Publications by authors named "Andrea Müller"

74 Publications

Listeriosis Caused by Persistence of Listeria monocytogenes Serotype 4b Sequence Type 6 in Cheese Production Environment.

Emerg Infect Dis 2021 Jan;27(1):284-288

A nationwide outbreak of human listeriosis in Switzerland was traced to persisting environmental contamination of a cheese dairy with Listeria monocytogenes serotype 4b, sequence type 6, cluster type 7488. Whole-genome sequencing was used to match clinical isolates to a cheese sample and to samples from numerous sites within the production environment.
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http://dx.doi.org/10.3201/eid2701.203266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774546PMC
January 2021

The Occurrence of Sulfated Salicinoids in Poplar and Their Formation by Sulfotransferase1.

Plant Physiol 2020 05 25;183(1):137-151. Epub 2020 Feb 25.

Department of Biochemistry, Max Planck Institute for Chemical Ecology, 07745 Jena, Germany

Salicinoids form a specific class of phenolic glycosides characteristic of the Salicaceae. Although salicinoids accumulate in large amounts and have been shown to be involved in plant defense, their biosynthesis is unclear. We identified two sulfated salicinoids, salicin-7-sulfate and salirepin-7-sulfate, in black cottonwood (). Both compounds accumulated in high amounts in above-ground tissues including leaves, petioles, and stems, but were also found at lower concentrations in roots. A survey of salicin-7-sulfate and salirepin-7-sulfate in a subset of poplar ( sp.) and willow ( sp.) species revealed a broader distribution within the Salicaceae. To elucidate the formation of these compounds, we studied the sulfotransferase () gene family in (). One of the identified genes, , was shown to encode an enzyme able to convert salicin and salirepin into salicin-7-sulfate and salirepin-7-sulfate, respectively. The expression of in different organs of matched the accumulation of sulfated salicinoids in planta. Moreover, RNA interference-mediated knockdown of in gray poplar ( × ) resulted in decreased levels of sulfated salicinoids in comparison to wild-type plants, indicating that SOT1 is responsible for their formation in planta. The presence of a nonfunctional allele in black poplar () was shown to correlate with the absence of salicin-7-sulfate and salirepin-7-sulfate in this species. Food choice experiments with leaves from wild-type and knockdown trees suggest that sulfated salicinoids do not affect the feeding preference of the generalist caterpillar A potential role of the sulfated salicinoids in sulfur storage and homeostasis is discussed.
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http://dx.doi.org/10.1104/pp.19.01447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210634PMC
May 2020

The multicomponent medication Spascupreel attenuates stress-induced gut dysfunction in rats.

Neurogastroenterol Motil 2020 05 14;32(5):e13798. Epub 2020 Feb 14.

INRA, ToxAlim, UMR 1331, Neuro-Gastroenterology and Nutrition Group, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France.

Background: Irritable bowel syndrome (IBS) is a common disorder worldwide. It is characterized by abdominal pain/discomfort and changes in bowel habits. Due to the multifactorial pathophysiology and the heterogeneity of IBS patients, appropriate treatment of IBS is still a challenge. Spascupreel (SP-11), as a multicomponent medication, has the potential to modulate multiple pathophysiological pathways simultaneously. Therefore, the objective of the current study was to investigate the effects of oral SP-11 treatment on stress-induced changes of peripheral and central functions in a rat model mimicking human IBS.

Methods: Naïve Wistar rats were treated with SP-11 (0.9 tab/kg) or NaCl 0.9% by oral gavage for 4 days before 2-hour partial restraint stress (PRS) procedure. Twenty minutes after PRS, central and peripheral stress-induced changes affecting IBS were assessed. These include the hypothalamic-pituitary-adrenal (HPA) axis response through plasma ACTH and corticosterone measurements, visceral pain in response to colorectal distension, gut permeability, colonic mast cell number, and sensitization as well as gut transit time.

Results: Treatment with SP-11 reduced the HPA axis activation in response to PRS. At the gut level, a reduction in colonic hypersensitivity to colorectal distension, a normalization of gut transit time acceleration, a reduced mast cell sensitization, and a trend toward reduced gut hyperpermeability were observed.

Conclusions: These data suggest that stress-induced IBS signs can be reduced using SP-11 in rats. The observed effects and the good tolerability of the drug make SP-11 an innovative candidate in the management of IBS.
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http://dx.doi.org/10.1111/nmo.13798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217055PMC
May 2020

Thyroid Hormone Effects on Mesenchymal Stem Cell Biology in the Tumour Microenvironment.

Exp Clin Endocrinol Diabetes 2020 Jun 24;128(6-07):462-468. Epub 2019 Oct 24.

Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany.

Non-classical thyroid hormone signalling via cell surface receptor integrin αvβ3, expressed on most cancer cells and proliferating endothelial cells, has been shown to drive tumour cell proliferation and survival, as well as angiogenesis. Tumours develop within a complex microenvironment that is composed of many different cell types, including mesenchymal stem cells. These multipotent progenitor cells actively home to growing tumours where they differentiate into cancer-associated fibroblast-like cells and blood vessel-stabilising pericytes and thus support the tumour's fibrovascular network. Integrin αvβ3 expression on mesenchymal stem cells makes them susceptible to thyroid hormone stimulation. Indeed, our studies demonstrated - for the first time - that thyroid hormones stimulate the differentiation of mesenchymal stem cells towards a carcinoma-associated fibroblast-/pericyte-like and hypoxia-responsive, pro-angiogenic phenotype, characterised by the secretion of numerous paracrine pro-angiogenic factors, in addition to driving their migration, invasion, and recruitment to the tumour microenvironment in an experimental hepatocellular carcinoma model. The deaminated thyroid hormone metabolite tetrac, a specific inhibitor of thyroid hormone action at the integrin site, reverses these effects. The modulation of mesenchymal stem cell signalling and recruitment by thyroid hormones via integrin αvβ3 adds a further layer to the multifaceted effects of thyroid hormones on tumour progression, with important implications for the management of cancer patients and suggests a novel mechanism for the anti-tumour activity of tetrac.
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http://dx.doi.org/10.1055/a-1022-9874DOI Listing
June 2020

Poly (ADP-Ribose) Polymerase-1 (PARP1) Deficiency and Pharmacological Inhibition by Pirenzepine Protects From Cisplatin-Induced Ototoxicity Without Affecting Antitumor Efficacy.

Front Cell Neurosci 2019 10;13:406. Epub 2019 Sep 10.

Department of Otorhinolaryngology, Head and Neck Surgery, Tübingen Hearing Research Center, University of Tübingen Medical Center, Tübingen, Germany.

