74; and medication group, 49.1. Scores represented significantly elevated anxiety for women in all three groups when compared with the normative value of 35.12 (P < .0001), with no statistically significant differences between the scores of the three groups. Women in medication group reported significant reductions in anxiety (-44%) from levels determined before the procedure to levels determined during the procedure (P = .02) and significant reduction during the procedure when compared with changes in usual care (+15%) and relaxation (-8%) groups (P = .02). Women in all three groups reported significant reduction in anxiety from levels determined before the procedure to levels determined at 24 hours after it (P < .0001). There was no significant difference (P = .95) in 24-hour postprocedural anxiety levels among the three groups. CONCLUSION: Use of oral anxiolytic medication before breast CNB can significantly reduce anxiety women experience during the procedure.

Effect of vessel size on creation of hepatic radiofrequency lesions in pigs: assessment of the "heat sink" effect.

OBJECTIVE: The effect of vessels and their size on radiofrequency lesion creation in the liver was evaluated with respect to potential for vascular injury and perfusion-mediated "heat sink" effect. SUBJECTS AND METHODS: Radiofrequency lesions targeted to tissue adjacent to a variety of vessels were created in vivo in the liver of 10 Yorkshire pigs. Postablation contrast-enhanced CT and then histopathologic analysis of the vessels and lesions were performed after sacrifice of the pigs. Degree of vascular injury and viability of perivascular hepatocytes were recorded and tabulated according to vessel size for both CT and histologic data sets. RESULTS: At CT, 42 (95%) of 44 veins greater than 3 mm remained patent, and four (20%) of 20 veins less than 3 mm were occluded. Heat sink effect, indicated by invagination of enhancing tissue between vessel and radiofrequency lesion, was observed in 32 (73%) of 44 veins greater than 3 mm and in zero of 20 veins less than 3 mm. On histopathology, 111 (100%) of 111 vessels less than 3 mm showed at least partial vessel wall injury, characterized by endothelial cell necrosis and luminal thrombus. In 24 vessels greater than 3 mm, the extent of vessel wall injury decreased with increasing vessel diameter. Viable perivascular tissue indicative of heat sink effect was identified in 12 of 24 veins greater than 3 mm, increasing to seven of seven veins greater than 5 mm. None of 96 vessels less than 2 mm and three of 111 vessels less than 3 mm showed any heat sink effect. CONCLUSION: There appears to be a narrow transition zone for hepatic vessels at 2-4 mm, beyond which the heat sink effect was seen consistently and substantial vascular injury was rare.