Biomedicines

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Open AccessReview

Cellular and Molecular Preconditions for Retinal Pigment Epithelium (RPE) Natural Reprogramming during Retinal Regeneration in Urodela

by Eleonora N. Grigoryan and Yuliya V. Markitantova

Biomedicines 2016, 4(4), 28; https://doi.org/10.3390/biomedicines4040028 - 1 Dec 2016

Cited by 22 | Viewed by 5642

Abstract

Many regeneration processes in animals are based on the phenomenon of cell reprogramming followed by proliferation and differentiation in a different specialization direction. An insight into what makes natural (in vivo) cell reprogramming possible can help to solve a number of biomedical problems. In particular, the first problem is to reveal the intrinsic properties of the cells that are necessary and sufficient for reprogramming; the second, to evaluate these properties and, on this basis, to reveal potential endogenous sources for cell substitution in damaged tissues; and the third, to use the acquired data for developing approaches to in vitro cell reprogramming in order to obtain a cell reserve for damaged tissue repair. Normal cells of the retinal pigment epithelium (RPE) in newts (Urodela) can change their specialization and transform into retinal neurons and ganglion cells (i.e., actualize their retinogenic potential). Therefore, they can serve as a model that provides the possibility to identify factors of the initial competence of vertebrate cells for reprogramming in vivo. This review deals mainly with the endogenous properties of native newt RPE cells themselves and, to a lesser extent, with exogenous mechanisms regulating the process of reprogramming, which are actively discussed. Full article

(This article belongs to the Special Issue Stem Cell Engineering: From Reprogramming Technologies to Translational Biomedicines)

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Open AccessReview

Complementary Approaches to Existing Target Based Drug Discovery for Identifying Novel Drug Targets

by Suhas Vasaikar, Pooja Bhatia, Partap G. Bhatia and Koon Chu Yaiw

Biomedicines 2016, 4(4), 27; https://doi.org/10.3390/biomedicines4040027 - 21 Nov 2016

Cited by 31 | Viewed by 10106

Abstract

In the past decade, it was observed that the relationship between the emerging New Molecular Entities and the quantum of R&D investment has not been favorable. There might be numerous reasons but few studies stress the introduction of target based drug discovery approach as one of the factors. Although a number of drugs have been developed with an emphasis on a single protein target, yet identification of valid target is complex. The approach focuses on an in vitro single target, which overlooks the complexity of cell and makes process of validation drug targets uncertain. Thus, it is imperative to search for alternatives rather than looking at success stories of target-based drug discovery. It would be beneficial if the drugs were developed to target multiple components. New approaches like reverse engineering and translational research need to take into account both system and target-based approach. This review evaluates the strengths and limitations of known drug discovery approaches and proposes alternative approaches for increasing efficiency against treatment. Full article

(This article belongs to the Special Issue Molecular Imaging as a Tool for Personalized Medicine)

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Graphical abstract

Graphical abstract
Full article ">Figure 1
(A) U.S. Food and Drug Administration (USFDA) approved new molecular entities (NMEs). Number NMEs approved by the USFDA; (B) Attrition rate across the different stages of drug discovery and development phase. Around 80% of attrition rate was observed in drug discovery phase. Whereas more than 90% attrition was observed in drug development phase. In summary, ~1 in 50 projects reach market from discovery phase [<a href="#B4-biomedicines-04-00027" class="html-bibr">4</a>]. Full article ">Figure 2
(A) Classification of drug targets based on FDA approved drug molecules [<a href="#B16-biomedicines-04-00027" class="html-bibr">16</a>]; (B) Druggable genome. (i) The Venn diagram shows the subset of human genome associated with disease and available drugs targeting subset of genes. (ii) Classification of the drug targets encoded by the human genome. Full article ">Figure 3
Multi-target drugs. (A) The chemical structure of metamine, only multi-drug molecule used to treat Alzheimer’s disease patients; (B) Proposed mode of action of multi-target drugs through weak-linkage of networks. Drug repositioning; (C) Drug repositioning is the process of identifying new indication for known drug; (D) The approach of identifying new indication for known drug includes drug based, disease based or treatment based methods. The drug based approach consist of blinded or target based discovery of new indication while knowledge based discovery shared by drug based and disease based approach. Treatment based approach consist of target mechanism based discovery. Disease based and treatment based approach shares pathway based discovery [<a href="#B47-biomedicines-04-00027" class="html-bibr">47</a>]. Full article ">Figure 4
Use of human cells for stem cell-based assays and therapies. The embryonic stem cells (ESCs), fetal stem/progenitor cells (FSCs), adult stem/progenitor cells (ASCs) and induced pluripotent stem cells (iPSCs) used in regenerative medicines. These stems cells cultured and reprogrammed to desired cell type. After differentiation obtained desired cell types studied and tested for treating different diseases including autoimmune diseases, neurological diseases, cardiovascular diseases, degenerative skeletal diseases and cancer. Full article ">Figure 5
Innovative NMEs approved in 2011–2015. CDER used a number of regulatory methods including Fast Track, Breakthrough, Priority Review, and Accelerated Approval to expedite innovative NMEs to market. Full article ">