Cisplatin remains an indispensable drug for the systemic treatment of many solid tumors. However, a major dose-limiting side-effect is ototoxicity. In some scenarios, such as treatment of germ cell tumors or adjuvant therapy of non-small cell lung cancer, cisplatin cannot be replaced without undue loss of efficacy. Inhibition of polyadenosine diphosphate-ribose polymerase-1 (PARP1), is presently being evaluated as a novel anti-neoplastic principle. Of note, cisplatin-induced PARP1 activation has been related to inner ear cell death. Thus, PARP1 inhibition may exert a protective effect on the inner ear without compromising the antitumor activity of cisplatin. Here, we evaluated PARP1 deficiency and PARP1 pharmacological inhibition as a means to protect the auditory hair cells from cisplatin-mediated ototoxicity. We demonstrate that cisplatin-induced loss of sensory hair cells in the organ of Corti is attenuated in PARP1-deficient cochleae. The PARP inhibitor pirenzepine and its metabolite LS-75 mimicked the protective effect observed in PARP1-deficient cochleae. Moreover, the cytotoxic potential of cisplatin was unchanged by PARP inhibition in two different cancer cell lines. Taken together, the results from our study suggest that the negative side-effects of cisplatin anti-cancer treatment could be alleviated by a PARP inhibition adjunctive therapy.
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http://dx.doi.org/10.3389/fncel.2019.00406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746891PMC
September 2019

Caligus rogercresseyi infestation is associated with Piscirickettsia salmonis-attributed mortalities in farmed salmonids in Chile.

Prev Vet Med 2019 Nov 6;171:104771. Epub 2019 Sep 6.

Laboratory of Biotechnology and Aquatic Genomics, Interdisciplinary Center for Aquaculture Research (INCAR), University of Concepción, Concepción, Chile. Electronic address:

Caligidosis and Piscirickettsiosis are currently the most important sanitary challenges for the Chilean salmon industry. Caligidosis is caused by the ectoparasite, Caligus rogercresseyi and Piscirickettsiosis is caused by the intracellular bacterium, Piscirickettsia salmonis. Both diseases are highly prevalent and widely distributed in farming areas in Chile. The co-occurrence of the two diseases is frequently reported on salmon farms. However, there is little epidemiological evidence as to whether these two diseases are associated and generate interactive effects. This study was undertaken to evaluate the potential effects of C. rogercresseyi infestation on P. salmonis-attributed mortalities in farmed salmonids in Chile. Using a linear regression model, the potential association between the mean abundance of adult C. rogercresseyi in a period of 10 weeks and Piscirickettsiosis cumulative mortalities observed in the following 10 weeks was evaluated, while controlling for important confounders. These two 10-week windows were set around the time-point at which Piscirickettsiosis weekly mortality exceeded 0.1% for the first time in a production cycle. We found that the mean abundance of adult C. rogercresseyi was significantly associated with the Piscirickettsiosis cumulative mortality, suggesting the two diseases have a synergistic relationship. This relationship was of the same intensity in Atlantic salmon and rainbow trout. Our findings highlight the importance of taking effective control measures for C. rogercresseyi as a part of the strategies in place to reduce P. salmonis-attributed mortalities on salmon farms in Chile.
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http://dx.doi.org/10.1016/j.prevetmed.2019.104771DOI Listing
November 2019

Occurrence of relevant mycotoxins in food commodities consumed in Chile.

Mycotoxin Res 2020 Feb 29;36(1):63-72. Epub 2019 Jul 29.

Department of Food Science and Technology, Faculty of Pharmacy, University of Concepción, Concepción, Chile.

The aims of this study were to analyse the occurrence of aflatoxins, aflatoxin M1 (AFM), fumonisins, ochratoxin A (OTA), patulin (PAT), zearalenone (ZEN) and deoxynivalenol (DON) in foodstuffs consumed in Chile between 2008 and 2017 and to estimate the contribution of main contaminated foodstuff in human exposure by the probable daily intake (PDI) estimation. In 9 years of surveillance, 2020 food samples were analysed with an occurrence of 18.2% and with 2.7% of the samples being over the Chilean regulation. The occurrence of mycotoxins in food were 16% for aflatoxins, 6% for AFM, 30% for OTA, 12% for DON, 7% for PAT, 21% for fumonisins and 2% for ZEN. The estimated median PDI of DON because of bread consumption was 129.2 ng/kg bw/day for children and 96.0 ng/kg bw/day in adults. Median PDI because of capsicum consumption was 0.006 ng/kg bw/day for OTA and 0.005 ng/kg bw/day for aflatoxins. Median PDI of aflatoxins was estimated at 0.02 ng/kg bw/day for spices and 0.04 ng/kg bw/day for nuts consumption. In children, the median PDI of AFM for dairy consumption was 0.07 ng/kg bw/day. The derived margin of exposure (MoE) values ranged from 1133 to 8500 suggested that aflatoxins would be of public health concern. The PDI of the other mycotoxins did not show a health risk. This is the first survey of mycotoxins in food made in Chile; further research is needed to improve surveillance and guidelines based on national risk assessments and considering sensitive population groups.
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http://dx.doi.org/10.1007/s12550-019-00369-5DOI Listing
February 2020

Draft Genome Sequence of Salmonella bongori N19-781, a Clinical Strain from a Patient with Diarrhea.

Microbiol Resour Announc 2019 Jul 18;8(29). Epub 2019 Jul 18.

Institute for Food Safety and Hygiene, Vetsuisse Faculty, University of Zurich, Zurich, Switzerland.

The genome of N19-781, a strain isolated from a patient with diarrhea, was sequenced. It consists of a 4.5-Mbp chromosome.
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http://dx.doi.org/10.1128/MRA.00691-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639624PMC
July 2019

Process design and development of a mammalian cell perfusion culture in shake-tube and benchtop bioreactors.

Biotechnol Bioeng 2019 08 19;116(8):1973-1985. Epub 2019 May 19.

Department of Chemistry and Applied Biosciences, Institute of Chemical and Bioengineering, ETH Zurich, Zurich, Switzerland.

The development of mammalian cell perfusion cultures is still laborious and complex to perform due to the limited availability of scale-down models and limited knowledge of time- and cost-effective procedures. The maximum achievable viable cell density (VCD ), minimum cell-specific perfusion rate (CSPR ), cellular growth characteristics, and resulting bleed rate at steady-state operation are key variables for the effective development of perfusion cultures. In this study, we developed a stepwise procedure to use shake tubes (ST) in combination with benchtop (BR) bioreactors for the design of a mammalian cell perfusion culture at high productivity (23 pg·cell ·day ) and low product loss in the bleed (around 10%) for a given expression system. In a first experiment, we investigated peak VCDs in STs by the daily discontinuous medium exchange of 1 reactor volume (RV) without additional bleeding. Based on this knowledge, we performed steady-state cultures in the ST system using a working volume of 10 ml. The evaluation of the steady-state cultures allowed performing a perfusion bioreactor run at 20 × 10 cells/ml at a perfusion rate of 1 RV/day. Constant cellular environment and metabolism resulted in stable product quality patterns. This study presents a promising strategy for the effective design and development of perfusion cultures for a given expression system and underlines the potential of the ST system as a valuable scale-down tool for perfusion cultures.
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http://dx.doi.org/10.1002/bit.26999DOI Listing
August 2019

Twenty-year trends in the characteristic, management and outcome of patients with ST-elevation myocardial infarction and out-of-hospital reanimation. Insight from the national AMIS PLUS registry 1997-2017.

Resuscitation 2019 01 15;134:55-61. Epub 2018 Nov 15.

AMIS Plus Data Center, Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Switzerland.

Background: Few studies describe recent changes in the incidence, treatment and outcome of successfully resuscitated STEMI patients after out-of-hospital cardiac arrest (OHCA) compared with non-OHCA STEMI patients.

Objective: To examine temporal trends in the incidence, therapeutic management, most serious complications, mortality rate and outcome of OHCA patients fulfilling criteria of STEMI compared with a reference group of STEMI patients without OHCA.

Methods: Analysis of registry data (AMIS Plus Registry) among STEMI patients both with and without OHCA between 1997 and 2017.

Results: Among 31,650 patients with STEMI, 6.8% were successfully resuscitated prior to hospital admission. Increasing incidences of hospital-admitted patients following successful out-of-hospital CPR were observed (4.5% in 1999 vs. 8.6% in 2017). OHCA STEMI patients were at higher clinical risk at presentation (36.1% vs. 2.7%; p < 0.001 with cardiogenic shock) despite a shorter time span from the onset of symptoms to hospitalization (195 min vs. 107 min; p < 0.001) and a lower prevalence of cardiovascular risk factors except smoking. More PCIs were performed in STEMI patients with OHCA (78.9% vs. 74.5% for non-OHCA patients; p < 0.001). However, over time PCI became the preferred primary intervention irrespective of the OHCA status of STEMI patients. For STEMI patients without OHCA, there was a significant correlation between PCI and time periods on in-hospital mortality (p < 0.001), which was p = 0.002 when adjusted for age and gender. For STEMI patients with OHCA, the interaction between PCI and time was unadjusted p = 0.395 and p = 0.438 when adjusted for age and gender.
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http://dx.doi.org/10.1016/j.resuscitation.2018.11.010DOI Listing
January 2019

High glucose and low specific cell growth but not mild hypothermia improve specific r-protein productivity in chemostat culture of CHO cells.

PLoS One 2018 16;13(8):e0202098. Epub 2018 Aug 16.

School of Biochemical Engineering, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile.

In the biopharmaceutical sector, Chinese hamster ovary (CHO) cells have become the host of choice to produce recombinant proteins (r-proteins) due to their capacity for correct protein folding, assembly, and posttranslational modification. However, the production of therapeutic r-proteins in CHO cells is expensive and presents insufficient production yields for certain proteins. Effective culture strategies to increase productivity (qp) include a high glucose concentration in the medium and mild hypothermia (28-34 °C), but these changes lead to a reduced specific growth rate. To study the individual and combined impacts of glucose concentration, specific growth rate and mild hypothermia on culture performance and cell metabolism, we analyzed chemostat cultures of recombinant human tissue plasminogen activator (rh-tPA)-producing CHO cell lines fed with three glucose concentrations in feeding media (20, 30 and 40 mM), at two dilution rates (0.01 and 0.018 1/h) and two temperatures (33 and 37 °C). The results indicated significant changes in cell growth, cell cycle distribution, metabolism, and rh-tPA productivity in response to the varying environmental culture conditions. High glucose feed led to constrained cell growth, increased specific rh-tPA productivity and a higher number of cells in the G2/M phase. Low specific growth rate and temperature (33 °C) reduced glucose consumption and lactate production rates. Our findings indicated that a reduced specific growth rate coupled with high feed glucose significantly improves r-protein productivity in CHO cells. We also observed that low temperature significantly reduced qp, but not cell growth when dilution rate was manipulated, regardless of the glucose concentration or dilution rate. In contrast, we determined that feed glucose concentration and consumption rate were the dominant aspects of the growth and productivity in CHO cells by using multivariate analysis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0202098PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6095543PMC
January 2019

Ropivacaine Plasma Concentrations after 192-Hour High Dose Epidural Ropivacaine Infusion in a Pediatric Patient without Side Effects.

Case Rep Anesthesiol 2018 11;2018:9150980. Epub 2018 Jul 11.

Department of Anesthesiology, Pain and Palliative Medicine, Radboudumc, Nijmegen, Netherlands.

This case report discusses continuous epidural administration of ropivacaine 0.56 mg kg h for 8 days in a 7-year-old trauma patient to prevent pain, after performing a lower right and upper left leg guillotine amputation. Venous sampling after 8 days revealed bound and unbound ropivacaine concentrations of 1.1 mg/l and 0.06 mg/l in plasma, respectively. Arterial sampling for bound and unbound ropivacaine was 1.2 mg/l and 0.05 mg/l in plasma, respectively. In this case report, long-term high dose epidural infiltration of ropivacaine did not result in severe side effects or complications. Further studies are needed to explore safety of these concentrations in larger populations of children.
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http://dx.doi.org/10.1155/2018/9150980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6076945PMC
July 2018

OMV-based vaccine formulations against Shiga toxin producing Escherichia coli strains are both protective in mice and immunogenic in calves.

Hum Vaccin Immunother 2018 12;14(9):2208-2213. Epub 2018 Jul 12.

c Instituto Finlay , La Habana , Cuba.

Strains of Shiga toxin-producing Escherichia coli (STEC) can cause the severe Hemolytic Uremic Syndrome (HUS). Shiga toxins are protein toxins that bind and kill microvascular cells, damaging vital organs. No specific therapeutics or vaccines have been licensed for use in humans yet. The most common route of infection is by consumption of dairy or farm products contaminated with STEC. Domestic cattle colonized by STEC strains represent the main reservoir, and thus a source of contamination. Outer Membrane Vesicles (OMV) obtained after detergent treatment of gram-negative bacteria have been used over the past decades for producing many licensed vaccines. These nanoparticles are not only multi-antigenic in nature but also potent immunopotentiators and immunomodulators. Formulations based on chemical-inactivated OMV (OMVi) obtained from a virulent STEC strain (O157:H7 serotype) were found to protect against pathogenicity in a murine model and to be immunogenic in calves. These initial studies suggest that STEC-derived OMV has a potential for the formulation of both human and veterinary vaccines.
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http://dx.doi.org/10.1080/21645515.2018.1490381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6183318PMC
May 2019

External Beam Radiation Therapy Enhances Mesenchymal Stem Cell-Mediated Sodium-Iodide Symporter Gene Delivery.

