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Biomedicines
Volume 5
Issue 4
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Biomedicines, Volume 5, Issue 4 (December 2017) – 14 articles

Cover Story (view full-size image): This confocal image shows a vessel in green (Flk1-GFP transgenic mice) coming from a muscle and entering a cortical bone. Osteocytes appear in red within the bone due to a Dextran Texas Red lysine fixable (10,000 MW) injection, 5 min before the sacrifice (Kamel‐ElSayed SA, et al. Bone. 2015), and all the cells are stained in blue with DAPI to show the nucleus (1:2000). The top of this image shows bone marrow. Briefly, the femur was fixed in 4% PFA for 48 h at +4 °C and demineralized in EDTA 10% for 1 week. It was then bathed in sucrose 15% and 30% before being embedded in OCT. A 50 µm cryosection was cut using a cryostat. This image has been realized by Dr. Delphine Maurel and Dr. Claudine Boiziau. View this paper
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4324 KiB  
Review
Histology of Non-Melanoma Skin Cancers: An Update
by Giovanni Paolino, Michele Donati, Dario Didona, Santo Raffaele Mercuri and Carmen Cantisani
Biomedicines 2017, 5(4), 71; https://doi.org/10.3390/biomedicines5040071 - 20 Dec 2017
Cited by 66 | Viewed by 13981
Abstract
Non-melanoma skin cancer (NMSC) is the most frequently diagnosed cancer in humans. Several different non-melanoma skin cancers have been reported in the literature, with several histologic variants that frequently cause important differential diagnoses with other cutaneous tumors basal cell carcinoma (BCC) is the [...] Read more.
Non-melanoma skin cancer (NMSC) is the most frequently diagnosed cancer in humans. Several different non-melanoma skin cancers have been reported in the literature, with several histologic variants that frequently cause important differential diagnoses with other cutaneous tumors basal cell carcinoma (BCC) is the most common malignant skin tumor, with different histologic variants that are associated with a greater or less aggressive behavior and that usually may be confused with other primitive skin tumors. Actinic keratosis, Bowen’s disease, keratoacanthoma, and invasive squamous cell carcinoma (SCC) correspond to the other line of NMSC, that may have only local tumoral behavior, easy to treat and with local management (as in the case of actinic keratosis (AK), Bowen’s disease, and keratoacanthoma) or a more aggressive behavior with a potential metastatic spread, as in case of invasive SCC. Therefore, histopathology serves as the gold standard during daily clinical practice, in order to improve the therapeutical approaches to patients with NMSC and to understand the distinct histopathological features of NMSC. Here, we reported the main pathological features of different non-melanoma skin cancers. Full article
(This article belongs to the Special Issue Photodynamic Therapy in Cancer)
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Figure 1

Figure 1
<p>Nodular basal cell carcinoma (hematoxylin and eosin, 20×).</p> Full article ">Figure 2
<p>Nodular basal cell carcinoma (hematoxylin and eosin, 20×).</p> Full article ">Figure 3
<p>Metatypical basal cell carcinoma (hematoxylin and eosin, 20×).</p> Full article ">Figure 4
<p>Basosquamous carcinoma (hematoxylin and eosin, 20×).</p> Full article ">Figure 5
<p>Typical small-to-medium-sized basophilic tumoral cells in a Merkel cell carcinoma. (hematoxilin and eosin, 30×).</p> Full article ">Figure 6
<p>Sometimes the differential diagnosis between a morpheaform BCC and a desmoplastic tricoepithelioma. Rims of collagen bundles surrounding basaloid cells without peripheral palisading and without the typical cleft of BCC, in a desmoplastic tricoepithelioma (hematoxilin and eosin, 10×).</p> Full article ">Figure 7
<p>Actinic keratosis with Bowenoid features (hematoxylin and eosin, 40×).</p> Full article ">Figure 8
<p>Desmoplastic squamous cell carcinoma (hematoxylin and eosin, 10×).</p> Full article ">
6690 KiB  
Article
Comparative Therapeutic Effects of Plant-Extract Synthesized and Traditionally Synthesized Gold Nanoparticles on Alcohol-Induced Inflammatory Activity in SH-SY5Y Cells In Vitro
by Ashok K. Singh
Biomedicines 2017, 5(4), 70; https://doi.org/10.3390/biomedicines5040070 - 15 Dec 2017
Cited by 14 | Viewed by 4996
Abstract
The present study describes potential beneficial and adverse effects of plant-extract synthesized gold nanoparticles (AuNPs) on ethanol toxicity in SH-SY5Y cells. Although kudzu root extract (K), edible-gum extract (G), alone or in combination (KG), reduced Au3+ into AuNPs, the extract’s composition and [...] Read more.
