Dual-Enzyme-Loaded Multifunctional Hybrid Nanogel System for Pathological Responsive Ultrasound Imaging and T2-Weighted MRI

Significance Statement

As an emerging material, nanogel system is hydrogel nanoparticle, its ideal fluid-like transport properties and hydrophilic environment make the nanogel a perfect candidate for bio-catalysis, biomedical diagnosis and therapy. The immobilization (encapsulation) of enzymes within the gel matrix provides protection from structural alterations and subsequent deactivation of the enzymes, ensuring higher loadings and better substrate mobility for efficient catalysis. In addition, the unique hydrophilic environment and water-rich structure of this nanogel make it an ideal probe for magnetic resonance (MR) imaging, where the signal detected is directly related to relaxation time.

In this work, focused on exploiting the structure-function relationships of hydrogel, the dual-enzyme loaded multifunctional magnetic nanogel, which is composed of functionalized superparamagnetic iron oxide (SPIO) particles, a dual enzyme species (catalase and superoxide dismutase) and a polysaccharide cationic polymer glycol chitosan gel, was developed to be an efficient and safe probe for dual-modality pathological responsive ultrasound (US) and T₂-weighted MR imaging both in vitro and in vivo.

 

About The Author

Prof. Dr. Hui-Xiong Xu, MD, PhD is the Head and Professor of Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Ultrasound Research and Education Institute, Tongji University School of Medicine (i.e. the First Affiliated Hospital), Shanghai, China. He is an Expert Panel Member of International Guideline of Contrast Enhanced Ultrasound in the Liver by World Federation of Ultrasound in Medicine and Biology (WFUMB), and a Member of International Contrast Ultrasound Society. His research interest includes US-guided ablation for tumor, Contrast-enhanced ultrasound, and US elastography.

_­­

About The Author

Dr. Qi-Gang Wang received his Ph.D. from Shanghai Institute of Ceramics, Chinese Academy of Sciences in 2005. From 2005 to 2011, he continued his research works in The Hong Kong University of Science and Technology, the University of Tokyo and Riken. He joined Tongji as a full professor and Young’s 1000 plan in 2011. His research interests will focus on 1) the mild radical polymerization for the preparation of nanocomposite gel, 2) the 3D printing and hierarchical pore design of functional gel, 3) the potential applications of functional gel in the interdisciplinary fields. He has published over thirty papers as first author and corresponding author including Nature.

About The Author

Dr. Xia Wang is an Assistant Professor of Chemistry department at Tongji University, China. Her research interests focus on the multifunctional nanogel composites and mesoporous silica-based nanomaterials for biomedical diagnosis and therapy.

Journal Reference

ACS Nano. 2015;9(6):5646-56.

Wang X¹, Niu D², Li P³, Wu Q¹, Bo X³, Liu B³, Bao S¹, Su T¹, Xu H³, Wang Q¹.

Show Affiliations

1. Department of Chemistry and Advanced Research Institute, Tongji University, Shanghai, 200092, China.
2. Lab of Low-Dimensional Materials Chemistry, Key Laboratory for Ultrafine Materials of Ministry of Education, School of Materials Science and Engineering, East China University of Science and Technology, Shanghai, 200237, China.
3. Department of MedicalUltrasound, Shanghai Tenth People’s Hospital, Tenth People’s Hospital of Tongji University, Shanghai, 200072, China.

Abstract

A dual-enzyme-loaded multifunctional hybrid nanogel probe (SPIO@GCS/acryl/biotin-CAT/SOD-gel, or SGC) has been developed for dual-modality pathological  responsive  ultrasound (US) imaging and enhanced T2-weighted magnetic resonance (MR) imaging. This probe is composed of functionalized superparamagnetic iron oxide particles, a dual enzyme species (catalase and superoxide dismutase), and a polysaccharide cationic polymer glycol chitosan gel. The dual-modality US/MR imaging capabilities of the hybrid  nanogel  for  responsive US imaging and enhanced T2-weighted MR imaging have been evaluated both in vitro and in vivo. These results show that the hybrid nanogel SGC can exhibit efficient dual-enzyme biocatalysis with pathological species for responsive US imaging. SGC also demonstrates increased accumulation in acidic environments for enhanced T2-weighted MR imaging. Further research on these nanogel systems may lead to the development of more efficient US/MR contrast agents.

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Figure legend: Dual-Enzyme Loaded Hybrid Nanogel System for Pathological Responsive US and MR imaging.

 

 

Novel role for cyclophilin A in regulation of chondrogenic commitment and endochondral ossification

Significance Statement

Chondrogenesis is an essential process in vertebrates. It leads to the formation of cartilage growth plates, thereby driving bodily growth while providing structural templates and induction signals for the formation of long bones through endochondral ossification. On the other hand, defects in chondrogenesis causes various chondrodysostoses and chondrodysplasias, with such skeletal malformations accounting for a significant proportion of human birth defects that often result in embryonic and perinatal lethality. The molecular mechanisms that drive chondrocyte differentiation and impact underlying cartilage diseases remain to be elucidated. Either knock-down of cyclophilin A (CypA) or pharmacological inhibition of cyclophilin A or NF-κB reduces or delays BMP-2 induced chondrogenic differentiation. cyclophilin A-deficient mice display chondrodysplasias and defective endochondral bone formation. Clearly cyclophilin A is required for chondrogenic differentiation and endochondral ossification. Studies of molecular details are important to better understand BMP-2-induced chondrogenesis signaling during vertebrate development and will help to develop better strategies for tissue repair and treatment of cartilage related diseases.

 

Journal Reference

Mol Cell Biol. 2015;35(12):2119-30.

Guo M¹, Shen J², Kwak JH², Choi B³, Lee M³, Hu S⁴, Zhang X², Ting K², Soo CB⁵, Chiu RH⁶.

Show Affiliations

1. Dental and Craniofacial Research Institute and Division of Oral Biology, School of Dentistry, University of California, Los Angeles, Los Angeles, California, USA Department of Neurosurgery, Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
2. Dental and Craniofacial Research Institute and Section of Orthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, California, USA.
3. Division of Advanced Prosthodontics, School of Dentistry, University of California, Los Angeles, Los Angeles, California, USA.
4. Dental and Craniofacial Research Institute and Division of Oral Biology, School of Dentistry, University of California, Los Angeles, Los Angeles, California, USA.
5. Department of Orthopedic Surgery, School of Medicine, University of California, Los Angeles, Los Angeles, California, USA Division of Plastic and Reconstructive Surgery, School of Medicine, University of California, Los Angeles, Los Angeles, California, USA.
6. Dental and Craniofacial Research Institute and Division of Oral Biology, School of Dentistry, University of California, Los Angeles, Los Angeles, California, USA Jonsson Comprehensive Cancer Center and Division of Surgical Oncology, School of Medicine, University of California, Los Angeles, Los Angeles, California, USA rchiu@dentistry.ucla.edu.

Abstract

Recent studies showed that cyclophilin A (CypA) promotes NF-κB/p65 nuclear translocation, resulting in enhanced NF-κB activity and altered expression of its target genes, such as the Sox9 transcriptional factor, which plays a critical role in chondrogenic differentiation and endochondral ossification. In this report, we unveil the role of cyclophilin A in signal-induced chondrogenic differentiation and endochondral ossification. Expression levels of the chondrogenic differentiation markers and transcriptional regulators Sox9 and Runx2 were all significantly lower in cyclophilin A knockdown chondrogenic cells than in wild-type cells, indicating that cyclophilin A plays a functional role in chondrogenic differentiation. In vitro differentiation studies using micromass cultures of mouse limb bud cells further supported the conclusion that cyclophilin A is needed for chondrogenic differentiation. Newborn CypA-deficient pups double stained with alcian blue and alizarin red exhibited generalized, pronounced skeletal defects, while high-resolution micro-computed tomography (microCT) analyses of the femurs and lumbar vertebrae revealed delayed or incomplete endochondral ossification. Comparative histology and immunohistochemistry (IHC) analyses further verified the effects of cyclophilin A deficiency on chondrogenic differentiation. Our results provide evidence for the important contribution of cyclophilin A as a pertinent component acting through NF-κB-Sox9 in regulation of chondrogenesis signaling. These findings are important to better understand signal-induced chondrogenesis of chondrogenic progenitors in physiological and pathophysiological contexts.

Copyright © 2015, American Society for Microbiology. All Rights Reserved.

Go To Mol Cell Biol.

Figure Legend 

cyclophilin A acts through the NF-kB-Sox9 pathway in regulation of chondrogenic differentiation. A. Sox9 is a key molecule for chondrogenic differentiation and cartilage formation and its activity dependent on NF-kB activation. B. RNA interference knock-down of endogenous cyclophilin A (CypA Kd) led to impaired NF-kB activity and significant attenuated NF-kB-dependent gene, such Sox9, expression. D indicates cyclophilin A Kd, blue bold blunt lines indicate inhibition, and red arrows indicate stimulation.

 

 

Endoplasmic reticulum stress and proteasomal system in amyotrophic lateral sclerosis

Journal Reference

Free Radic Biol Med. 2015 Nov;88(Pt A):42-50.

Karademir B¹, Corek C¹, Ozer NK².

Show Affiliations

1. Department of Biochemistry, Faculty of Medicine, Genetic and Metabolic Diseases Research and Investigation Center (GEMHAM), Marmara University, 34854 Maltepe, Istanbul, Turkey.
2. Department of Biochemistry, Faculty of Medicine, Genetic and Metabolic Diseases Research and Investigation Center (GEMHAM), Marmara University, 34854 Maltepe, Istanbul, Turkey. Electronic address: nkozer@marmara.edu.tr.

Abstract

Protein processing including folding, unfolding and degradation is involved in the mechanisms of many diseases. Unfolded protein response and/or endoplasmic reticulum stress are accepted to be the first steps which should be completed via protein degradation. In this direction, proteasomal system and autophagy play important role as the degradation pathways and controlled via complex mechanisms. Amyotrophic lateral sclerosis is a multifactorial neurodegenerative disease which is also known as the most catastrophic one. Mutation of many different genes are involved in the pathogenesis such as superoxide dismutase 1, chromosome 9 open reading frame 72 and ubiquilin 2. These genes are mainly related to the antioxidant defense systems,  endoplasmic reticulum stress related proteins and also protein aggregation, degradation pathways and therefore mutation of these genes cause related disorders. This review focused on the role of protein processing via endoplasmic  reticulum and proteasomal system in amyotrophic lateral sclerosis which are the main players in the pathology. In this direction, dysfunction of endoplasmic reticulum associated degradation and related cell death mechanisms that are autophagy/apoptosis have been detailed.

Copyright © 2015 Elsevier Inc. All rights reserved.

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In vitro Selection and Interaction Studies of DNA Aptamer Targeting Protein A

Significance Statement

Affinity reagents are key tools in the field of life sciences, in pharmaceutical and medical research, and therapy. They are of great interest for analytical and diagnostic applications for specific and sensitive detection of biomolecules. DNA aptamers are new affinity molecules matching these specifications. They are short, single-stranded oligonucleotides folding into complex 3D-structures that facilitate highly affine and specific interaction with their target molecules. Aptamers offer outstanding features for practical applications. They are developed by in vitro selection procedure and are produced afterwards by chemical synthesis enabling high availability and reproducibility. Aptamers are small in size, can be easily modified to expand their binding features and to adapt the aptamer to any assay concepts. They possess high storage stability, and regenerability of target binding. Affinity based processes like purification or filtration are further application areas for aptamers.

In this article, a new Protein A – binding aptamer is presented by description of its development and comprehensive characterization of its functionality. Different methods like surface plasmon resonance (SPR) spectroscopy, MicroScale Thermophoresis and bead-based binding assays with fluorescence-labeled aptamer were applied to analyze the binding features. Protein A is known for its ability to bind immunoglobulins and is therefore widely used as affinity matrix in immunological research but also in purification processes throughout the production of commercial/clinical-stage antibodies. This also includes a product testing for leached Protein A as a potential process contaminant. Against this background, the described aptamer has significance for the development of detection assays for Protein A. Moreover, because Protein A is naturally located on the cell surface of Staphylococcus aureus and serves for the binding of the aptamer to the bacterial cells, this aptamer provides the possibility to act as analytical agent for Staphylococcus aureus detection.