Hum Gene Ther 2018 11 3;29(11):1287-1300. Epub 2018 May 3.

1 Department of Internal Medicine IV, University Hospital of Munich , LMU Munich, Munich, Germany .

The tumor-homing properties of mesenchymal stem cells (MSC) have led to their development as delivery vehicles for the targeted delivery of therapeutic genes such as the sodium-iodide symporter (NIS) to solid tumors. External beam radiation therapy may represent an ideal setting for the application of engineered MSC-based gene therapy, as tumor irradiation may enhance MSC recruitment into irradiated tumors through the increased production of select factors linked to MSC migration. In the present study, the irradiation of human liver cancer cells (HuH7; 1-10 Gy) showed a strong dose-dependent increase in steady-state mRNA levels of CXCL8, CXCL12, FGF2, PDGFB, TGFB1, THBS1, and VEGF (0-48 h), which was verified for most factors at the protein level (after 48 h). Radiation effects on directed MSC migration were tested in vitro using a live cell tracking migration assay and supernatants from control and irradiated HuH7 cells. A robust increase in mean forward migration index, mean center of mass, and mean directionality of MSCs toward supernatants was seen from irradiated as compared to non-irradiated tumor cells. Transferability of this effect to other tumor sources was demonstrated using the human breast adenocarcinoma cell line (MDA-MB-231), which showed a similar behavior to radiation as seen with HuH7 cells in quantitative polymerase chain reaction and migration assay. To evaluate this in a more physiologic in vivo setting, subcutaneously growing HuH7 xenograft tumors were irradiated with 0, 2, or 5 Gy followed by CMV-NIS-MSC application 24 h later. Tumoral iodide uptake was monitored using I-scintigraphy. The results showed increased tumor-specific dose-dependent accumulation of radioiodide in irradiated tumors. The results demonstrate that external beam radiation therapy enhances the migratory capacity of MSCs and may thus increase the therapeutic efficacy of MSC-mediated NIS radionuclide therapy.
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http://dx.doi.org/10.1089/hum.2018.025DOI Listing
November 2018

EGFR-targeted nonviral NIS gene transfer for bioimaging and therapy of disseminated colon cancer metastases.

Oncotarget 2017 Nov 16;8(54):92195-92208. Epub 2017 Sep 16.

Department of Internal Medicine IV, University Hospital of Munich, LMU Munich, Munich, Germany.

Liver metastases present a serious problem in the therapy of advanced colorectal cancer (CRC), as more than 20% of patients have distant metastases at the time of diagnosis with less than 5% being cured. Consequently, new therapeutic approaches are of major need together with high-resolution imaging methods that allow highly specific detection of small metastases. The unique combination of reporter and therapy gene function of the sodium iodide symporter (NIS) may represent a promising theranostic strategy for CRC liver metastases allowing non-invasive imaging of functional NIS expression and therapeutic application of I. For targeted NIS gene transfer polymers containing linear polyethylenimine (LPEI), polyethylene glycol (PEG) and the epidermal growth factor receptor (EGFR)-specific ligand GE11 were complexed with human NIS DNA (LPEI-PEG-GE11/NIS). Tumor specificity and transduction efficiency were examined in high EGFR-expressing LS174T metastases by non-invasive imaging using F-tetrafluoroborate (F-TFB) as novel NIS PET tracer. Mice that were injected with LPEI-PEG-GE11/NIS 48 h before F-TFB application showed high tumoral levels (4.8±0.6% of injected dose) of NIS-mediated radionuclide uptake in comparison to low levels detected in mice that received untargeted control polyplexes. Three cycles of intravenous injection of EGFR-targeted NIS polyplexes followed by therapeutic application of 55.5 MBq I resulted in marked delay in metastases spread, which was associated with improved animal survival. In conclusion, these preclinical data confirm the enormous potential of EGFR-targeted synthetic polymers for systemic NIS gene delivery in an advanced multifocal CRC liver metastases model and open the exciting prospect of NIS-mediated radionuclide therapy in metastatic disease.
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http://dx.doi.org/10.18632/oncotarget.21028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5696174PMC
November 2017

Aldosterone and renin in cardiac patients referred for catheterization.

Medicine (Baltimore) 2017 Jun;96(25):e7282

Laboratory of Signal Transduction, Department of Biomedicine, University Hospital Basel, Hebelstrasse, Basel Department of Cardiology, Luzerner Kantonsspital, Spitalstrasse, Luzern Clinica dell'Ipertensione Arteriosa, Department of Medicine, University Hospital of Padua, Padua, Italy Division of Biostatistics, University of Zurich, EBPI, Hirschengraben, Zürich Institute Viollier, Hagmattstrasse, Allschwil, Switzerland Inovise Medical, Inc., Creekside Corporate Park, Nimbus Ave D, Beaverton, OR AMIS Plus Data Center, University of Zurich, EBPI, Hirschengraben, Zurich, Switzerland.

Little is known regarding alterations of the renin-angiotensin system in patients referred for cardiac catheterization. Here, we measured plasma levels of active renin and aldosterone in patients referred for cardiac catheterization in order to determine the prevalence of elevated renin, aldosterone, and the aldosterone-renin ratio.A chemiluminescence assay was used to measure plasma aldosterone concentration (PAC) and active renin levels in 833 consecutive patients, after an overnight fasting and without any medication for least 12 hours. We evaluated associations of the hormonal elevations in relation to hypertension, atrial fibrillation (AF), hypertensive cardiomyopathy, coronary artery disease (CAD), valvular disease, impaired left ventricular ejection fraction (LVEF < 35%), and pulmonary hypertension (arterial pulmonary mean pressure >25 mm Hg).Hyperaldosteronism occurred in around one-third of all examined patients, without significant differences between patients with or without the named cardiac diseases. In a comparison between patients with or without any given cardiac disease condition, renin was significantly elevated in patients with either hypertension (36.4% vs 15.9%), CAD (33.9% vs 22.1%), or impaired LVEF (47.3% vs 24.8%). The angiotensin-renin ratio was elevated in AF patients and in patients with hypertensive cardiomyopathy. Patients with AF and coexisting hypertension had elevated renin more frequently than AF patients without coexisting hypertension (35.3% vs 16.5%; P  =  .005). Patients with persistent/permanent AF more frequently had elevated renin than patients with paroxysmal AF (34.1% vs 15.8%; P  =  .007).This prospective study of consecutive cardiac disease patients referred for cardiac catheterization has revealed distinct cardiac disease condition-associated differences in the frequencies of elevations in plasma renin, PAC, and the aldosterone-renin ratio.
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http://dx.doi.org/10.1097/MD.0000000000007282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5484248PMC
June 2017

RNA-Guided Cas9-Induced Mutagenesis in Tobacco Followed by Efficient Genetic Fixation in Doubled Haploid Plants.

Front Plant Sci 2016 4;7:1995. Epub 2017 Jan 4.

Plant Reproductive Biology, Physiology and Cell Biology, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben, Germany.

Customizable endonucleases are providing an effective tool for genome engineering. The resulting primary transgenic individuals (T) are typically heterozygous and/or chimeric with respect to any mutations induced. To generate genetically fixed mutants, they are conventionally allowed to self-pollinate, a procedure which segregates individuals into mutant heterozygotes/homozygotes and wild types. The chances of recovering homozygous mutants among the progeny depend not only on meiotic segregation but also on the frequency of mutated germline cells in the chimeric mother plant. In species, the heritability of Cas9-induced mutations has not been demonstrated yet. RNA-guided Cas9 endonuclease-mediated mutagenesis was targeted to the () gene harbored by a transgenic tobacco line. Upon retransformation using a -specific guide RNA/Cas9 construct, the T plants were allowed to either self-pollinate, or were propagated via regeneration from cultured embryogenic pollen which give rise to haploid/doubled haploid plants or from leaf explants that form plants vegetatively. Single or multiple mutations were detected in 80% of the T plants. About half of these mutations proved heritable via selfing. Regeneration from cultured embryogenic pollen allowed for homozygous mutants to be produced more efficiently than via sexual reproduction. Consequently, embryogenic pollen culture provides a convenient method to rapidly generate a variety of genetically fixed mutants following site-directed mutagenesis. The recovery of a mutation not found among sexually produced and analyzed progeny was shown to be achievable through vegetative plant propagation , which eventually resulted in heritability when the somatic clones were selfed. In addition, some in-frame mutations were associated with functional attenuation of the target gene rather than its full knock-out. The generation of mutants with compromised rather than abolished gene functionality holds promise for future approaches to the conclusive functional validation of genes which are indispensible for the plant.
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http://dx.doi.org/10.3389/fpls.2016.01995DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5209389PMC
January 2017

From the exposome to mechanistic understanding of chemical-induced adverse effects.

Environ Int 2017 Feb 8;99:97-106. Epub 2016 Dec 8.

US EPA, National Center for Computational Toxicology, Research Triangle Park, NC 27711, USA.

The exposome encompasses an individual's exposure to exogenous chemicals, as well as endogenous chemicals that are produced or altered in response to external stressors. While the exposome concept has been established for human health, its principles can be extended to include broader ecological issues. The assessment of exposure is tightly interlinked with hazard assessment. Here, we explore if mechanistic understanding of the causal links between exposure and adverse effects on human health and the environment can be improved by integrating the exposome approach with the adverse outcome pathway (AOP) concept that structures and organizes the sequence of biological events from an initial molecular interaction of a chemical with a biological target to an adverse outcome. Complementing exposome research with the AOP concept may facilitate a mechanistic understanding of stress-induced adverse effects, examine the relative contributions from various components of the exposome, determine the primary risk drivers in complex mixtures, and promote an integrative assessment of chemical risks for both human and environmental health.
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http://dx.doi.org/10.1016/j.envint.2016.11.029DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6116522PMC
February 2017

Assessment of the risk of foodborne transmission and burden of hepatitis E in Switzerland.

Int J Food Microbiol 2017 Feb 22;242:107-115. Epub 2016 Nov 22.

SAFOSO AG, Waldeggstrasse 1, CH 3097 Liebefeld, Switzerland. Electronic address:

The objective of this study was i) to quantify the risk of hepatitis E for Swiss consumers by specified pork products and ii) to estimate the total burden of human food-borne hepatitis E in Switzerland. A quantitative risk assessment from slaughter to consumption was carried out according to the Codex Alimentarius framework. In the hazard characterization, assumptions were made due to the lack of a dose-response relationship for oral exposure to hepatitis E virus (HEV). The prevalence of HEV in 160 pig livers of 40 different Swiss fattening farms was examined and determined to be 1.3% (CI 0.3%; 4.4%). This result was used as input in the risk assessment model, together with data from other published studies. The annual burden of hepatitis E was estimated in terms of Disability Adjusted Life Years (DALY), using data about hepatitis E cases diagnosed between 2010 and 2015 at two major hospitals located in the canton Ticino. Only the risk of foodborne hepatitis E from products containing pork liver was evaluated, as those containing only pork meat could not be evaluated because of lack of data on HEV load in pork. Assuming that successful oral infection occurs in 1% of servings contaminated with high HEV loads (>10 genome copies), and that acute illness develops in 5% of susceptible consumers, the most likely annual number of foodborne hepatitis E cases in Switzerland was estimated to be 1481 (95% CI 552; 4488) if all products containing pork liver were considered. If only high-risk products, such as plain pork liver and liver sausages (e.g. Saucisse au Foie), were considered, the annual number of cases was estimated to be 176 (95% CI 64; 498). We were unable to calculate the total burden of hepatitis E in Switzerland due to lack of data. Yet, for the canton Ticino, it was shown that a significant increase had occurred from <5 DALY per 100,000 inhabitants before 2012 to >50 DALY per 100,000 inhabitants in 2015. This change could partly be due to an increased reporting and higher awareness among medical practitioners. Extrapolation to other regions could be accomplished if detailed information on food consumption patterns were available. Notification of HEV cases and attempts of cases source attribution would improve the basis for risk assessments.
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http://dx.doi.org/10.1016/j.ijfoodmicro.2016.11.018DOI Listing
February 2017

Effect of Increased Blood Flow on Pulmonary Circulation Before and During High Altitude Acclimatization.

High Alt Med Biol 2016 Dec 18;17(4):305-314. Epub 2016 Oct 18.

1 Medical Intensive Care Unit, University Hospital of Zurich , Switzerland .

Matthias Peter Hilty, Andrea Mueller, Daniela Flück, Christoph Siebenmann, Peter Rasmussen, Stefanie Keiser, Katja Auinger, Carsten Lundby, and Marco Maggiorini. Effect of increased blood flow on the pulmonary circulation before and during high altitude acclimatization. High Alt Med Biol. 17:305-314, 2016.-Introduction and Methods: Acute exposure to high altitude increases pulmonary artery pressure (Ppa) and pulmonary vascular resistance (PVR). The evolution of Ppa and PVR with continuous hypoxic exposure remains, however, elusive. To test the hypothesis that altitude exposure leads to a persistent elevation in Ppa and PVR throughout acclimatization in seven healthy male subjects, echocardiography was performed at sea level (SL; 488 m) weekly during a 4-week sojourn at 3454 m (HA1-HA4) and upon return (SL2). Pulmonary artery catheterization and bilateral thigh cuff release maneuver were performed at SL and HA3 to study the properties of pulmonary circulation after 3 weeks of acclimatization.

Results: Pulmonary artery catheter determined that systolic Ppa (mean ± SEM) was increased from 20 ± 1 at SL to 27 ± 2 mmHg at HA3 (p < 0.01). Echocardiography assessed that systolic Ppa remained equally increased throughout acclimatization (26 ± 2, 25 ± 2, 25 ± 2, and 24 ± 2 mmHg at HA1-HA4; p = 0.93) and returned to baseline upon return (17 ± 2, 18 ± 1 mmHg at SL, SL2; p = 0.3). The same was shown for PVR. Right heart function remained unaffected. Thigh cuff release maneuvers at SL and HA3 resulted in similar increase in cardiac output (2.5 ± 0.5 and 2.2 ± 0.4 L/min; p = 0.61) without affecting mean Ppa.

Conclusions: Prolonged altitude exposure leads to a persistent increase in Ppa and PVR without affecting right heart function and is fully reversible within 1 week after return to SL. The thigh cuff release maneuver-induced increase in cardiac output suggests a preserved ability of pulmonary circulation to cope with sudden remarkable increase in pulmonary blood flow throughout acclimatization.
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http://dx.doi.org/10.1089/ham.2016.0004DOI Listing
December 2016

Hypoxia-targeted 131I therapy of hepatocellular cancer after systemic mesenchymal stem cell-mediated sodium iodide symporter gene delivery.

Oncotarget 2016 Aug;7(34):54795-54810

Department of Internal Medicine II, University Hospital of Munich, Ludwig Maximilian University of Munich, Munich, Germany.

Adoptively transferred mesenchymal stem cells (MSCs) home to solid tumors. Biologic features within the tumor environment can be used to selectively activate transgenes in engineered MSCs after tumor invasion. One of the characteristic features of solid tumors is hypoxia. We evaluated a hypoxia-based imaging and therapy strategy to target expression of the sodium iodide symporter (NIS) gene to experimental hepatocellular carcinoma (HCC) delivered by MSCs.MSCs engineered to express transgenes driven by a hypoxia-responsive promoter showed robust transgene induction under hypoxia as demonstrated by mCherry expression in tumor cell spheroid models, or radioiodide uptake using NIS. Subcutaneous and orthotopic HCC xenograft mouse models revealed significant levels of perchlorate-sensitive NIS-mediated tumoral radioiodide accumulation by tumor-recruited MSCs using 123I-scintigraphy or 124I-positron emission tomography. Functional NIS expression was further confirmed by ex vivo 123I-biodistribution analysis. Administration of a therapeutic dose of 131I in mice treated with NIS-transfected MSCs resulted in delayed tumor growth and reduced tumor perfusion, as shown by contrast-enhanced sonography, and significantly prolonged survival of mice bearing orthotopic HCC tumors. Interestingly, radioiodide uptake into subcutaneous tumors was not sufficient to induce therapeutic effects. Our results demonstrate the potential of using tumor hypoxia-based approaches to drive radioiodide therapy in non-thyroidal tumors.
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http://dx.doi.org/10.18632/oncotarget.10758DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5342382PMC
August 2016

Sequence-defined cMET/HGFR-targeted Polymers as Gene Delivery Vehicles for the Theranostic Sodium Iodide Symporter (NIS) Gene.

Mol Ther 2016 08 9;24(8):1395-404. Epub 2016 May 9.

Department of Internal Medicine II, LMU Munich, Munich, Germany.

The sodium iodide symporter (NIS) as well-characterized theranostic gene represents an outstanding tool to target different cancer types allowing noninvasive imaging of functional NIS expression and therapeutic radioiodide application. Based on its overexpression on the surface of most cancer types, the cMET/hepatocyte growth factor receptor serves as ideal target for tumor-selective gene delivery. Sequence-defined polymers as nonviral gene delivery vehicles comprising polyethylene glycol (PEG) and cationic (oligoethanoamino) amide cores coupled with a cMET-binding peptide (cMBP2) were complexed with NIS-DNA and tested for receptor-specificity, transduction efficiency, and therapeutic efficacy in hepatocellular cancer cells HuH7. In vitro iodide uptake studies demonstrated high transduction efficiency and cMET-specificity of NIS-encoding polyplexes (cMBP2-PEG-Stp/NIS) compared to polyplexes without targeting ligand (Ala-PEG-Stp/NIS) and without coding DNA (cMBP2-PEG-Stp/Antisense-NIS). Tumor recruitment and vector biodistribution were investigated in vivo in a subcutaneous xenograft mouse model showing high tumor-selective iodide accumulation in cMBP2-PEG-Stp/NIS-treated mice (6.6 ± 1.6% ID/g (123)I, biological half-life 3 hours) by (123)I-scintigraphy. Therapy studies with three cycles of polyplexes and (131)I application resulted in significant delay in tumor growth and prolonged survival. These data demonstrate the enormous potential of cMET-targeted sequence-defined polymers combined with the unique theranostic function of NIS allowing for optimized transfection efficiency while eliminating toxicity.
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http://dx.doi.org/10.1038/mt.2016.95DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5023389PMC
August 2016

Establishment of an Effective Radioiodide Thyroid Ablation Protocol in Mice.

Eur Thyroid J 2015 Sep 23;4(Suppl 1):74-80. Epub 2015 May 23.

Department of Internal Medicine II, Munich, Germany.

Due to the high variance in available protocols on iodide-131 ((131)I) ablation in rodents, we set out to establish an effective method to generate a thyroid-ablated mouse model that allows the application of the sodium iodide symporter (NIS) as a reporter gene without interference with thyroidal NIS. We tested a range of (131)I doses with and without prestimulation of thyroidal radioiodide uptake by a low-iodine diet and thyroid-stimulating hormone (TSH) application. Efficacy of induction of hypothyroidism was tested by measurement of serum T4 concentrations, pituitary TSHβ and liver deiodinase type 1 (DIO1) mRNA expression, body weight analysis, and (99m)Tc-pertechnetate scintigraphy. While 200 µCi (7.4 MBq) (131)I alone was not sufficient to abolish thyroidal T4 production, 500 µCi (18.5 MBq) (131)I combined with 1 week of a low-iodine diet decreased serum concentrations below the detection limit. However, the high (131)I dose resulted in severe side effects. A combination of 1 week of a low-iodine diet followed by injection of bovine TSH before the application of 150 µCi (5.5 MBq) (131)I decreased serum T4 concentrations below the detection limit and significantly increased pituitary TSHβ concentrations. The systemic effects of induced hypothyroidism were shown by growth arrest and a decrease in liver DIO1 expression below the detection limit. (99m)Tc-pertechnetate scintigraphy revealed absence of thyroidal (99m)Tc-pertechnetate uptake in ablated mice. In summary, we report a revised protocol for radioiodide ablation of the thyroid gland in the mouse to generate an in vivo model that allows the study of thyroid hormone action using NIS as a reporter gene.
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http://dx.doi.org/10.1159/000381019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640294PMC
September 2015

One amino acid makes the difference: the formation of ent-kaurene and 16α-hydroxy-ent-kaurane by diterpene synthases in poplar.

BMC Plant Biol 2015 Oct 28;15:262. Epub 2015 Oct 28.

Max Planck Institute for Chemical Ecology, Hans-Knöll-Strasse 8, D-07745, Jena, Germany.

Background: Labdane-related diterpenoids form the largest group among the diterpenes. They fulfill important functions in primary metabolism as essential plant growth hormones and are known to function in secondary metabolism as, for example, phytoalexins. The biosynthesis of labdane-related diterpenes is mediated by the action of class II and class I diterpene synthases. Although terpene synthases have been well investigated in poplar, little is known about diterpene formation in this woody perennial plant species.

Results: The recently sequenced genome of Populus trichocarpa possesses two putative copalyl diphosphate synthase genes (CPS, class II) and two putative kaurene synthase genes (KS, class I), which most likely arose through a genome duplication and a recent tandem gene duplication, respectively. We showed that the CPS-like gene PtTPS17 encodes an ent-copalyl diphosphate synthase (ent-CPS), while the protein encoded by the putative CPS gene PtTPS18 showed no enzymatic activity. The putative kaurene synthases PtTPS19 and PtTPS20 both accepted ent-copalyl diphosphate (ent-CPP) as substrate. However, despite their high sequence similarity, they produced different diterpene products. While PtTPS19 formed exclusively ent-kaurene, PtTPS20 generated mainly the diterpene alcohol, 16α-hydroxy-ent-kaurane. Using homology-based structure modeling and site-directed mutagenesis, we demonstrated that one amino acid residue determines the different product specificity of PtTPS19 and PtTPS20. A reciprocal exchange of methionine 607 and threonine 607 in the active sites of PtTPS19 and PtTPS20, respectively, led to a complete interconversion of the enzyme product profiles. Gene expression analysis revealed that the diterpene synthase genes characterized showed organ-specific expression with the highest abundance of PtTPS17 and PtTPS20 transcripts in poplar roots.

Conclusions: The poplar diterpene synthases PtTPS17, PtTPS19, and PtTPS20 contribute to the production of ent-kaurene and 16α-hydroxy-ent-kaurane in poplar. While ent-kaurene most likely serves as the universal precursor for gibberellins, the function of 16α-hydroxy-ent-kaurane in poplar is not known yet. However, the high expression levels of PtTPS20 and PtTPS17 in poplar roots may indicate an important function of 16α-hydroxy-ent-kaurane in secondary metabolism in this plant organ.
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http://dx.doi.org/10.1186/s12870-015-0647-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4625925PMC
October 2015

Distribution of virulence factors in ESBL-producing Escherichia coli isolated from the environment, livestock, food and humans.

Sci Total Environ 2016 Jan 2;541:667-672. Epub 2015 Oct 2.

Institute for Food Safety and Hygiene, University of Zurich, Winterthurerstr. 272, 8057 Zurich, Switzerland. Electronic address:

In this study, extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli isolates recovered from the following sources were characterized with regard to the occurrence and distribution of uropathogenic and enteric pathogenic virulence factors: surface waters (rivers and lakes, n=60), the intestines of freshwater fish (n=33), fresh vegetables (n=26), retail poultry meat (n=13) and the fecal samples of livestock (n=28), healthy humans (n=34) and primary care patients (n=13). Among the 207 isolates, 82% tested positive by PCR for one or more of the virulence factors (VF) that predict uropathogenicity, TraT, fyuA, chuA, PAI, yfcv or vat. Uropathogenic E. coli (UPEC) were detected in each of the analyzed sources. Regarding virulence factors for intestinal pathogenic E. coli, these were found more rarely and predominantly associated with the aquatic environment, with aagR (EAEC) found in isolates from surface waters and STp (porcine heat stable enterotoxin) and LT (heat-labile enterotoxin) associated with isolates from fish. Aggregate VF scores (the number of unique virulence factors detected for each isolate) were lowest among isolates belonging to phylogenetic group B1 and highest among group B2. Clustering of the isolates by phylogenetic group, multilocus sequence type (MLST) and ESBL-types revealed clonal overlaps of A:ST10(CTX-M-1) and D:ST350(CTX-M-1) between the sources of livestock, poultry meat and healthy humans, suggesting livestock, in particular poultry, represents a potential reservoir for these particular UPEC clones. The clones A:ST10(CTX-M-55) and B2:ST131(CTX-M-27), harboring uropathogenic virulence factors were significantly associated with fresh vegetables and with fish, respectively. Further clonal complexes with source overlaps included D:ST38(CTX-M-14), D:ST69(CTX-M-15), D:ST405(CTX-M-15) and D:ST648(CTX-M-15), which were found in surface water and healthy humans. Identifying potential reservoirs of UPEC in the environment, animals, food and humans is important in order to assess routes of transmission and risk factors for acquiring UPEC.
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http://dx.doi.org/10.1016/j.scitotenv.2015.09.135DOI Listing
January 2016

The Impact of Vitamin D, Calcium, Protein Supplementation, and Physical Exercise on Bone Metabolism After Bariatric Surgery: The BABS Study.

J Bone Miner Res 2016 Mar 30;31(3):672-82. Epub 2015 Sep 30.

Department of Pathophysiology and Allergy Research, Center for Pathophysiology, Infectiology and Immunology, the Medical University of Vienna, Vienna, Austria.

Laparoscopic Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are common and effective methods to treat severe obesity, but these procedures can adversely influence bone metabolism and areal bone mineral density (aBMD). This was a prospective 24-month single-center interventional two-arm study in 220 women and similarly aged men (median age 40.7 years) with a body mass index (BMI) >38 kg/m(2) after RYGB and SG procedures. Patients were randomized into: 1) an intervention group receiving: 28,000 IU cholecalciferol/wk for 8 weeks before bariatric surgery, 16,000 IU/wk and 1000 mg calciummonocitrate/d after surgery, daily BMI-adjusted protein supplementation and physical exercise (Nordic walking, strength perseverance, and equipment training); 2) a non-intervention group: no preoperative loading, nutritional supplementation, or obligatory physical exercise. At study endpoint, when comparing the intervention group to the non-intervention group, the relative percentage changes of serum levels of sclerostin (12.1% versus 63.8%), cross-linked C-telopeptide (CTX, 82.6% versus 158.3%), 25-OH vitamin D (13.4% versus 18.2%), phosphate (23.7% versus 32%, p < 0.001 for all), procollagen type 1 amino-terminal propeptide (P1NP, 12% versus 41.2%), intact parathyroid hormone (iPTH, -17.3% versus -7.6%), and Dickkopf-1 (-3.9% versus -8.9%, p < 0.05 for all) differed. The decline in lumbar spine, total hip and total body aBMD, changes in BMI, lean body mass (LBM), as well as changes in trabecular bone score (TBS) values (p < 0.005 for all) were less, but significantly, pronounced in the intervention group. We conclude that vitamin D loading and ongoing vitamin D, calcium, and BMI-adjusted protein supplementation in combination with physical exercise decelerates the loss of aBMD and LBM after bariatric surgery. Moreover, the well-known increases of bone turnover markers are less pronounced.
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http://dx.doi.org/10.1002/jbmr.2707DOI Listing
March 2016

Thyroid hormones and tetrac: new regulators of tumour stroma formation via integrin αvβ3.

Endocr Relat Cancer 2015 Dec 25;22(6):941-52. Epub 2015 Aug 25.

Department of Internal Medicine IIUniversity Hospital of Munich, Munich, GermanyMedizinische Klinik und Poliklinik IVUniversity Hospital of Munich, Munich, GermanyDepartment of Biology IILudwig-Maximilians-University, Munich, GermanyLeibniz Institute for Environmental MedicineDüsseldorf, GermanyDepartment of Nuclear MedicineUniversity Hospital of Munich, Munich, GermanyUniversity Medical Center Hamburg-EppendorfHamburg, Germany

To improve our understanding of non-genomic, integrin αvβ3-mediated thyroid hormone action in tumour stroma formation, we examined the effects of triiodo-l-thyronine (T3), l-thyroxine (T4) and integrin-specific inhibitor tetrac on differentiation, migration and invasion of mesenchymal stem cells (MSCs) that are an integral part of the tumour's fibrovascular network. Primary human bone marrow-derived MSCs were treated with T3 or T4 in the presence of hepatocellular carcinoma (HCC) cell-conditioned medium (CM), which resulted in stimulation of the expression of genes associated with cancer-associated fibroblast-like differentiation as determined by qPCR and ELISA. In addition, T3 and T4 increased migration of MSCs towards HCC cell-CM and invasion into the centre of three-dimensional HCC cell spheroids. All these effects were tetrac-dependent and therefore integrin αvβ3-mediated. In a subcutaneous HCC xenograft model, MSCs showed significantly increased recruitment and invasion into tumours of hyperthyroid mice compared to euthyroid and, in particular, hypothyroid mice, while treatment with tetrac almost completely eliminated MSC recruitment. These studies significantly improve our understanding of the anti-tumour activity of tetrac, as well as the mechanisms that regulate MSC differentiation and recruitment in the context of tumour stroma formation, as an important prerequisite for the utilisation of MSCs as gene delivery vehicles.
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http://dx.doi.org/10.1530/ERC-15-0245DOI Listing
December 2015

Mesenchymal stem cell-mediated, tumor stroma-targeted radioiodine therapy of metastatic colon cancer using the sodium iodide symporter as theranostic gene.

J Nucl Med 2015 Apr 5;56(4):600-6. Epub 2015 Mar 5.

Department of Internal Medicine II, Ludwig-Maximilians-University, Munich, Germany

Unlabelled: The tumor-homing property of mesenchymal stem cells (MSCs) allows targeted delivery of therapeutic genes into the tumor microenvironment. The application of sodium iodide symporter (NIS) as a theranostic gene allows noninvasive imaging of MSC biodistribution and transgene expression before therapeutic radioiodine application. We have previously shown that linking therapeutic transgene expression to induction of the chemokine CCL5/RANTES allows a more focused expression within primary tumors, as the adoptively transferred MSC develop carcinoma-associated fibroblast-like characteristics. Although RANTES/CCL5-NIS targeting has shown efficacy in the treatment of primary tumors, it was not clear if it would also be effective in controlling the growth of metastatic disease.

Methods: To expand the potential range of tumor targets, we investigated the biodistribution and tumor recruitment of MSCs transfected with NIS under control of the RANTES/CCL5 promoter (RANTES-NIS-MSC) in a colon cancer liver metastasis mouse model established by intrasplenic injection of the human colon cancer cell line LS174t. RANTES-NIS-MSCs were injected intravenously, followed by (123)I scintigraphy, (124)I PET imaging, and (131)I therapy.

Results: Results show robust MSC recruitment with RANTES/CCL5-promoter activation within the stroma of liver metastases as evidenced by tumor-selective iodide accumulation, immunohistochemistry, and real-time polymerase chain reaction. Therapeutic application of (131)I in RANTES-NIS-MSC-treated mice resulted in a significant delay in tumor growth and improved overall survival.

Conclusion: This novel gene therapy approach opens the prospect of NIS-mediated radionuclide therapy of metastatic cancer after MSC-mediated gene delivery.
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http://dx.doi.org/10.2967/jnumed.114.146662DOI Listing
April 2015

Barley (Hordeum vulgare L.) transformation using embryogenic pollen cultures.

Methods Mol Biol 2015 ;1223:85-99

Plant Reproductive Biology, Leibniz Institute of Plant Genetics and Crop Plant Research (IPK) Gatersleben, Corrensstrasse 3, Gatersleben, Stadt Seeland, OT, 06466, Germany,

The temperate cereal barley is grown as a source of food, feed, and malt. The development of a broad range of genetic resources and associated technologies in this species has helped to establish barley as the prime model for the other Triticeae cereals. The specific advantage of the transformation method presented here is that transgene homozygosity is attained in the same generation as the transgenic event occurred through the coupling of haploid technology with Agrobacterium-mediated transformation. Pollen is haploid and, following transformation, can be induced to regenerate into haploid plantlets, which can subsequently subjected to colchicine treatment to obtain diploid, genetically fixed plants. The routine application of the method based on the winter-type barley cultivar 'Igri' over a period of over 10 years has achieved an average yield of about two transgenic plants per donor spike. The whole procedure from pollen isolation to non-segregating transgenic, mature grain takes less than 12 months.
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http://dx.doi.org/10.1007/978-1-4939-1695-5_7DOI Listing
June 2015

Complete Recovery From Severe Tachycardia-Induced Cardiomyopathy in a Patient With Ebstein's Anomaly.

World J Pediatr Congenit Heart Surg 2014 07;5(3):484-7

Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland

We report the case of a young patient with repaired Ebstein's anomaly who developed severe tachycardia-induced cardiomyopathy and a large apical thrombus as a consequence of sustained atrial flutter with a 2:1 conduction. In spite of a dramatic course in hospital with prolonged mechanical resuscitation and extracorporeal membrane oxygenation, she survived and made a rapid and full recovery. This remarkable case underlines that atrial arrhythmias, the most common complication in adults with congenital heart disease, may have devastating outcomes when timely recognition is missed and treatment delayed-thus, emphasizing the importance of good patient education.
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http://dx.doi.org/10.1177/2150135114528222DOI Listing
July 2014