The present study describes potential beneficial and adverse effects of plant-extract synthesized gold nanoparticles (AuNPs) on ethanol toxicity in SH-SY5Y cells. Although kudzu root extract (K), edible-gum extract (G), alone or in combination (KG), reduced Au3+ into AuNPs, the extract’s composition and the reaction temperature determined their size (AuNPKG(90<50<37) << AuNPK (90,50<37) < AuNPG (90<50); the subscript KG, K, or G is extract identification and numerical vales are reaction temperature in Celsius) and biological properties (AuNPKG (90,50>37) << AuNPK (90,50>37) < AuNPG (90,50)). The surface of each AuNP contained the extract’s active ingredients, that were analyzed and confirmed using laser desorption ionization (LDI)) and low-matrix laser desorption-ionization (LMALDI). AuNPKG-50 was (i) least toxic to SH-SY5Y cells, but most effective in suppressing the adverse effects of ethanol on SH-SY5Y cells, and (ii) more effective than a combination of free kudzu and gum extracts. The beneficial and adverse effects of AuNPs may have been modified by the formation of proteins corona. This study provides a proof of concept for possible application of plant-extract synthesized AuNPs in mitigating ethanol toxicity. Full article
(This article belongs to the Special Issue Impact of Nanobiotechnology (Nanomedicine) on the Future of Medicine: The Road toward Precision Medicine)
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Experimental protocol. SH-SY5Y cells were expanded in growth media for 3 days. On day-1, 4, 3 × 10<sup>7</sup> cells were transferred into each well, and incubated for 4 days in media containing different doses of gold nanoparticles (AuNPs) (AuNP positive (Ap) cells) or matrix alone (AuNP negative (An) cells). At day 8, cells were washed and incubated in media containing 54 mM (final concentration) ethanol (Ap ethanol exposed (ApEp), or An ethanol exposed (AnEp) cells) or the matrix alone (AuNP and ethanol negative (AnEn), or Ap ethanol negative (ApEn) cells) for 24 h. Then, cells were washed and incubated in media alone. At different time intervals after ethanol exposure, cells were harvested and analyzed for AuNP internalization, AuNPs’ adverse effects, and modulation of ethanol toxicity. PEG: polyethylene glycol; K: kudzu root extract; G: gum extract; KG: combination of kudzu root and gum; MTT: 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; NFκB: nuclear factor kappa B.</p> Full article ">Figure 2
<p>Typical FTIR spectra for AuNP<sub>KG</sub>, kudzu extracts, and gum solution.</p> Full article ">Figure 3
<p>Optical absorption curves (<b>A</b>); size distribution and transmission electron microscopy (<b>B</b>) of different AuNP preparations. Abbreviations: K: kudzu, G: gum, and 37, 50, and 90: reaction temperature in °C.</p> Full article ">Figure 4
<p>Mass spectral identification of surface ligands. (<b>A</b>) <sub>L</sub>MALDI that detects Au ions; (<b>B</b>) typical LDI (matric free) analysis of AuNP<sub>KG-50</sub> synthesized by a mixture of kudzu root and gum; (<b>C</b>) typical LDI analysis of a mixture of kudzu and gum solutions; (<b>D</b>) typical LDI (matrix free) analysis of AuNP<sub>G-50</sub> synthesized by a gum solution alone; (<b>E</b>) typical LDI (matrix free) analysis of AuNP<sub>K-50</sub> synthesized by a kudzu extract alone; and (<b>F</b>) analysis of a blank solution. Peak identification 1: 73 <span class="html-italic">m</span>/<span class="html-italic">z</span> arabinose, galactose, fructose; 2: 147 <span class="html-italic">m</span>/<span class="html-italic">z</span> galactose; 3: 217 arabinose; 4: 225 <span class="html-italic">m</span>/<span class="html-italic">z</span> daidzein; 5: 229 <span class="html-italic">m</span>/<span class="html-italic">z</span> d4-daidzein; 6: 370 <span class="html-italic">m</span>/<span class="html-italic">z</span> not identified; 7: 417 <span class="html-italic">m</span>/<span class="html-italic">z</span> puerarin, 8: 429 not identified; 9: 894 kakkasaponin; Au<sup>+</sup> 193 <span class="html-italic">m</span>/<span class="html-italic">z</span>; Au<sub>3</sub><sup>+</sup> 396 <span class="html-italic">m</span>/<span class="html-italic">z</span>.</p> Full article ">Figure 5
<p>The dose (mg/L of AuNPs) versus response (intracellular Au concentration—iAuC) curves for internalization of different AuNPs at day 16 of cell incubation. (<b>A</b>) Ap/En cells, and (<b>B</b>) Ap/Ep cells. Values are mean ± SD. *: <span class="html-italic">p</span> &lt; 0.05, significant, when compared with corresponding data from different groups, x: <span class="html-italic">p</span> &lt; 0.05, significant, when compared with different dose values from the same group.</p> Full article ">Figure 6
<p>The time course of change in intracellular AuNP<sub>KG-50</sub> (<b>A</b>), AuNP<sub>K-50</sub> (<b>B</b>), AuNP<sub>G-50</sub> (<b>C</b>), and AuNP<sub>PEG+K+G</sub> (<b>D</b>) concentrations in Ap/En cells (solid line) and Ap/Ep cells (broken line). x: <span class="html-italic">p</span> &lt; 0.05 when day 8 (before ethanol/matrix exposure) values were compared with post-ethanol values. #: <span class="html-italic">p</span> &lt; 0.05 when corresponding Ap/En values were compared with corresponding An/Ep values. Please define *: <span class="html-italic">p</span> &lt; 0.05, significant, when compared with the lowest value from the same group. Abbreviations: i: three days of cell growth (days 1 to 3); ii: four days of AuNP or matrix pretreatment (day 4 to day 7); iii: 24 h ethanol or saline (matrix) exposure (day 8) and iv: AuNP and ethanol free media for 16 days.</p> Full article ">Figure 7
<p>Identification of surface ligands on AuNPs collected from Ap/En and Ap/Ep cells. (<b>A</b>) the plant component peaks at 1 (fAuNP LDI<sub>1</sub>), 2 (fAuNP LDI<sub>2</sub>), 4 (fAuNP LDI<sub>4</sub>), 8 (fAuNP LDI<sub>8</sub>), and 16 (fAuNP LDI<sub>16</sub>) days after ethanol exposure; (<b>B</b>) Time course of change in total number of peaks adsorbed onto the AuNP surface. Total number of peaks decreased significantly at day 16 (filled circle: number of peaks in matrix exposed cells, open circle: number of peaks in ethanol exposed cells). (<b>C</b>) AuNP dose versus (ligand peak/IS peak) ratio plots for surface ligands in matrix exposed (subscript <sub>M</sub>) and ethanol exposed (subscript <sub>E</sub>) cells. Abbreviations: PU: puerarin, KA: kakkasaponin, DI: daidzin, DE<sub>:</sub> daidzein, AR: arabinose, GA: galactose, FR: fructose. Values are mean ± SD. x: <span class="html-italic">p</span> &lt; 0.05 when compared with corresponding open circle values, and *: <span class="html-italic">p</span> &lt; 0.05 when compared with values from same group.</p> Full article ">Figure 8
<p>(<b>A</b>) Plots of dose (AuNP mg/L) versus viable Ap/En cells (% of control) at day 16. A 5 to 60 mg/L dose of all AuNP exhibited comparable response. Only 100 mg/L dose caused significant decrease in viable cell enumeration. Values are mean ± SD; (<b>B</b>) Plots of dose (AuNP mg/L) versus viable Ap/Ep cells (% of control) at day 16). Different AuNPs yielded variable response, but maximum protection was provided by AuNP<sub>KG-50,-90</sub> at 20 mg/L dose. Values are mean ± SD. *: <span class="html-italic">p &lt;</span> 0.05 when compared with An/En response and x, # or @: <span class="html-italic">p</span> &lt; 0.05, when viability of Ap/Ep cells exposed to a given dose of and AuNP compared with viability of Ap/Ep exposed to the same dose of other AuNPs. 1: AuNP<sub>KG-90</sub>, 2: AuNP<sub>KG-50</sub>, 3: AuNP<sub>KG-50</sub>, 4: AuNP<sub>KG-37</sub>, 5: AuNP<sub>K-50,90</sub>, 6: AuNP<sub>PEG</sub>+KG, 7: AuNP<sub>KG-37</sub>, 8: AuNP<sub>PEG</sub>, 9: AuNP<sub>G-50,G90</sub>.</p> Full article ">Figure 9
<p>The time course of change in viability of Ap/En (broken line) and Ap/Ep (solid line) cell pre-exposed to a 20 mg/L dose of AuNP<sub>KG-50</sub>. *: <span class="html-italic">p</span> &lt; 0.05 when exposed to day 0 values and x: <span class="html-italic">p</span> &lt; 0.05 when Ap/En and Ap/Ep values were compared at each time interval.</p> Full article ">Figure 10
<p>(<b>A</b>) Plots of dose (AuNP mg/L) versus intracellular lipid peroxidase activity in Ap/En cells (% of control) at day 16. A 5 to 60 mg/L dose of all AuNPs exhibited comparable response. Only 100 mg/L dose caused significant but variable increase in enzyme activity (AuNP<sub>KG-50</sub> exhibited lowest, while AuNP<sub>G-50</sub> exhibited highest activity in response to 100 mg/L dose). Values are mean ± SD; (<b>B</b>) Plots of dose (AuNP mg/L) versus intracellular lipid peroxidase activity in Ap/Ep cells (% of control) at day 16. Different AuNPs yielded variable response, but maximum protection was provided by AuNP<sub>KG-50</sub> at 20 to 60 mg/L dose. Values are mean ± SD. *: <span class="html-italic">p</span> &lt; 0.05 when Ap/En or Ap/Ep values were compared with An/En values. X, # or @: <span class="html-italic">p</span> &lt; 0.05, when enzyme activity of Ap/Ep cells exposed to a given dose of and AuNP compared with enzyme activity of Ap/Ep cells exposed to the same dose of other AuNPs; (<b>C</b>) The time course of change in enzyme activity of Ap/En (broken line) and Ap/Ep (solid line) cell pre-exposed to a 20 mg/L dose of AuNP<sub>KG-50</sub>. *: <span class="html-italic">p</span> &lt; 0.05 when exposed to day 0 values, and x: <span class="html-italic">p</span> &lt; 0.05 when Ap/En and Ap/Ep values were compared at each time interval.</p> Full article ">Figure 11
<p>(<b>A</b>) Plots of dose (AuNP mg/L) versus lactate dehydrogenase (LDH) activity in Ap/En cells (% of control) at day 16. A 5 to 60 mg/L dose of all AuNPs exhibited comparable response. Only 100 mg/L dose caused significant in enzyme activity. Values are mean ± SD; (<b>B</b>) Plots of dose (AuNP mg/L) versus LDH activity in Ap/Ep cells (% of control) at day 16. Maximum protection was provided by AuNP<sub>KG-50</sub> at 20 to 60 mg/L dose. Values are mean ± SD. *: <span class="html-italic">p</span> &lt; 0.05 when Ap/En or Ap/Ep values were compared with An/En values, x: <span class="html-italic">p</span> &lt; 0.05, when enzyme activity of Ap/Ep cells exposed to a given dose of and AuNP compared with enzyme activity of Ap/Ep cells exposed to the same dose of other AuNPs; (<b>C</b>) The time course of change in LDH activity of Ap/En (broken line) and Ap/Ep (solid line) cells pre-exposed to a 20 mg/L dose of AuNP<sub>KG-50</sub>. *: <span class="html-italic">p</span> &lt; 0.05 when exposed to day 0 values, and x: <span class="html-italic">p</span> &lt; 0.05 when Ap/En and Ap/Ep values were compared at each time interval.</p> Full article ">Figure 12
<p>Effects of different doses of AuNPs on incorporation of annexin V and propidium iodide (PI) in An/En (bottom 0 mg/L), Ap/En (bottom 5 to 100 mg/L), Ap/Ep (top 5 to 100 mg/L AuNP) and An/Ep (top 0 mg/L) cells. Superscripts <sup>+</sup> to <sup>+++</sup> represent relative distribution of An and/or PI positive cells (<sup>−</sup>: An negative, <sup>+</sup>: lowest distribution, <sup>++</sup>: intermediate distribution and <sup>+++</sup>: high distribution).</p> Full article ">Figure 13
<p>The time course of incorporation of annexin V and propidium iodide in An/En cells (C), Ap/En cells (bottom, 1 to 16 days, fixed AuNP dose of 20 mg/L), Ap/Ep cells (top, 1 to 16 days, fixed AuNP dose of 20 mg/L) and An/Ep cells (top day 1) cells. An: Annexin, PI: Propidium iodide, Superscripts: <sup>−</sup>: within control range, <sup>+</sup>: 10% to 15% increase, <sup>++</sup>: &gt;15% to 30% increase and <sup>+++</sup>: &gt;30% increase.</p> Full article ">Figure 14
<p>(<b>A</b>) Typical electrophoretic separation of NFκB dimer, p65–p50, in An/En (matrix), An/Ep (E+matrix), Ap/Ep (E+ 5 to 100 mg/L, data for AuNP<sub>KG-50</sub> is shown), and Ap/En (saline + 5 to 100 mg/L, data for AuNP<sub>KG-50</sub> is shown) cells. [a] matrix exposed control, An/En cells, [be] AuNP negative but ethanol positive An/Ep cells, [bm] AuNP and ethanol negative An/En cells, [ce] Ap/Ep cells receiving 5 mg/L AuNP<sub>KG-50</sub>, [cm] Ap/En cells receiving 5 mg/L AuNP<sub>KG-50</sub>, [de] Ap/Ep cells receiving 10 mg/L AuNP<sub>KG-50</sub>, [dm] Ap/En cells receiving 10 mg/L AuNP<sub>KG-50</sub>, [f] Ap/Ep cells receiving 20 mg/L AuNP<sub>PEG+K+G</sub> (fi), AuNP<sub>KG-50</sub>, (fiii), AuNP<sub>K-50</sub> (fv) and AuNP<sub>G-50</sub> (fvii), and [ge, he, ie] Ap/Ep cells receiving 40, 60, and 100 mg/L, respectively, and <span class="html-italic">[gm, hm, im]</span> Ap/En cells receiving 40, 60, and 100 mg/L, respectively; (<b>B</b>) Scan of the p65–p50 fluorescence—dose–response and time course studies. (0 –Pre E) Ap/En cells were exposed to different doses of AuNP<sub>KG-50</sub>. (1 to 16 days post ethanol exposure): Ap/Ep cells were exposed to different doses of AuNP<sub>KG-50</sub> for 4 days then ethanol for 24 h. Cells were analyzed at day 1, day 2, day 4, day 8 and day 16 post ethanol. Values are mean ± SD. x: <span class="html-italic">p</span> &lt; 0.05 when values for cells exposed to 60 mg/L were compared with cells exposed to lower AuNP doses. #: <span class="html-italic">p</span> &lt; 0.05 when values for cells exposed to 100 mg/L were compared with cells exposed to lower AuNP doses. b: <span class="html-italic">p</span> &lt; 0.05 when values for cells exposed to 0, 5, and 10 mg/L were significantly higher than the values for cells exposed to higher doses. y: <span class="html-italic">p</span> &lt; 0.05 when values for cells exposed to 20 and 40 mg/L were compared with other values. @: <span class="html-italic">p</span> &lt; 0.05 when values for same AuNP dose collected at different time intervals were compared. Values are mean ± SD, <span class="html-italic">n</span> = 5.</p> Full article ">Figure 15
<p>Characterization of protein corona on AuNP surface. (<b>Top</b>) Effects of ethanol exposure on composition of corona proteins. (<b>Bottom left)</b> Chromatographic separation of peptides extracted from ethanol-negative cells. <b>(Bottom right)</b> Chromatographic separation of peptides extracted from ethanol-positive cells. Protein identification: 1: alcohol dehydrogenase, 2: cAMP/cGMP phosphodiesterase, 3: Tyr phosphatase, 4: transferrin, 5: glutamate CoA phosphodiesterase, 6: arginine <span class="html-italic">N</span>-methyltransferase, 7: casein kinase, 8: MAPK kinase-9, and 10: parvalbumin. C<sub>0</sub>: control cells, C16: control cells exposed for 16 days; ADH: alcohol dehydrogenase; cAMP: cyclic adenosine dinucleotide mono phosphate; cGMP: cyclic guanine dinucleotide mono phosphate; MAPK: mitogen activated protein kinase; CPS: cAMP/gAMP phosphodiesterase.</p> Full article ">Figure 16
<p>Time course of change in individual protein concentrations in cytosol and desorbed from AuNP<sub>KG-50</sub>. Abbreviation: CaK: casein kinase, Tyr: tyrosine, Palb: parvalbumin, UI: unidentified.</p> Full article ">Figure 17
<p>Possible mechanism proposed for uptake and accumulation of AuNPs in cells. N: nucleus, M: mitochondria, E: endoplasmic reticulum.</p> Full article ">Figure 18
<p>Proposed mechanism for ethanol-induced cytotoxicity. *: proposed target sites for AuNP’s protective effects. Solid lines: activation, broken lines: inhibition, (−): inhibitory effects of AuNPs and (+): activation by AuNPs. AI: anti-inflammatory, PI: pro-inflammatory.</p> Full article ">
3060 KiB  
Review
Photodynamic Therapy for Eye Cancer
by Paul Rundle
Biomedicines 2017, 5(4), 69; https://doi.org/10.3390/biomedicines5040069 - 8 Dec 2017
Cited by 25 | Viewed by 8131
Abstract
Photodynamic therapy is well-established as a treatment for a number of conditions in ophthalmology, principally in the field of medical retina, but less so in ocular oncology. Cancer of the eye is rare, the commonest lesions to affect the globe being choroidal melanoma [...] Read more.
Photodynamic therapy is well-established as a treatment for a number of conditions in ophthalmology, principally in the field of medical retina, but less so in ocular oncology. Cancer of the eye is rare, the commonest lesions to affect the globe being choroidal melanoma (as a primary malignancy) and choroidal metastases (a secondary malignancy). The mainstay of treatment of such lesions remains radiotherapy in various forms, however, photodynamic therapy does have a useful role to play in the management of such patients. In this article, I hope to review the current indications, treatment regimes, and the risks and benefits of photodynamic therapy (PDT) as a treatment for eye cancer. Full article
(This article belongs to the Special Issue Photodynamic Therapy in Cancer)
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Figure 1

Figure 1
<p>(<b>a</b>) Fundal photograph of left eye showing melanoma (<b>black arrow</b>) adjacent to the fovea (<b>white arrow</b>); (<b>b</b>) ultrasound of lesion in <a href="#biomedicines-05-00069-f001" class="html-fig">Figure 1</a>a; (<b>c</b>) ocular coherence tomography (OCT) scan demonstrating sub-retinal fluid (<b>black arrow</b>); (<b>d</b>) post-treatment fundal photograph showing flat scar; (<b>e</b>) post-treatment ultrasound demonstrating flat scar; (<b>f</b>) post-treatment OCT showing resolution of sub-retinal fluid.</p> Full article ">Figure 2
<p>(<b>a</b>) pre-treatment fundal photograph of right eye demonstrating metastasis; (<b>b</b>) OCT scan demonstrating fluid beneath the fovea (<b>black arrow</b>); (<b>c</b>) post-PDT photograph showing regression of metastasis; (<b>d</b>) post-PDT OCT scan showing resolution of fluid; (<b>e</b>) fundal photograph showing recurrent tumour at edge of treatment scar (<b>black arrow</b>).</p> Full article ">Figure 2 Cont.
<p>(<b>a</b>) pre-treatment fundal photograph of right eye demonstrating metastasis; (<b>b</b>) OCT scan demonstrating fluid beneath the fovea (<b>black arrow</b>); (<b>c</b>) post-PDT photograph showing regression of metastasis; (<b>d</b>) post-PDT OCT scan showing resolution of fluid; (<b>e</b>) fundal photograph showing recurrent tumour at edge of treatment scar (<b>black arrow</b>).</p> Full article ">
4218 KiB  
Article
The Modulation of NMDA and AMPA/Kainate Receptors by Tocotrienol-Rich Fraction and Α-Tocopherol in Glutamate-Induced Injury of Primary Astrocytes
by Zahra Abedi, Huzwah Khaza’ai, Sharmili Vidyadaran and Mohd Sokhini Abd Mutalib
Biomedicines 2017, 5(4), 68; https://doi.org/10.3390/biomedicines5040068 - 1 Dec 2017
Cited by 9 | Viewed by 5465
Abstract
Astrocytes are known as structural and supporting cells in the central nervous system (CNS). Glutamate, as a main excitatory amino acid neurotransmitter in the mammalian central nervous system, can be excitotoxic, playing a key role in many chronic neurodegenerative diseases. The aim of [...] Read more.
Astrocytes are known as structural and supporting cells in the central nervous system (CNS). Glutamate, as a main excitatory amino acid neurotransmitter in the mammalian central nervous system, can be excitotoxic, playing a key role in many chronic neurodegenerative diseases. The aim of the current study was to elucidate the potential of vitamin E in protecting glutamate-injured primary astrocytes. Hence, primary astrocytes were isolated from mixed glial cells of C57BL/6 mice by applying the EasySep® Mouse CD11b Positive Selection Kit, cultured in Dulbecco’s modified Eagle medium (DMEM) and supplemented with special nutrients. The IC20 and IC50 values of glutamate, as well as the cell viability of primary astrocytes, were assessed with 100 ng/mL, 200 ng/mL, and 300 ng/mL of tocotrienol-rich fraction (TRF) and alpha-tocopherol (α-TCP), as determined by an 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The mitochondrial membrane potential (MMP) detected in primary astrocytes was assessed with the same concentrations of TRF and α-TCP. The expression levels of the ionotropic glutamate receptor genes (Gria2, Grin2A, GRIK1) were independently determined using RT-PCR. The purification rate of astrocytes was measured by a flow-cytometer as circa 79.4%. The IC20 and IC50 values of glutamate were determined as 10 mM and 100 mM, respectively. Exposure to 100 mM of glutamate in primary astrocytes caused the inhibition of cell viability of approximately 64.75% and 61.10% in pre- and post-study, respectively (p < 0.05). Both TRF and α-TCP (at the lowest and highest concentrations, respectively) were able to increase the MMP to 88.46% and 93.31% pre-treatment, and 78.43% and 81.22% post-treatment, respectively. Additionally, the findings showed a similar pattern for the expression level of the ionotropic glutamate receptor genes. Increased extracellular calcium concentrations were also observed, indicating that the presence of vitamin E altered the polarization of astrocytes. In conclusion, α-TCP showed better recovery and prophylactic effects as compared to TRF in the pre-treatment of glutamate-injured primary astrocytes. Full article
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Glial fibrillary acidic protein (GFAP) immunophenotyping to determine the purity of astrocyte culture. Cultures were stained with GFAP antibodies tagged with FITC (Fluorescein Isothiocyanate) and analyzed on a flow cytometer. P1 shows the population of cells; P2 shows the debris cells which are located in the lower left-hand side of scatter plots; P4 shows the primary astrocyte cells; P5 shows the contaminated cells. The plot shows that 79.4% of cells in the culture are GFAP+.</p> Full article ">Figure 2
<p>The effect of various concentrations of glutamate on primary astrocyte cells. Cultures were treated with various concentrations of glutamate for 24 h, y is showing the cell viability, x is showing the glutamate concentration and R<sup>2</sup> is showing coefficient of determination. IC<sub>20</sub> and IC<sub>50</sub> were calculated based on an equation with almost 97% accuracy. The figure shows 80% and 50% cell viability in 10 mM and 100 mM glutamate concentrations, respectively.</p> Full article ">Figure 3
<p>The effect of pre- and post-treatment with TRF and α-TCP against 100 mM glutamate on cell viability in astrocytes. Data represent the mean ± SEM of three independent experiments (<span class="html-italic">n</span> = 3 in each experiment). * <span class="html-italic">p</span> &lt; 0.05, TRF- and α-TCP-treated groups compared with the glutamate-treated group. This shows that TRF and α-TCP, at a low concentration (100 ng/mL) in pre-incubation, and at a high concentration (300 ng/mL) in post-incubation, exerted potential prophylactic effects against glutamate toxicity in the primary astrocyte.</p> Full article ">Figure 4
<p>The effect of pre- and post-treatment with TRF and α-TCP on glutamate-injured astrocytes with respect to mitochondrial membrane potentiality. Data represent the mean ± SEM of three independent experiments (<span class="html-italic">n</span> = 3 in each experiment). * <span class="html-italic">p</span> &lt; 0.05, TRF- and α-TCP-treated groups compared with the glutamate-treated group. This shows that TRF and α-TCP, at a low concentration (100 ng) in pre-incubation, and at a high concentration (300 ng) in post-incubation, demonstrated better prophylactic properties against the toxicity of glutamate in primary astrocytes.</p> Full article ">Figure 5
<p><span class="html-italic">Gria2</span> mRNA expression in primary astrocytes with TRF and α-TCP pre-treatment against glutamate insult. Fold change of <span class="html-italic">Gria2</span> normalized to <span class="html-italic">ACTB</span> mRNA expression. Data are the mean ± SEM of three independent experiments (<span class="html-italic">n</span> = 3 in each experiment). * <span class="html-italic">p</span> &lt; 0.05, TRF- and α-TCP-treated groups compared with the glutamate-treated group. Pre- and post-treatment with 100–300 ng/mL TRF and α-TCP significantly reduced the transcription levels of <span class="html-italic">Gria2</span> in comparison to the positive control (glutamate).</p> Full article ">Figure 6
<p><span class="html-italic">GRIK1</span> mRNA expression in primary astrocytes with TRF and α-TCP pre-treatment against glutamate insult. Fold change of <span class="html-italic">GRIK1</span> normalized to <span class="html-italic">ACTB</span> mRNA expression. Data are the mean ± SEM of three independent experiments (<span class="html-italic">n</span> = 3 in each experiment). * <span class="html-italic">p</span> &lt; 0.05, TRF- and α-TCP-treated groups compared with the glutamate-treated group. Pre- and post-treatment with 100–300 ng/mL TRF and α-TCP significantly reduced the transcription levels of <span class="html-italic">GRIK1</span> in comparison to the positive control (glutamate).</p> Full article ">Figure 7
<p><span class="html-italic">Grin2A</span> mRNA expression in primary astrocytes with TRF and α-TCP pre-treatment against glutamate insult. Fold change of <span class="html-italic">Grin2A</span> normalized to <span class="html-italic">ACTB</span> mRNA expression. Data are the mean ± SEM of three independent experiments (<span class="html-italic">n</span> = 3 in each experiment). * <span class="html-italic">p</span> &lt; 0.05, TRF- and α-TCP-treated groups compared with the glutamate-treated group. Pre- and post-treatment with 100–300 ng/mL TRF and α-TCP significantly reduced the transcription levels of <span class="html-italic">Grin2A</span> in comparison to the positive control (glutamate).</p> Full article ">Figure 8
<p>Pre- and post-treatment of TRF and α-TCP against glutamate-injured astrocytes in extracellular Ca<sup>2+</sup> ions. Data represent the mean ± SEM of three independent experiments (<span class="html-italic">n</span> = 3 in each experiment). * <span class="html-italic">p</span> &lt; 0.05, TRF- and α-TCP-treated groups compared with the glutamate-treated group. This shows that TRF and α-TCP, at a low concentration (100 ng) in pre-incubation, increased the levels of extracellular Ca<sup>2+</sup> ions, while a high concentration of TRF and α-TCP (300 ng) in post-incubation decreased the level of extracellular Ca<sup>2+</sup> ions against the toxicity of glutamate in primary astrocytes.</p> Full article ">
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Review
The Role of Anti-Thymocyte Globulin or Alemtuzumab-Based Serotherapy in the Prophylaxis and Management of Graft-Versus-Host Disease
by Robert Ali, Jeremy Ramdial, Sandra Algaze and Amer Beitinjaneh
Biomedicines 2017, 5(4), 67; https://doi.org/10.3390/biomedicines5040067 - 29 Nov 2017
Cited by 18 | Viewed by 5004
Abstract
Allogeneic hematopoietic stem cell transplant is an established treatment modality for hematologic and non-hematologic diseases. However, it is associated with acute and long-term sequelae which can translate into mortality. Graft-versus-host disease (GVHD) remains a glaring obstacle, especially with the advent of reduced-intensity conditioning. [...] Read more.
Allogeneic hematopoietic stem cell transplant is an established treatment modality for hematologic and non-hematologic diseases. However, it is associated with acute and long-term sequelae which can translate into mortality. Graft-versus-host disease (GVHD) remains a glaring obstacle, especially with the advent of reduced-intensity conditioning. Serotherapy capitalizes on antibodies which target T cells and other immune cells to mitigate this effect. This article focuses on the utility of two such agents: anti-thymocyte globulin (ATG) and alemtuzumab. ATG has demonstrated benefit in prophylaxis against GVHD, especially in the chronic presentation. However, there is limited impact of ATG on overall survival and it has little utility in the treatment context. There may be an initial improvement, particularly in skin manifestations, but no substantial benefit has been elicited. Alemtuzumab has shown benefit in both prophylaxis and treatment of GVHD, but at the consequence of a more profound immunosuppressive phase, mandating aggressive viral prophylaxis. There remains heterogeneity in the doses and regimens of the agents, with no standardized protocol in place. Furthermore, it seems that once steroid-refractory GVHD has been established, there is little that can be offered to offset the ultimately dismal outcome. Here we present a systematic overview of ATG- or alemtuzumab-based serotherapy in the prophylaxis and management of GVHD. Full article
(This article belongs to the Special Issue Cell Therapy for the Treatment of GVHD)
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Communication
Evaluation of Posaconazole Pharmacokinetics in Adult Patients with Invasive Fungal Infection
by Sarah Allegra, Giovanna Fatiguso, Silvia De Francia, Fabio Favata, Elisa Pirro, Chiara Carcieri, Amedeo De Nicolò, Jessica Cusato, Giovanni Di Perri and Antonio D’Avolio
Biomedicines 2017, 5(4), 66; https://doi.org/10.3390/biomedicines5040066 - 20 Nov 2017
Cited by 15 | Viewed by 5968
Abstract
Mortality and morbidity due to invasive fungal infections have increased over the years. Posaconazole is a second-generation triazole agent with an extended spectrum of activity, which shows a high interindividual variability in its plasma levels, rendering dosing in many patients inconsistent or inadequate. [...] Read more.
Mortality and morbidity due to invasive fungal infections have increased over the years. Posaconazole is a second-generation triazole agent with an extended spectrum of activity, which shows a high interindividual variability in its plasma levels, rendering dosing in many patients inconsistent or inadequate. Hence, posaconazole therapeutic drug monitoring, which is easily available in clinical practice, may improve treatment success and safety. The aim of the study was to describe posaconazole pharmacokinetics, and to evaluate the utility of therapeutic drug monitoring for therapy and prophylaxis in a cohort of adult patients. A fully validated chromatographic method was used to quantify posaconazole concentration in plasma collected from adult patients at the end of the dosing interval. Associations between variables were tested using the Pearson test. The Mann-Whitney test was used to probe the influence of categorical variables on continuous ones. A high inter-individual variability was shown. Of the 172 enrolled patients, among those receiving the drug by the oral route (N = 170), gender significantly influenced drug exposure: males showed greater posaconazole concentration than females (p = 0.028). This study highlights the importance of therapeutic drug monitoring in those with invasive fungal infections and its significant clinical implications; moreover we propose, for the first time, the possible influence of gender on posaconazole exposure. Full article
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<p>Plots of gender influence on posaconazole trough concentration, considering all the 172 enrolled patients (<span class="html-italic">p</span> = 0.028). Boxes and black lines in boxes represent respectively interquartile ranges (IQR) and median values; open dots and stars represent outlier values. Median values (horizontal line), interquartile range (IQR, bars), patient values (black square), highest and lowest value (whiskers) are shown. Males (<span class="html-italic">N</span> = 96) had 521.50 ng/mL (IQR: 256.00–240.25 ng/mL) median concentrations; Females (<span class="html-italic">N</span> = 76) had 376.50 ng/mL (IQR: 240.25–376.50 ng/mL) median concentrations.</p> Full article ">
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Review
Pancreatic Cancer: Molecular Characterization, Clonal Evolution and Cancer Stem Cells
by Elvira Pelosi, Germana Castelli and Ugo Testa
Biomedicines 2017, 5(4), 65; https://doi.org/10.3390/biomedicines5040065 - 18 Nov 2017
Cited by 80 | Viewed by 11719
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is the fourth most common cause of cancer-related death and is the most lethal of common malignancies with a five-year survival rate of <10%. PDAC arises from different types of non-invasive precursor lesions: intraductal papillary mucinous neoplasms, mucinous cystic [...] Read more.
Pancreatic Ductal Adenocarcinoma (PDAC) is the fourth most common cause of cancer-related death and is the most lethal of common malignancies with a five-year survival rate of <10%. PDAC arises from different types of non-invasive precursor lesions: intraductal papillary mucinous neoplasms, mucinous cystic neoplasms and pancreatic intraepithelial neoplasia. The genetic landscape of PDAC is characterized by the presence of four frequently-mutated genes: KRAS, CDKN2A, TP53 and SMAD4. The development of mouse models of PDAC has greatly contributed to the understanding of the molecular and cellular mechanisms through which driver genes contribute to pancreatic cancer development. Particularly, oncogenic KRAS-driven genetically-engineered mouse models that phenotypically and genetically recapitulate human pancreatic cancer have clarified the mechanisms through which various mutated genes act in neoplasia induction and progression and have led to identifying the possible cellular origin of these neoplasias. Patient-derived xenografts are increasingly used for preclinical studies and for the development of personalized medicine strategies. The studies of the purification and characterization of pancreatic cancer stem cells have suggested that a minority cell population is responsible for initiation and maintenance of pancreatic adenocarcinomas. The study of these cells could contribute to the identification and clinical development of more efficacious drug treatments. Full article
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Figure 1
<p>Mutational landscape of pancreatic ductal cancer. The genetic alterations are subdivided into various biochemical pathways, and their global frequency is reported. The most frequent and relevant drivers of pancreatic tumorigenesis are indicated in bold.</p> Full article ">Figure 2
<p>Various stages of pancreatic cancer evolution. The various stages of pancreatic cancer evolution are outlined, together with the main genetic alterations occurring at these stages.</p> Full article ">Figure 3
<p>Two different models of PDAC development: (<b>A</b>) progressive accumulation of mutational events at various stages of tumor development; (<b>B</b>) after an initial transformation event, a unique chromothripsis event determines the rapid acquisition of additional mutations and copy number alterations. There is evidence that about 40% of PDACs develop following the A model and in about 60% of cases following the B model.</p> Full article ">Figure 4
<p>Frequency of the main genetic abnormalities observed in ampullary carcinomas, subdivided into intestinal-type (IAP) and pancreatobiliary-type (PAC).</p> Full article ">Figure 5
<p>Frequency of the main genetic abnormalities observed in pancreatic neuroendocrine tumors (PanNET), subdivided into biochemical pathways. For each gene are reported the mutations (black bars) and copy number alterations (grey bars).</p> Full article ">
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Review
Site-Specific Antibody Conjugation for ADC and Beyond
by Qun Zhou
Biomedicines 2017, 5(4), 64; https://doi.org/10.3390/biomedicines5040064 - 9 Nov 2017
Cited by 83 | Viewed by 14569
Abstract
Antibody-drug conjugates (ADCs) have become a promising class of antitumor agents with four conjugates being approved by regulatory agencies for treating cancer patients. To improve the conventional conjugations that are currently applied to generate these heterogeneous products, various site-specific approaches have been developed. [...] Read more.
Antibody-drug conjugates (ADCs) have become a promising class of antitumor agents with four conjugates being approved by regulatory agencies for treating cancer patients. To improve the conventional conjugations that are currently applied to generate these heterogeneous products, various site-specific approaches have been developed. These methods couple cytotoxins or chemotherapeutic drugs to specifically defined sites in antibody molecules including cysteine, glutamine, unnatural amino acids, short peptide tags, and glycans. The ADCs produced showed high homogeneity, increased therapeutic index, and strong antitumor activities in vitro and in vivo. Moreover, there are recent trends in using these next generation technologies beyond the cytotoxin-conjugated ADC. These site-specific conjugations have been applied for the generation of many different immunoconjugates including bispecific Fab or small molecule–antibody conjugates, immunosuppressive antibodies, and antibody–antibiotic conjugates. Thus, it is likely that additional technologies and related site-specific conjugates will emerge in the near future, with various chemicals or small molecular weight proteins in addition to cytotoxin for better treatment of many challenging diseases. Full article
(This article belongs to the Special Issue Immunoconjugates)
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<p>Binding and internalization of antibody-drug conjugate (ADC) followed by the release of its cytotoxins inside the cell.</p> Full article ">Figure 2
<p>The categories of the site-specific ADC with cytotoxin coupled at unique and defined sites in an antibody molecule.</p> Full article ">Figure 3
<p>The application of the site-specific ADCs in coupling antibody with small protein, radioisotope, and non-cytotoxic compounds.</p> Full article ">
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Article
In Vitro and In Vivo Biological Activities of Cissus adnata (Roxb.)
by Mohammed Shoibe, Md. Nazim Uddin Chy, Morshed Alam, Md. Adnan, Md. Zobidul Islam, Shababa Wajida Nihar, Nishat Rahman and Ehsan Suez
Biomedicines 2017, 5(4), 63; https://doi.org/10.3390/biomedicines5040063 - 30 Oct 2017
Cited by 19 | Viewed by 6866
Abstract
This study was conducted to evaluate the in vitro polyphenol content, antioxidant, cytotoxic, antibacterial, anthelmintic properties, and in vivo antinociceptive activity of the ethanol extract of Cissus adnata leaves (EECA) in different experimental models. Polyphenol contents were investigated using spectrophotometric techniques. Antioxidant activity [...] Read more.
This study was conducted to evaluate the in vitro polyphenol content, antioxidant, cytotoxic, antibacterial, anthelmintic properties, and in vivo antinociceptive activity of the ethanol extract of Cissus adnata leaves (EECA) in different experimental models. Polyphenol contents were investigated using spectrophotometric techniques. Antioxidant activity was determined by 1,1-diphenyl-2-picrylhydrazyl radical (DPPH) radical-scavenging, ferric reducing power, and total antioxidant capacity assays. Cytotoxicity was determined by brine shrimp lethality bioassay and disc diffusion method was used for the antibacterial activity. Anthelmintic activity was studied using aquarium worm (Tubifex tubifex) whereas antinociceptive activity was evaluated in mice by acetic acid and formalin test. Phytochemical screening of EECA revealed the presence of alkaloids, carbohydrates, flavonoids, phenols, terpenoids, saponins, and tannins. EECA showed strong antioxidant activity with high polyphenol contents. It was observed that EECA possessed significant antibacterial activity with a low toxicity profile. EECA also demonstrated dose-dependent and statistically significant anthelmintic and antinociceptive activities. Our study shows that ethanol extract of C. adnata leaves possess strong antioxidant, antibacterial, anthelmintic and antinociceptive activities with lower toxicity. Further studies are needed to identify bioactive phytomolecules and to understand the mechanism of such actions better. Full article
(This article belongs to the Special Issue Plant Derived Biomedicines)
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<p>1,1-diphenyl-2-picrylhydrazyl radical (DPPH) free radical scavenging activity of ethanol extract of <span class="html-italic">C. adnata</span> leaf (EECA) compared with the standard as assessed by spectrophotometric method using DPPH free radicals. (<b>A</b>) Percentage (%) of DPPH radical scavenging by different concentrations of the EECA and reference standard Ascorbic acid. Results are represented as mean ± SD (<span class="html-italic">n</span> = 3); (<b>B</b>) IC<sub>50</sub> for DPPH radical scavenging activity of the EECA and Ascorbic acid.</p> Full article ">Figure 2
<p>Reducing power capacity of EECA compared with the reference standard ascorbic acid.</p> Full article ">Figure 3
<p>Determination of LC<sub>50</sub> value of ethanol extract of the <span class="html-italic">Cissus adnata</span> leaf from linear correlation between concentrations versus percentage of mortality.</p> Full article ">Figure 4
<p>Antinociceptive effect of ethanol extract of <span class="html-italic">Cissus adnata</span> (EECA) in acetic acid-induced abdominal writhing test in mice. Each value is presented as mean ± SEM (<span class="html-italic">n</span> = 6). *** <span class="html-italic">p</span> ˂ 0.001 compared with the control group (Dunnett’s Test).</p> Full article ">Figure 5
<p>Antinociceptive effect of ethanol extract of <span class="html-italic">Cissus adnata</span> (EECA) in formalin-induced licking test in mice. Each value is presented as mean ± SEM (<span class="html-italic">n</span> = 6). *** <span class="html-italic">p</span> ˂ 0.001 compared with the control group (Dunnett’s Test).</p> Full article ">
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Review
Muscle–Bone Crosstalk: Emerging Opportunities for Novel Therapeutic Approaches to Treat Musculoskeletal Pathologies
by Delphine B. Maurel, Katharina Jähn and Nuria Lara-Castillo
Biomedicines 2017, 5(4), 62; https://doi.org/10.3390/biomedicines5040062 - 24 Oct 2017
Cited by 78 | Viewed by 8130
Abstract
Osteoporosis and sarcopenia are age-related musculoskeletal pathologies that often develop in parallel. Osteoporosis is characterized by a reduced bone mass and an increased fracture risk. Sarcopenia describes muscle wasting with an increasing risk of injuries due to falls. The medical treatment of both [...] Read more.
Osteoporosis and sarcopenia are age-related musculoskeletal pathologies that often develop in parallel. Osteoporosis is characterized by a reduced bone mass and an increased fracture risk. Sarcopenia describes muscle wasting with an increasing risk of injuries due to falls. The medical treatment of both diseases costs billions in health care per year. With the impact on public health and economy, and considering the increasing life expectancy of populations, more efficient treatment regimens are sought. The biomechanical interaction between both tissues with muscle acting on bone is well established. Recently, both tissues were also determined as secretory endocrine organs affecting the function of one another. New exciting discoveries on this front are made each year, with novel signaling molecules being discovered and potential controversies being described. While this review does not claim completeness, it will summarize the current knowledge on both the biomechanical and the biochemical link between muscle and bone. The review will highlight the known secreted molecules by both tissues affecting the other and finish with an outlook on novel therapeutics that could emerge from these discoveries. Full article
(This article belongs to the Special Issue Bone Cells and Related Interactions)
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<p>Using the search term “musculoskeletal interaction”, this graph demonstrated the increase in published papers in recent years with regard to the topic. The search has been made using PubMed, in September 2017.</p> Full article ">Figure 2
<p>Role of vessels in the muscle–bone crosstalk: (<b>A</b>) Presence of vessels coming from the skeletal muscle in bone (white arrowheads). The vessels are stained in green, in transgenic mice model Flk1-GFP, where the green fluorescent protein is driven by a promoter targeting a receptor of VEGF-A [<a href="#B50-biomedicines-05-00062" class="html-bibr">50</a>]. Magnification: 10×; (<b>B</b>) physical connection between osteocytes in the femur (stained in red by a Dextran-lysine fixable stain) and a vessel, in green (Flk1-GFP mice) (white arrowhead). Magnification: 63×. Scale bars represent: 100 μm (<b>A</b>); and 25 μm (<b>B</b>).</p> Full article ">
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Review
The Role of B Cell Targeting in Chronic Graft-Versus-Host Disease
by Ruben Rhoades and Sameh Gaballa
Biomedicines 2017, 5(4), 61; https://doi.org/10.3390/biomedicines5040061 - 17 Oct 2017
Cited by 8 | Viewed by 4549
Abstract
Chronic graft-versus-host disease (cGVHD) is a leading cause of late morbidity and mortality following allogeneic stem cell transplantation. Current therapies, including corticosteroids and calcineurin inhibitors, are only effective in roughly 50% of cases; therefore, new treatment strategies are under investigation. What was previously [...] Read more.
Chronic graft-versus-host disease (cGVHD) is a leading cause of late morbidity and mortality following allogeneic stem cell transplantation. Current therapies, including corticosteroids and calcineurin inhibitors, are only effective in roughly 50% of cases; therefore, new treatment strategies are under investigation. What was previously felt to be a T cell disease has more recently been shown to involve activation of both T and B cells, as well as a number of cytokines. With a better understanding of its pathophysiology have come more expansive preclinical and clinical trials, many focused on B cell signaling. This report briefly reviews our current understanding of cGVHD pathophysiology and reviews clinical and preclinical trials with B cell-targeted agents. Full article
(This article belongs to the Special Issue Cell Therapy for the Treatment of GVHD)
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Review
A Critical Appraisal of Extracorporeal Photopheresis as a Treatment Modality for Acute and Chronic Graft-Versus-Host Disease
by Hind Rafei, Mohamed A. Kharfan-Dabaja and Taiga Nishihori
Biomedicines 2017, 5(4), 60; https://doi.org/10.3390/biomedicines5040060 - 11 Oct 2017
Cited by 11 | Viewed by 5352
Abstract
Although significant advances have been made in the biologic understanding of graft-versus-host disease (GVHD) and its treatment options, GVHD remains the single most challenging obstacle to the success of allogeneic hematopoietic cell transplantation (HCT) due to high risk of disabling morbidity and mortality. [...] