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Maurer V.,Hannover Medical School | Reimers K.,Hannover Medical School | Luck H.J.,Hannover | Vogt P.M.,Hannover Medical School | Bucan V.,Hannover Medical School
Oncology Letters | Year: 2017

The aim of the present study was to use an enzyme-linked immunosorbent assay (ELISA) to determine the concentrations of Lifeguard (LFG) protein in the serum of 36 patients diagnosed with breast cancer and to compare these values with the concentrations of LFG protein in the serum of 7 healthy volunteers in order to detect a possible association between the expression of LFG in the serum and the degree of malignancy of the disease. Although there is no direct association between the LFG protein concentration in the serum and the degree of malignancy of breast cancer, a statistically significant distribution of the concentration in all investigated samples was observed. This indicated an association between the LFG protein concentration in human serum with a currently unknown factor. © 2017, Spandidos Publications. All rights reserved.

Migliori G.B.,World Health Organization | Sotgiu G.,University of Sassari | Gandhi N.R.,Yeshiva University | Falzon D.,World Health Organization | And 69 more authors.
European Respiratory Journal | Year: 2013

The broadest pattern of tuberculosis (TB) drug resistance for which a consensus definition exists is extensively drug-resistant (XDR)-TB. It is not known if additional drug resistance portends worsened patient outcomes. This study compares treatment outcomes of XDR-TB patients with and without additional resistance in order to explore the need for a new definition. Individual patient data on XDR-TB outcomes were included in a meta-analysis comparing outcomes between XDR alone and three nonmutually exclusive XDR-TB patient groups: XDR plus resistance to all the second-line injectables (sli) and capreomycin and kanamycin/amikacin (XDR+2sli) XDR plus resistance to second-line injectables and to more than one group 4 drug, i.e. ethionamide/protionamide, cycloserine/ terizidone or para-aminosalicylic acid (XDR+sliG4) and XDR+sliG4 plus resistance to ethambutol and/or pyrazinamide (XDR+sliG4EZ). Of 405 XDR-TB cases, 301 were XDR alone, 68 XDR+2sli, 48 XDR+sliG4 and 42 XDR+sliG4EZ. In multivariate analysis, the odds of cure were significantly lower in XDR+2sli (adjusted OR 0.4, 95%CI 0.2- 0.8) compared to XDR alone, while odds of failure and death were higher in all XDR patients with additional resistance (adjusted OR 2.6-2.8). Patients with additional resistance beyond XDR-TB showed poorer outcomes. Limitations in availability, accuracy and reproducibility of current drug susceptibility testing methods preclude the adoption of a useful definition beyond the one currently used for XDR-TB. Copyright © ERS 2013.

Pakalniskis M.G.,Hannover | Wells W.A.,Hannover | Wells W.A.,Dartmouth Hitchcock Medical Center | Schwab M.C.,Hannover | And 11 more authors.
Radiology | Year: 2011

Purpose: To investigate if changes in tumor angiogenesis associated with complete pathologic response (pCR) or partial pathologic response (pPR) to treatment can be demonstrated by using diffuse optical spectroscopic (DOS) tomography. Materials and Methods: All participants in this prospective, HIPAA-compliant, institutional review board-approved study provided written informed consent. Eleven women with invasive breast carcinoma were imaged with DOS tomography prior to, during, andat completion of neoadjuvant chemotherapeutic regimens. By using region of interest (ROI) analysis, the DOS measure of total tissue hemoglobin (Hb T ) was temporally correlated with quantitative measures of existing (CD31-expressing) and tumor-induced (CD105-expressing) vessels, in pretreatment and posttreatment tissue specimens, to assess change. Results: Quantifi ed angiogenesis alone in pretreatment core biopsy specimens did not predict treatment response, but mean vessel density (MVD) and mean vessel area (MVA) of CD105-expressing vessels were signifi cantly decreased in women with pCR ( n = 7) ( P < .001 and P = .003, respectively). MVA of CD105-expressing vessels was also signifi cantly reduced at comparison of pre- and posttreatment residual tumor for women with pPR ( n = 4) ( P = .033). A longitudinal analysis showed signifi cant decreases ( P = .001) in mean Hb T levels during neoadjuvant chemotherapy in breast abnormality ROIs for women with pCR but not women with pPR. For women with pCR, but not women with pPR, pretreatment MVD of CD105-expressing vessels correlated with pretreatment Hb T ( P < .001). Conclusion: DOS tomographic examinations in women with breast cancer who are receiving neoadjuvant chemotherapy show a mean decrease in Hb T with time in patients with pCR only. Observed pretreatment and posttreatment correlates with quantifi ed angiogenesis markers confi rm the likely biologic origin for this DOS signature and support its potential to predict angiogenic tissue response early in the treatment cycle. © RSNA, 2011.

Liu X.,Dartmouth Hitchcock Medical Center | Mody K.,Hannover | De Abreu F.B.,Dartmouth Hitchcock Medical Center | Pipas J.M.,Hannover | And 14 more authors.
Clinical Chemistry | Year: 2014

BACKGROUND: Some epithelial neoplasms of the appendix, including low-grade appendiceal mucinous neoplasm and adenocarcinoma, can result in pseudomyxoma peritonei (PMP). Little is known about the mutational spectra of these tumor types and whether mutations may be of clinical significance with respect to therapeutic selection. In this study, we identified somatic mutations using the Ion Torrent AmpliSeq Cancer Hotspot Panel v2. METHODS: Specimens consisted of 3 nonneoplastic retention cysts/mucocele, 15 low-grade mucinous neoplasms (LAMNs), 8 low-grade/well-differentiated mucinous adenocarcinomas with pseudomyxoma peritonei, and 12 adenocarcinomas with/without goblet cell/signet ring cell features. Barcoded libraries were prepared from up to 10 ng of extractedDNAand multiplexed on single 318 chips for sequencing. Data analysis was performed using Golden Helix SVS. Variants that remained after the analysis pipeline were individually interrogated using the Integrative Genomics Viewer. RESULTS: A single Janus kinase 3 (JAK3) mutation was detected in the mucocele group. Eight mutations were identified in the V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and GNAS complex locus (GNAS) genes among LAMN samples. Additional gene mutations were identified in the AKT1(v-akt murine thymoma viral oncogene homolog 1), APC (adenomatous polyposis coli), JAK3, MET (met proto-oncogene), phosphatidylinositol-4,5-bisphosphate 3-kinase (PIK3CA), RB1 (retinoblastoma 1), STK11 (serine/threonine kinase 11), and tumor protein p53 (TP53) genes. Among the PMPs, 6 mutations were detected in the KRAS gene and also in the GNAS, TP53, and RB1 genes. Appendiceal cancers showed mutations in the APC, ATM (ataxia telangiectasia mutated), KRAS, IDH1 [isocitrate dehydrogenase 1 (NADP+)], NRAS [neuroblastoma RAS viral (v-ras) oncogene homolog], PIK3CA, SMAD4 (SMAD family member 4), and TP53 genes. CONCLUSIONS: Our results suggest molecular heterogeneity among epithelial tumors of the appendix. Next generation sequencing efforts have identified mutational spectra in several subtypes of these tumors that may suggest a phenotypic heterogeneity showing mutations that are relevant for targeted therapies. © 2014 American Association for Clinical Chemistry.

Baig M.H.,Hannover | Torresani L.,Hannover
Computer Vision and Image Understanding | Year: 2017

In this work we focus on the problem of colorization for image compression. Since color information occupies a large proportion of the total storage size of an image, a method that can predict accurate color from its grayscale version can produce a dramatic reduction in image file size. But colorization for compression poses several challenges. First, while colorization for artistic purposes simply involves predicting plausible chroma, colorization for compression requires generating output colors that are as close as possible to the ground truth. Second, many objects in the real world exhibit multiple possible colors. Thus, in order to disambiguate the colorization problem some additional information must be stored to reproduce the true colors with good accuracy. To account for the multimodal color distribution of objects we propose a deep tree-structured network that generates for every pixel multiple color hypotheses, as opposed to a single color produced by most prior colorization approaches. We show how to leverage the multimodal output of our model to reproduce with high fidelity the true colors of an image by storing very little additional information. In the experiments we show that our proposed method outperforms traditional JPEG color coding by a large margin, producing colors that are nearly indistinguishable from the ground truth at the storage cost of just a few hundred bytes for high-resolution pictures! © 2017 Elsevier Inc.

Gochman S.R.,Hannover | Gochman S.R.,Dartmouth College | Brown M.B.,Hannover | Dominy N.J.,Hannover | Dominy N.J.,Dartmouth College
Royal Society Open Science | Year: 2016

Recent reports suggest that dietary ethanol, or alcohol, is a supplemental source of calories for some primates. For example, slow lorises (Nycticebus coucang) consume fermented nectars with a mean alcohol concentration of 0.6% (range: 0.0-3.8%). A similar behaviour is hypothesized for aye-ayes (Daubentonia madagascariensis) based on a single point mutation (A294V) in the gene that encodes alcohol dehydrogenase class IV (ADH4), the first enzyme to catabolize alcohol during digestion. The mutation increases catalytic efficiency 40-fold and may confer a selective advantage to aye-ayes that consume the nectar of Ravenala madagascariensis. It is uncertain, however, whether alcohol exists in this nectar or whether alcohol is preferred or merely tolerated by nectarivorous primates. Here, we report the results of a multiple-choice food preference experiment with two aye-ayes and a slow loris. We conducted observer-blind trials with randomized, serial dilutions of ethanol (0-5%) in a standard array of nectarsimulating sucrose solutions. We found that both species can discriminate varying concentrations of alcohol; and further, that both species prefer the highest available concentrations. These results bolster the hypothesized adaptive function of the A294V mutation in ADH4, and a connection with fermented foods, both in aye-ayes and the last common ancestor of African apes and humans. © 2016 The Authors.

Macari E.R.,Hannover | Macari E.R.,Leibniz University of Hanover | Macari E.R.,Dartmouth Hitchcock Medical Center | Schaeffer E.K.,Hannover | And 8 more authors.
Blood | Year: 2013

Although increased fetal hemoglobin (HbF) levels have proven benefit for people with β-hemoglobinopathies, all current HbF-inducing agents have limitations. We previously reported that drugs that activate the NRF2 antioxidant response signaling pathway increase HbF in primary human erythroid cells. In an attempt to increase HbF levels achieved with NRF2 activators, in the present study, we investigated potential complementary activity between these agents and HMG-CoA reductase inhibitors (statins) based on their ability to induce KLF2 protein levels. Experiments in K562 cells showed that simvastatin increased KLF2 mRNA and protein and KLF2 binding to HS2 of the β-globin locus control region and enhanced γ-globin mRNA production by the NRF2 activator Tert-butylhydroquinone (tBHQ). When tested in differentiating primary human erythroid cells, simvastatin induced HbF alone and additively with tBHQ, but it did not increase KLF2 mRNA or locus control region binding above levels seen with normal differentiation. Investigating alternative mechanisms of action, we found that both simvastatin and tBHQ suppress β-globin mRNAand KLF1 and BCL11A mRNAand protein, similar to what is seen in people with an HPFH phenotype because of KLF1 haploinsufficiency. These findings identify statins as a potential class of HbF-inducing agents and suggest a novel mechanism of action based on pharmacologic suppression of KLF1 and BCL11A gene expression. © 2013 by The American Society of Hematology.

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