 

Journal Reference

PLoS One. 2015;10(7):e0134403.

Stoltenburg R¹, Schubert T², Strehlitz B³.

Show Affiliations

1. UFZ-Helmholtz Centre for Environmental Research, Department of Soil Ecology, Halle, Germany.
2. 2bind GmbH, Regensburg, Germany.
3. UFZ-Helmholtz Centre for Environmental Research, Department Environmental and Biotechnology Centre, Leipzig, Germany.

Abstract

A new DNA aptamer targeting Protein A is presented. The aptamer was selected by use of the FluMag-SELEX procedure. The SELEX technology (Systematic Evolution of Ligands by EXponential enrichment) is widely applied as an in vitro selection and amplification method to generate target-specific aptamers and exists in various modified variants. FluMag-SELEX is one of them and is characterized by the use of magnetic beads for target immobilization and fluorescently labeled oligonucleotides for monitoring the aptamer selection progress. Structural investigations and sequence truncation experiments of the selected aptamer for Protein A led to the conclusion, that a stem-loop structure at its 5′-end including the 5′-primer binding site is essential for aptamer-target binding. Extensive interaction analyses between aptamer and Protein A were performed by methods like surface plasmon resonance, MicroScale Thermophoresis and bead-based binding assays using fluorescence measurements. The binding of the aptamer to its target was thus investigated in assays with immobilization of one of the binding partners each, and with both binding partners in solution. Affinity constants were determined in the low micromolar to submicromolar range, increasing to the nanomolar range under the assumption of avidity. Protein A provides more than one binding site for the aptamer, which may overlap with the known binding sites for immunoglobulins. The aptamer binds specifically to both native and recombinant Protein A, but not to other immunoglobulin-binding proteins likeProtein G and L. Cross specificity to other proteins was not found. The application of the aptamer is directed to Protein A detection or affinity purification. Moreover, whole cells of Staphylococcus aureus, presenting Protein A on the cell surface, could also be bound by the aptamer.

Go To PLoS One.

Figure legend

Schematic illustration of SPR-based interaction analyses between aptamer and its target Protein A (using Biacore X100). In most of the experiments, biotin-labeled aptamer was immobilized on the streptavidin-modified sensor surface and Protein A was injected as analyte across this surface for interaction with the aptamer. The binding and dissociation profile of a measurement is generated in real-time and recorded in a sensorgram. A typical concentration-dependent binding of Protein A to the aptamer on the sensor surface is shown.

image description

A novel benzenediamine derivative FC98 reduces insulin resistance in high fat diet-induced obese mice by suppression of metaflammation

Significance Statement

Metaflammation is known as chronic low-grade metabolic inflammation in adipose tissue that drives obesity-induced insulin resistance. Clinical studies using non-steroid anti-inflammatory drugs (NSAIDs) such as salicylates have established a causative role of metaflammation in the pathogenesis of metabolic diseases and associated complications.

As a proof-of concept study, Chen et al. demonstrated the effectiveness of a newly identified benzenediamine derivative (FC98, PubChem CID: 14989837) against obesity-induced insulin resistance by reducing the degree of metaflammation and adipose tissue macrophage (ATM) infiltration using a high fat diet induced obesity (DIO) mouse model.

This work highlighted the potential of novel benzenediamine derivatives against obesity-induced insulin resistance and also provided evidence for targeting metaflammation as a therapeutic strategy for metabolic diseases.

 

About The Author

 Changmai Chen: A graduate student at the College of Life Sciences of Nanjing University and State Key Laboratory of Pharmaceutical Biotechnology. His research interest includes molecular pharmacology, endocrine pharmacology and translational pharmacology with focus on lead compound identification and mechanism studies. His mentors are Drs. R.X. Tan and E. Li.

Journal Reference

Eur J Pharmacol. 2015;761:298-308.

Chen C¹, Zhang W², Shi H², Zhuo Y³, Yang G⁴, Zhang A⁵, Hou Y², Xiang Tan R⁵, Li E⁶.

Show Affiliations

1. Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China; Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, China; College of Life Sciences, Nanjing University, China.
2. Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China; Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, China.
3. Nanjing Children’s Hospital, Nanjing Medical University, China.
4. Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, China; Nanjing Children’s Hospital, Nanjing Medical University, China.
5. Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China; College of Life Sciences, Nanjing University, China.
6. Medical School and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, China; Jiangsu Laboratory of Molecular Medicine, Medical School, Nanjing University, China. Electronic address: erguang@nju.edu.cn.

Abstract

Chronic low-grade metabolic inflammation (metaflammation) is a hallmark of metabolic diseases. The aim of this study was to determine the effectiveness of a newly identified benzenediamine derivative (FC98, PubChem CID: 14989837) against metaflammation and insulin resistance using a high fat diet-induced obesity (DIO) murine model. LPS and free fatty acids (FFAs)-induced gene expression and signaling was determined in cell culture systems. Inflammasome activation was determined by measuring IL-1β release with ELISA. The in vivo activity was assayed in C57BL/6Jmice fed with a high fat diet (HFD) by measuring body weight gains, glucose tolerance and insulin sensitivity. The effect was also evaluated by H&E and IHC staining, by measuring gene expression and cytokine production, and by analysis of F4/80(+)CD11b(+) macrophage infiltration. FC98exhibited anti-inflammatory activity against LPS- and FFAs-induced IL-1β, IL-6, and TNF-α gene expression and JNK and p38 activation. The IC50 for FC98 to inhibit NO production was determined at 6.8μM. FC98 also dose-dependently inhibited IL-1β secretion. In DIO mice, FC98 at 10 and 20mg/kg significantly improved metabolic parameters, including body weight, fat mass, glucose disposal and insulin sensitivity. The reduction in adipocyte area, F4/80(+)CD11b(+) macrophage infiltration, proinflammatory gene expression, along with JNK activation, was also significant in those groups. Additionally, FC98-treated animals had increased AKT phosphorylation in response to insulin stimulation. FC98 inhibits metaflammation and ameliorates insulin resistance mainly by inhibiting signaling pathways of proinflammatory response in DIO animals. This study highlights the significance of targeting metaflammation for obesity-attributive metabolic syndrome.

Copyright © 2015 Elsevier B.V. All rights reserved.

Go To Eur J Pharmacol.

 

Graphene-Based Platform for Infrared Near-Field Nanospectroscopy of Water and Biological Materials in an Aqueous Environment

Journal Reference

ACS Nano. 2015;9(8):7968-75.

Khatib O¹, Wood JD², McLeod AS, Goldflam MD, Wagner M, Damhorst GL, Koepke JC, Doidge GP, Rangarajan A, Bashir R, Pop E³, Lyding JW, Thiemens MH,Keilmann F⁴, Basov DN.

Show Affiliations

1. Department of Physics, Department of Chemistry, and JILA, University of Colorado , Boulder, Colorado 80309, United States.
2. Department of Materials Science and Engineering, Northwestern University , Evanston, Illinois 60208, United States.
3. Department of Electrical Engineering, Stanford University , Stanford, California 94305, United States.
4. Ludwig-Maximilians-Universität and Center for Nanoscience , 80539 München, Germany.

Abstract

Scattering scanning near-field optical microscopy (s-SNOM) has emerged as a powerful nanoscale spectroscopic tool capable of characterizing individual biomacromolecules and molecular materials. However, applications of scattering-based near-field techniques in the infrared (IR) to native biosystems still await a solution of how to implement the required aqueous environment. In this work, we demonstrate an IR-compatible liquid cell architecture that enables near-field imaging and nanospectroscopy by taking advantage of the unique properties of graphene. Large-area graphene acts as an impermeable monolayer barrier that allows for nano-IR inspection of underlying molecular materials in liquid. Here, we use s-SNOM to investigate the tobacco mosaic virus (TMV) in water underneath graphene. We resolve individual virus particles and register the amide I and II bands of TMV at ca. 1520 and 1660 cm(-1), respectively, using nanoscale Fourier transform infrared spectroscopy (nano-FTIR). We verify the presence ofwater in the graphene liquid cell by identifying a spectral feature associated with water absorption at 1610 cm(-1).

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Discovery and resupply of pharmacologically active plant-derived natural products

Significance Statement

Natural products research on the rise

Natural products research on the rise Natural products yielded many successful medications in the past, but in the recent decades pharmaceutical industry shifted its focus on synthetic compounds as major source for development of new small molecule therapeutics. One of the important underlying reasons for this shift is the more difficult resupply of natural products, which are often not present in their natural sources in sufficient amounts to meet market needs, or have complex chemical structures hindering the development of economically viable total chemical synthesis approaches. Further difficulties are caused by the lower compatibility of natural products with established high throughput screening platforms, and patentability complications arising from the need to share patent rights with countries from which the natural product originates and from the general uncertainty existing in respect of patenting of unmodified natural products (resulting from the fundamental complexity of the question whether a natural material or phenomenon is patentable or not).

Paralleling the change of pharmaceutical industry focus, there has been a decline in the number of new drugs reaching the market in the recent years. Despite of being neglected, natural compounds have some important advantages as a pool for drug discovery, including high structural diversity, chemico-physical properties distinct from synthetic compounds, and sometimes the existence of prior hints for therapeutic effectiveness coming from use in traditional folk medicine. Reflecting better appreciation of advantages of natural products and the re-emerging scientific interest in medicinal plants-based natural product drug discovery, an increase in the number of scientific publications dealing with this research area is observed by publication trend analysis (http://ift.tt/20nVMBm). Consequently, despite the recent neglecting by pharmaceutical industry, it appears very likely that natural products will remain an important source of new small molecule pharmaceuticals also in the future.

Reference: Atanasov AG, Waltenberger B, Pferschy-Wenzig EM, Linder T, Wawrosch C, Uhrin P, Temml V, Wang L, Schwaiger S, Heiss EH, Rollinger JM, Schuster D, Breuss JM, Bochkov V, Mihovilovic MD, Kopp B, Bauer R, Dirsch VM, Stuppner H. Discovery and resupply of pharmacologically active plant-derived natural products: A review. Biotechnol Adv. 2015 Aug 15. pii: S0734-9750(15)30027-6. http://ift.tt/20nVMBm

About The Author

Dr. Atanas G. Atanasov is a research scientist and principle investigator at Department of Pharmacognosy, Faculty of Life Sciences, University of Vienna, Austria. He has published over 50 peer-reviewed original research articles and reviews in the field of molecular medicine, mechanisms of pharmacological action, cell signaling, and regulatory mechanisms relevant for cardiometabolic disease and inflammation. Exploring innovative approaches for public research dissemination, he is also actively engaged in science communication in the social media.

Journal Reference

Biotechnology Advances, Available online 15 August 2015

Atanasov AG¹, Waltenberger B², Pferschy-Wenzig EM³, Linder T⁴, Wawrosch C⁵, Uhrin P⁶, Temml V⁷, Wang L⁵, Schwaiger S⁸, Heiss EH⁵, Rollinger JM⁹,Schuster D⁷, Breuss JM⁶, Bochkov V¹⁰, Mihovilovic MD⁴, Kopp B⁵, Bauer R¹¹, Dirsch VM⁵, Stuppner H⁸.

Show Affiliations

¹Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria. Electronic address: atanas.atanasov@univie.ac.at.

²Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria. Electronic address: birgit.waltenberger@uibk.ac.at.

³Institute of Pharmaceutical Sciences, Department of Pharmacognosy, University of Graz, Universitätsplatz 4/I, 8010 Graz, Austria. Electronic address: eva-maria.wenzig@uni-graz.at.

⁴Institute of Applied Synthetic Chemistry, Vienna University of Technology, Getreidemarkt 9/163-OC, 1060 Vienna, Austria.

⁵Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria.

⁶Institute of Vascular Biology and Thrombosis Research, Center of Physiology and Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.

⁷Institute of Pharmacy/Pharmaceutical Chemistry and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.

⁸Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.

⁹Department of Pharmacognosy, University of Vienna, Althanstrasse 14, 1090 Vienna, Austria; Institute of Pharmacy/Pharmacognosy and Center for Molecular Biosciences Innsbruck (CMBI), University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria.

¹⁰Institute of Pharmaceutical Sciences, Department of Pharmaceutical Chemistry, University of Graz, Humboldtstrasse 46/III, 8010 Graz, Austria.

¹¹Institute of Pharmaceutical Sciences, Department of Pharmacognosy, University of Graz, Universitätsplatz 4/I, 8010 Graz, Austria.

Abstract

Medicinal plants have historically proven their value as a source of molecules with therapeutic potential, and nowadays still represent an important pool for the identification of novel drug leads. In the past decades, pharmaceutical industry focused mainly on libraries of synthetic compounds as drug discovery source. They are comparably easy to produce and resupply, and demonstrate good compatibility with established high throughput screening (HTS) platforms. However, at the same time there has been a declining trend in the number of new drugs reaching the market, raising renewed scientific interest in drug discovery from natural sources, despite of its known challenges. In this survey, a brief outline of historical development is provided together with a comprehensive overview of used approaches and recent developments relevant to plant-derived natural product drug discovery. Associated challenges and major strengths of natural product-based drug discovery are critically discussed. A snapshot of the advanced plant-derived natural products that are currently in actively recruiting clinical trials is also presented. Importantly, the transition of a natural compound from a “screening hit” through a “drug lead” to a “marketed drug” is associated with increasingly challenging demands for compound amount, which often cannot be met by re-isolation from the respective plant sources. In this regard, existing alternatives for resupply are also discussed, including different biotechnology approaches and total organic synthesis.

While the intrinsic complexity of natural product-based drug discovery necessitates highly integrated interdisciplinary approaches, the reviewed scientific developments, recent technological advances, and research trends clearly indicate that natural products will be among the most important sources of new drugs also in the future.

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Development of Ti-Nb-Zr alloys with high elastic admissible strain for temporary orthopedic devices

Journal Reference

Acta Biomater. 2015;20:176-87. doi: 10.1016/j.actbio.2015.03.023.

Ozan S¹, Lin J², Li Y³, Ipek R⁴, Wen C⁵.

Show Affiliations

1. Faculty of Engineering and Industrial Sciences, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia; Department of Mechanical Engineering, Ege University, 35100 Bornova, Izmir, Turkey.
2. Advanced Material Research andDevelopment Center, Zhejiang Industry & Trade Vocational College, Wenzhou, Zhejiang 325003, China; Department of Materials Science and Engineering, Jilin University, Changchun, Jilin 130025, China.
3. School of Aerospace, Mechanical and Manufacturing Engineering, RMIT University, Melbourne, Victoria 3083, Australia.
4. Department of Mechanical Engineering, Ege University, 35100 Bornova, Izmir, Turkey.
5. Faculty of Engineering and Industrial Sciences, Swinburne University of Technology, Hawthorn, Victoria 3122, Australia; School of Aerospace, Mechanical and Manufacturing Engineering, RMIT University, Melbourne, Victoria 3083, Australia. Electronic address: cuie.wen@rmit.edu.au.

Abstract

A new series of beta Ti-Nb-Zr (TNZ) alloys with considerable plastic deformation ability during compression test, high elastic admissible strain, and excellent cytocompatibility have been developed for removable bone tissue implant applications. TNZ alloys with nominal compositions of Ti-34Nb-25Zr, Ti-30Nb-32Zr, Ti-28Nb-35.4Zr and Ti-24.8Nb-40.7Zr (wt.% hereafter) were fabricated using the cold-crucible levitation technique, and the effects of alloying element content on their microstructures, mechanical properties (tensile strength, yield strength, compressive yield strength, Young’s modulus, elastic energy, toughness, and micro-hardness), and cytocompatibilities were investigated and compared. Microstructural examinations revealed that the TNZ alloys consisted of β phase. The alloy samples displayed excellent ductility with no cracking, or fracturing during compression tests. Their tensile strength, Young’s modulus, elongation at rupture, and elastic admissible strain were measured in the ranges of 704-839 MPa, 62-65 GPa, 9.9-14.8% and 1.08-1.31%, respectively. The tensile strength, Young’s modulus and elongation at rupture of the Ti-34Nb-25Zr alloy were measured as 839 ± 31.8 MPa, 62 ± 3.6 GPa, and 14.8 ± 1.6%, respectively; this alloy exhibited the elastic admissible strain of approximately 1.31%. Cytocompatibility tests indicated that the cell viability ratios (CVR) of the alloys are greater than those of the control group; thus the TNZ alloys possess excellent cytocompatibility.

Copyright © 2015 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.

Go To Acta Biomater.

About The Author

Dr Sertan Ozan received his MSc and PhD degrees in Mechanical Engineering from Ege University, Turkey. During his PhD study, he has spent 18 months at Swinburne University of Technology, Australia as a visiting research student under supervision of Professor Cuie Wen. Currently, he is a research fellow in the Department of Mechanical Engineering of Bozok University, Turkey. His research focuses on the mechanical behaviour of metallic biomaterials and developing new Ti alloys.

About The Author

Mr Jixing Lin received his BS (2004) and MS (2007) degrees from Jiangxi university of Science and Technology, China. He is currently a PhD candidate under supervision of Professor Guanyu Li at Jilin University and Professor Cuie Wen at RMIT University. Since 2015, he has been appointed as Associate Professor in the Advanced Material Research & Development Center, Zhejiang Industry and Trade Vocational College, China. His research interests include biocompatible titanium alloys, biodegradable magnesium alloys, corrosion and surface modification for metals and alloys.

About The Author

Dr Yuncang Li obtained his PhD in Materials Engineering from Deakin University, Australia in 2004 and then took up a research fellow position in Biomaterials Engineering at Deakin University to the end of 2014. He joined RMIT University as a Senior Research Fellow of Biomaterials Engineering in the beginning of 2015. His research focuses on the developing of biomaterials, amorphous and nano-structured materials, titanium based shape memory alloys, biodegradable magnesium alloys, nano particulate-reinforced titanium composites and surface functionalisation on metallic implant materials. He has published more than 140 peer-reviewed articles: ttps://scholar.google.com.au/citations?user=1DlmTHgAAAAJ&hl=en.

About The Author

Dr Cuie Wen is Professor of Biomaterials Engineering at RMIT University and leads the biomaterials research team. This team’s research focuses on biocompatible titanium alloys and scaffolds, shape memory alloys and surface modification, biodegradable magnesium alloys, nanostructured metals, alloys and composites, metal foams and nanolaminates. Cuie was Professor of Surface Engineering at Swinburne University of Technology from 2010 to 2014. She joined Deakin University as a Research fellow 2003 and was appointed senior researcher 2007 and associate professor 2010. She worked in the National Institute of Advanced Industrial Science and Technology (Japan) before she moved to Australia. She has published over 300 refereed articles: http://ift.tt/1l3JxKa

 

 

 

Age-dependent alterations in the inflammatory response to pulmonary challenge

Significance Statement 

Changes in pulmonary physiology, pathology, and function are common in older populations, and lead to altered responses and increased morbidity and mortality associated with lung infections.  However, in many respects, the reasons for the altered susceptibility remain unclear.  Our previous studies have revealed that age influences early changes (6hrs after pulmonary challenge) in lung water and oxygen saturation (Lee et al Shock  2013, 40:Suppl 1, 27), and temperature control, hemodynamics and myocardial proteasome activity (Linge et al  Exp Lung Res  2015, 41:4, 216-227). Understanding age-related changes in the immune response within the pulmonary compartment and its impact on lung host defense and systemic responses, is of critical importance for developing effective therapeutic strategies for the treatment of the older patient. The current study highlights age-related changes and the possible interactions between inflammatory (MIF) and metabolic pathways (thyroxine) that are not immediately obvious (Al-Abed et al  PNAS 2011, 108:20, 8224–8227).  It also underlines the importance of using age-appropriate models for studying clinical conditions.

The research team brought together individuals  with a variety of ethnic backgrounds (Sweden, Pakistan, China, S. Korea and England) and specialties/interests (host response, internal medicine, analytical chemistry, pulmonary critical care, bio/clinical chemistry). A diverse group can result  in different approaches to a single  problem, and differences in interpretation of data achieved. This has led to a series of interesting studies and publications (including the current manuscript) that have revealed some aspects of disease pathogenesis that have not previously been considered.

Journal Reference  

Immunol Res. 2015 Aug 29. 

Linge HM, Ochani K, Lin K, Lee JY, Miller EJ.

Center for Heart and Lung Research, The Feinstein Institute for Medical Research, 350 Community Drive, Manhasset, NY, 11030, USA.

Abstract

The aging lung is increasingly susceptible to infectious disease. Changes in pulmonary physiology and function are common in older populations, and in those older than 60 years, pneumonia is the major cause of infectious death. Understanding age-related changes in the innate and adaptive immune systems, and how they affect both pulmonary and systemic responses to pulmonary challenge are critical to the development of novel therapeutic strategies for the treatment of the elderly patient. In this observational study, we examined age-associated differences in inflammatory responses to pulmonary challenge with cell wall components from Gram-positive bacteria. Thus, male Sprague-Dawley rats, aged 6 months or greater than 18 months (approximating humans of 20 and 55-65 years), were challenged, intratracheally, with lipoteichoic acid and peptidoglycan. Cellular and cytokine evaluations were performed on both bronchoalveolar lavage fluid (BAL) and plasma, 24 h post-challenge. The plasma concentration of free thyroxine, a marker of severity in non-thyroidal illness, was also evaluated. The older animals had an increased chemotactic gradient in favor of the airspaces, which was associated with a greater accumulation of neutrophils and protein. Furthermore, macrophage migration inhibitory factor (MIF), an inflammatory mediator and putative biomarker in acute lung injury, was increased in both the plasma and BAL of the older, but not young animals. Conversely, plasma free thyroxine, a natural inhibitor of MIF, was decreased in the older animals. These findings identify age-associated inflammatory/metabolic changes following pulmonary challenge that it may be possible to manipulate to improve outcome in the older, critically ill patient.

Go To Immunol Res.

 

 

 

Upregulation of miR-125b by estrogen protects against non-alcoholic fatty liver in female mice

Significance Statement

Non-alcohol fatty liver disease (NAFLD) is considered to be the hepatic manifestation of the metabolic syndrome. NAFLD occurs mainly due to the fat accumulation in the liver, and can lead to cirrhosis, which is not reversible and may ultimately progress to hepatocellular carcinoma.

The previous reports showed that estrogen protects against hepatic steatosis. The risk of developing NAFLD markedly increases in postmenopausal women and men. The hormone (estrogen) replacement therapy might be one consideration for prevention or treatment of NAFLD, but estrogen may lead to side effects like breast cancer. And we can’t treat men with estrogen against NAFLD.

Here, we firstly demonstrated that estrogen could regulate miR-125b expression via estrogen receptor alpha and that miR-125b could inhibit lipid accumulation in vitro and in vivo. Notably, we discovered FAS as a novel functional target of miR-125b. We demonstrated the function of miR-125b on limiting fat accumulation and inflammatory insults in the liver of both male and females, providing new understanding of a molecular mechanism underlying hepatic steatosis.

We identify a novel mechanism that estrogen protects against hepatic steatosis in female mice by miR-125b and provide a potential treatment strategy for metabolic disorders.

 

 

Journal Reference

J Hepatol. 2015. pii: S0168-8278(15)00541-3.

Zhang ZC¹, Liu Y¹, Xiao LL¹, Li SF¹, Jiang JH¹, Zhao Y¹, Qian SW¹, Tang QQ², Li X³.

Show Affiliations

1. Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai 200032, PR China.
2. Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai 200032, PR China; Institute of Stem Cell and Regenerative Medicine, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, PR China.
3. Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Fudan University Shanghai Medical College, Shanghai 200032, PR China. Electronic address: lixi@shmu.edu.cn.

ABSTRACT

BACKGROUND & AIMS:
Due to the protective effect of estrogen against hepatic fat accumulation, the prevalence of non-alcoholic fatty liver disease (NAFLD) in premenopausal women is lower than that in men at the same age and in postmenopausal women. Our study was to further elucidate an underlying mechanism by which estrogen prevents NAFLD from miRNA perspective in female mice.

METHODS:
miRNA expression was evaluated by TaqMan miRNA assay. Luciferase and ChIP assay were done to validate regulation of miR-125bby estrogen via estrogen receptor alpha (ERα). Nile red and Oil red O staining were used to check lipid content. Overexpressing or inhibiting the physiological role of miR-125b in the liver of mice through injecting adenovirus were used to identify the function of miR-125b in vivo.

RESULTS:
miR-125b expression was activated by estrogen via ERα in vitro and in vivo. miR-125b inhibited lipid accumulation both in HepG2 cells and primary mouse hepatocytes. Consistently, ovariectomized or liver-specific ERα knockdown mice treated with miR-125b overexpressing adenoviruses were resistant to hepatic steatosis induced by high-fat diet, due to decreased fatty acid uptake and synthesis and decreased triglyceride synthesis. Conversely, inhibiting the physiological role of miR-125b with a sponge decoy slightly promoted liver steatosis with a high-fat diet. Notably, we provided evidence showing that fatty acid synthase was a functional target of miR-125b.

CONCLUSION:
Our findings identify a novel mechanism by which estrogen protects against hepatic steatosis in female mice via upregulating miR-125b expression.

Copyright © 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Go To J Hepatol. 

About The Author

Xi Li: Prof. Li is a Professor in Department of Biochemistry and Molecular Biology at Fudan University Basic Medical School, with a Ph.D. in Physiology from Nanjing University, and post-doctoral training at Johns Hopkins University Medical School. Dr. Li‘s research interests are transcriptional and epigenetic regulation of adipogenesis, and the molecular mechanism of obesity related disease. 

 

 

Mechanistic Insights into R776H Mediated Activation of Epidermal Growth Factor Receptor Kinase

Significance Statement

Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that is frequently mutated in a variety of human cancers. Researchers from the University of Georgia characterized a novel recurrent oncogenic mutation (R776H) in the hinge region of EGFR kinase domain through a combination of cell-based assays and molecular dynamics simulations. The authors show that the R776H mutation activates the kinase domain by enhancing EGFR dimerization, a critical step in EGFR activation, and the mutant form preferentially adopts the acceptor position in the asymmetric dimer. The authors also demonstrate that the asymmetric dimer can phosphorylate monomeric EGFR, providing insights into lateral phosphorylation and downstream signaling. Using molecular modeling and molecular dynamics simulations, the authors propose a mechanistic model in which loss of key auto-inhibitory interactions with the regulatory αC-helix results in constitute activation. These findings have implications for the design of mutant-specific EGFR inhibitors for personalized cancer therapy

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About The Author

Dr. Natarajan Kannan is an Associate Professor in the Department of Biochemistry & Molecular Biology and Institute of Bioinformatics at the University of Georgia, Athens, GA. He obtained his PhD at the Indian Institute of Science, Bangalore in 2001, and post-doctoral training at University of California, San Diego and Cold Spring Harbor Laboratory, New York. Dr. Kannan is a Georgia Cancer Coalition Distinguished Cancer Scholar.

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About The Author

Zheng Ruan is a PhD student at The University of Georgia in Athens, GA.  He finished his undergraduate study at Huazhong Agricultural University, Wuhan, China. ZhengRuan’s current research focuses on understanding the dynamics and functions of protein kinases using computational and experimental approaches.

 

Journal Reference

Biochemistry. 2015;54(27):4216-25.

Ruan Z, Kannan N.

Department of Biochemistry & Molecular Biology and ^‡Institute of Bioinformatics, University of Georgia, Athens, Georgia, United States

Abstract

The epidermal growth factor receptor (EGFR) kinase is activated by a variety of mutations in human cancers. R776H is one such recurrent mutation (R752H in another numbering system) in the αC-β4 loop of the tyrosine kinase domain that activates EGFR in the absence of the activating EGF ligand. However, the mechanistic details of how R776H contributes to kinase activation are not well understood. Here using cell-based cotransfection assays, we show that the R776H mutation activates EGFR in a dimerization-dependent manner by preferentially adopting the acceptor position in the asymmetric dimer. The acceptor function, but not the donor function, is enhanced for the R776H mutant, supporting the “superacceptor” hypothesis proposed for oncogenic mutations in EGFR. We also find that phosphorylation of monomeric EGFR is increased by R776H mutation, providing insights into EGFR lateral phosphorylation and oligomerization. On the basis of molecular modeling and molecular dynamics simulation, we propose a model in which loss of key autoinhibitory αC-helix capping interaction and alteration of coconserved cis regulatory interactions between the kinase domain and the flanking regulatory segments contribute to mutational activation. Since the R776 equivalent position is mutated in ErbB2 and ErbB4, our studies have implications for understanding kinase mutational activation in other ErbB family members as well.

Go To Biochemistry

Figure legend

Background: DNA sequences of EGFR with the R776 codon highlighted in red. Upper left panel: WT EGFR adopts αC-helix “out” conformation, whereas R776H favors αC-helix “in” conformation. Right panel: R776H mutant adopts the “acceptor” position in the asymmetric dimer. Lower left panel: R776H mutant exerts lateral phosphorylation of monomeric EGFR.

 

An Early and Robust Activation of Caspases Heads Cells for a Regulated Form of Necrotic-like Cell Death

Journal Reference

J Biol Chem. 2015;290(34):20841-55.

Garcia-Belinchón M¹, Sánchez-Osuna M¹, Martínez-Escardó L², Granados-Colomina C², Pascual-Guiral S², Iglesias-Guimarais V¹, Casanelles E¹, Ribas J³,Yuste VJ⁴.

Show Affiliations

1. From the Cell Death, Senescence and Survival group, Departament de Bioquímica i Biologia Molecular-Unitat de Medicina and Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona, Campus de Bellaterra, 08193 Cerdanyola del Vallès, Barcelona, Spain, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, Campus de Bellaterra, 08193 Cerdanyola del Vallès, Barcelona, Spain, and.
2. From the Cell Death, Senescence and Survival group, Departament de Bioquímica i Biologia Molecular-Unitat de Medicina and Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona, Campus de Bellaterra, 08193 Cerdanyola del Vallès, Barcelona, Spain.
3. Celldeath regulation by non-coding RNA group, Pharmacology Unit, Departament de Medicina Experimental, Universitat de Lleida/Institut de Recerca Biomèdica de Lleida, Avinguda Rovira Roure 80, 25198 Lleida, Spain.
4. From the Cell Death, Senescence and Survival group, Departament de Bioquímica i Biologia Molecular-Unitat de Medicina and Institut de Neurociències, Facultat de Medicina, Universitat Autònoma de Barcelona, Campus de Bellaterra, 08193 Cerdanyola del Vallès, Barcelona, Spain, Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Universitat Autònoma de Barcelona, Campus de Bellaterra, 08193 Cerdanyola del Vallès, Barcelona, Spain, and victor.yuste@uab.cat

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Abstract

Apoptosis is triggered by the activation of caspases and characterized by chromatin condensation and nuclear fragmentation (type II nuclear morphology). Necrosis is depicted by a gain in cell volume (oncosis), swelling of organelles, plasma membrane leakage, and subsequent loss of intracellular contents. Although considered as different cell death entities, there is an overlap between apoptosis and necrosis. In this sense, mounting evidence suggests that both processes can be morphological expressions of a common biochemical network known as “apoptosis-necrosis continuum.” To gain insight into the events driving the apoptosis-necrosis continuum, apoptotically proficient cells were screened facing several apoptotic inducers for the absence of type II apoptotic nuclear morphologies. Chelerythrine was selected for further studies based on its cytotoxicity and the lack of apoptotic nuclear alterations. Chelerythrine triggered an early plasma membrane leakage without condensed chromatin aggregates. Ultrastructural analysis revealed that chelerythrine-mediated cytotoxicity was compatible with a necrotic-like type of cell death. Biochemically, chelerythrine induced the activation of caspases. Moreover, the inhibition of caspases prevented chelerythrine-triggered necrotic-like cell death. Compared with staurosporine, chelerythrine induced stronger caspase activation detectable at earlier times. After using a battery of chemicals, we found that high concentrations of thiolic antioxidants fully prevented chelerythrine-driven caspase activation and necrotic-like celldeath. Lower amounts of thiolic antioxidants partially prevented chelerythrine-mediated cytotoxicity and allowed cells to display type II apoptotic nuclear morphology correlating with a delay in caspase-3 activation. Altogether, these data support that an early and pronounced activation of caspases can drive cells to undergo a form of necrotic-like regulated cell death.

© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Go To J Biol Chem.

 

Par6G suppresses cell proliferation and is targeted by loss-of-function mutations in multiple cancers

Journal Reference

Oncogene. 2015 Jun 15 (Advance online publication).

Marques E¹, Englund JI¹, Tervonen TA¹, Virkunen E¹, Laakso M², Myllynen M¹, Mäkelä A¹, Ahvenainen M¹, Lepikhova T³, Monni O³, Hautaniemi S², Klefström J¹.

Show Affiliations

1. Cancer Cell Circuitry Laboratory, Research programs unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Finland.
2. Systems Biology Laboratory, Genome-Scale Biology Program and Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
3. Genome-Scale Biology Program and Institute of Biomedicine, Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.

 

Abstract

Differentiated epithelial structure communicates with individual constituent epithelial cells to suppress their proliferation activity. However, the pathways linking epithelial structure to cessation of the cell proliferation machinery or to unscheduled proliferation in the context of tumorigenesis are not well defined. Here we demonstrate the strong impact of compromised epithelial integrity on normal and oncogenic Myc-driven proliferation in three-dimensional mammary epithelial organoid culture. Systematic silencing of 34 human homologs of Drosophila genes, with previously established functions in control of epithelial integrity, demonstrates a role for human genes of apico-basal polarity, Wnt and Hippo pathways and actin dynamics in regulation of the size, integrity and cell proliferation in organoids. Perturbation of these pathways leads to diverse functional interactions with Myc: manifested as a RhoA-dependent synthetic lethality and Par6-dependent effects on the cell cycle. Furthermore, we show a role for Par6G as a negative regulator of the phosphatidylinositol 3′-kinase/phosphoinositide-dependent protein kinase 1/Akt pathway and epithelial cell proliferation and evidence for frequent inactivation of Par6G gene in epithelial cancers. The findings demonstrate that determinants of epithelial structure regulate thecell proliferation activity via conserved and cancer-relevant regulatory circuitries, which are important for epithelial cell cycle restriction and may provide new targets for therapeutic intervention.

Go To Oncogene.

About The Author

Juha Klefström, PhD, is a Research Director in Research Programs Unit, Medical Faculty, University of Helsinki and in Biomedicum Functional Genomics Unit. Klefström’s primary research interests are in breast cancer biology, genetically engineered mouse models of breast cancer, mammary gland reconstitution techniques, ex vivo organoid cultures and recombinant viral gene transfer methods. His laboratory has established variety of three-dimensional culture systems for primary mammary epithelial and tumor organoids to explore roles and targetability of Myc, Lkb1 and cell polarity pathways in breast cancer

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About The Author

Elsa Marques, MSc, is a PhD student in Research Programs Unit/ Translational Cancer Biology, University of Helsinki. She graduated from University of Coimbra, Portugal and followed her interests in cancer biology to Finland where she joined the laboratory of Juha Klefström. Her current main research interests are in the role of apicobasal polarity genes in development of breast cancer.