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Open AccessReview

The Strategies to Homogenize PET/CT Metrics: The Case of Onco-Haematological Clinical Trials

by Stephane Chauvie and Fabrizio Bergesio

Biomedicines 2016, 4(4), 26; https://doi.org/10.3390/biomedicines4040026 - 15 Nov 2016

Cited by 11 | Viewed by 4965

Abstract

Positron emission tomography (PET) has been a widely used tool in oncology for staging lymphomas for a long time. Recently, several large clinical trials demonstrated its utility in therapy management during treatment, paving the way to personalized medicine. In doing so, the traditional way of reporting PET based on the extent of disease has been complemented by a discrete scale that takes in account tumour metabolism. However, due to several technical, physical and biological limitations in the use of PET uptake as a biomarker, stringent rules have been used in clinical trials to reduce the errors in its evaluation. Within this manuscript we will describe shortly the evolution in PET reporting, examine the main errors in uptake measurement, and analyse which strategy the clinical trials applied to reduce them. Full article

(This article belongs to the Special Issue Molecular Imaging as a Tool for Personalized Medicine)

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SUV (standardized uptake value) mean in the blood pool versus liver in a cohort of 1132 patients acquired on 56 different PET/CT scanners. Full article ">Figure 2
Recovery coefficient curves describing the loss of uptake in the function of a lesion’s size. The blue line is an example in which the reconstruction algorithm has been optimized in respect to the green line. Purple and orange curves are tolerated deviations. Full article ">Figure 3
Residual activity remaining in syringe after injection versus injected activity in a cohort of 50 patients from Santa Croce e Carle Hospital. Injection is carried out with a three-way valve system and the syringe is flushed with physiological saline after the injection. Full line represents average residual activity while dashed lines are the 95% confidence interval (±2 standard deviation). Full article ">Figure 4
Histogram of uptake time in 1700 PET/CT scans acquired from over 56 PET sites across the world. The average uptake time is 79 ± 28 min (range 23–256). Full article ">Figure 5
SUV of the liver as a function of uptake time in 1132 PET scans acquired from over 56 PET sites across the world. SUV of the liver is the mean SUV in a 5 cm diameter circle positioned in the VII–VIII lobes far from liver’s edge and dome. The average SUV is 1.97 ± 0.55 min (range 0.42–8.87). Full article ">Figure 6
SUV of the blood pool as a function of uptake time in 1132 PET scans acquired from over 56 PET sites across the world. SUV of the blood pool is the mean SUV of a 1 cm diameter circle positioned in the descending aorta. The average SUV is 1.40 ± 0.38 min (range 0.40–3.45). Full article ">

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Open AccessFeature PaperReview

Personalized Dosimetry for Radionuclide Therapy Using Molecular Imaging Tools

by Michael Ljungberg and Katarina Sjögreen Gleisner

Biomedicines 2016, 4(4), 25; https://doi.org/10.3390/biomedicines4040025 - 15 Nov 2016

Cited by 29 | Viewed by 10230

Abstract

For treatment of systemic malignancies, when external radiation therapy is not applicable, radionuclide therapy can be an alternative. In this form of therapy, radionuclides are administered to the patient, often in a form where the radionuclide is labelled to a molecule that plays the active part in the localization of the tumor. Since the aim is to impart lethal damage to tumor cells while maintaining possible side-effects to normal tissues at tolerable levels, a proper and accurate personalized dosimetry should be a pre-requisite. In radionuclide therapy, there is a need to measure the distribution of the radiopharmaceutical in vivo, as well as its re-distribution over time, in order estimate the total energy released in radioactive decays and subsequent charged-particle interactions, governing the absorbed dose to different organs and tumors. Measurements are usually performed by molecular imaging, more specifically planar and SPECT (Single-Photon Emission Computed Tomography) imaging, combined with CT. This review describes the different parts in the dosimetry chain of radionuclide therapy. Emphasis is given to molecular imaging tools and the requirements for determining absorbed doses from quantitative planar and SPECT images. As example solutions to the different problems that need to be addressed in such a dosimetric chain, we describe our tool, Lundadose, which is a set of methods that we have developed for personalized dosimetry. Full article

(This article belongs to the Special Issue Molecular Imaging as a Tool for Personalized Medicine)

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Overview of the chain for personal dosimetry using molecular imaging. Full article ">Figure 2
Flow-chart of the iterative reconstruction process. Full article ">Figure 3
The figure shows tomographic images of the 111In-labeled monoclonal antibody distribution in the liver. The upper row shows images reconstructed with ML-EM and where one, five and 20 iterations have been used. The lower row shows corresponding images reconstructed with OS-EM. Full article ">Figure 4
Schematic sketch showing the principles behind photon attenuation, scatter and collimator resolution effects (geometric resolution and effects from septal penetration). Full article ">Figure 5
Three images showing anterior and posterior whole-body images. Before applying the geometric-mean on a pixel-by-pixel level, the posterior image is mirrored. The image to the right is the scout image whose intensity describes the amount of photon attenuation in the patient. Bright areas indicate a large probability for photon attenuation. This image is acquired with the X-ray unit, and the values are scaled to represent the attenuation factor for the relevant photon energy. The spatial misregistration between the scout image and the two planar images is accounted for by an image registration procedure, tailored for whole-body images, as described further down in the text. Full article ">Figure 6
Overlay of a raw and processed planar scintillation-camera image on a scout image. The improvement in the appearance of the processed image, i.e., after attenuation and scatter corrections, is marked. Full article ">Figure 7
A flow-chart describing the essential steps needed to obtain quantitative 3D activity and related absorbed-dose images. If using a combined SPECT/CT system, explicit registration of SPECT and CT images is not required, since positioning and interpolation are inherent in the imaging system. In most commercial SPECT/CT systems, necessary corrections are embedded within the iterative reconstruction method, at least for non-homogeneous attenuation correction, scatter correction and compensation for collimator resolution. For most radionuclides used in radionuclide therapy, the path-lengths of the electrons (i.e., the particles that deliver the energy) are short compared to the voxel size, and therefore, a simple scaling, by assuming a local energy deposition within a voxel, will be justified. This makes 3D dosimetry based on SPECT/CT relatively straight-forward. Full article ">Figure 8
Calculated integral dose-volume histograms (DVHs) obtained in a VOI defined over the whole liver region for the six reconstructions as shown in <a href="#biomedicines-04-00025-f003" class="html-fig">Figure 3</a>. Full article ">

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Open AccessArticle

Glioma FMISO PET/MR Imaging Concurrent with Antiangiogenic Therapy: Molecular Imaging as a Clinical Tool in the Burgeoning Era of Personalized Medicine

by Ramon F. Barajas, Kenneth A. Krohn, Jeanne M. Link, Randall A. Hawkins, Jennifer L. Clarke, Miguel H. Pampaloni and Soonmee Cha

Biomedicines 2016, 4(4), 24; https://doi.org/10.3390/biomedicines4040024 - 31 Oct 2016

Cited by 13 | Viewed by 5005

Abstract

The purpose of this article is to provide a focused overview of the current use of positron emission tomography (PET) molecular imaging in the burgeoning era of personalized medicine in the treatment of patients with glioma. Specifically, we demonstrate the utility of PET imaging as a tool for personalized diagnosis and therapy by highlighting a case series of four patients with recurrent high grade glioma who underwent 18F-fluoromisonidazole (FMISO) PET/MR (magnetic resonance) imaging through the course of antiangiogenic therapy. Three distinct features were observed from this small cohort of patients. First, the presence of pseudoprogression was retrospectively associated with the absence of hypoxia. Second, a subgroup of patients with recurrent high grade glioma undergoing bevacizumab therapy demonstrated disease progression characterized by an enlarging nonenhancing mass with newly developed reduced diffusion, lack of hypoxia, and preserved cerebral blood volume. Finally, a reduction in hypoxic volume was observed concurrent with therapy in all patients with recurrent tumor, and markedly so in two patients that developed a nonenhancing reduced diffusion mass. This case series demonstrates how medical imaging has the potential to influence personalized medicine in several key aspects, especially involving molecular PET imaging for personalized diagnosis, patient specific disease prognosis, and therapeutic monitoring. Full article

(This article belongs to the Special Issue Molecular Imaging as a Tool for Personalized Medicine)

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Abseent FMISO hypoxic volume in pseudoprogression prior to and following bevacizumab therapy. FMISO PET/MR imaging obtained simultaneously 7 days prior to (A) and 155 days after initiation of antiangiogenesis therapy (B) demonstrates pseudoprogression characterized by decreased volume of contrast enhancement (middle left) and nonenhancing FLAIR hyperintense mass (middle right) with associated focus of reduced diffusion (adc map, right). Unprocessed (left) and fused FMISO PET imaging (middle left, middle right, and right) demonstrates absence of FMISO accumulation above 1.2 time background. Pre-therapy FMISO PET/MR demonstrates slightly decreased focus of radiotracer uptake (upper left, arrow) relative to background which slightly increases to background uptake levels following bevacizumab therapy. FMISO HV is not observed at any time point in this patient with pseudoprogression. Full article ">Figure 2
Absent FMISO hypoxic volume with associated development of reduced diffusion in recurrent high grade glioma concurrent with bevacizumab therapy. FMISO PET/MR imaging obtained simultaneously 5 days prior to (A) and 100 days following antiangiogenesis therapy (B) demonstrates progression of recurrent disease characterized by increased volume of nonenhancing mass (contrast, top row; FLAIR, top middle row) associated with the development of reduced diffusion (adc map, bottom row). Fused FMISO PET imaging (baseline, middle left; follow-up, middle right) demonstrates the resolution of tumor hypoxia concurrent with antiangiogenesis therapy. The unprocessed FMISO PET image (baseline, middle left; follow-up, middle right; bottom middle row) demonstrates the marked decrease in radiotracer accumulation below background tissue levels within regions of preserved cerebral blood volume (baseline, left; follow-up, right; bottom middle row) suggesting tissue consisting of highly cellular recurrent tumor with transformed or normalized tumor microvasculature. Full article ">Figure 3
Decreased but persistent FMISO hypoxic volume in recurrent high grade glioma concurrent with bevacizumab therapy. FMISO PET/MR imaging obtained simultaneously 7 days prior to (A) and 36 days following antiangiogenesis therapy (B) demonstrates response to therapy characterized by decreased volume of contrast enhancement (top row) and nonenhancing FLAIR hyperintense mass (middle row) without evidence of reduced diffusion (adc map, bottom row). Unprocessed (bottom) and fused FMISO PET imaging (baseline, middle left; follow-up, middle right) demonstrates decreased but persistent tumor hypoxic volume predominately within the enhancing component. Follow-up MR imaging did not demonstrate the development of nonenhancing reduced diffusion mass at any point of therapy. Full article ">

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Biomedicines, Volume 4, Issue 4 (December 2016) – 5 articles

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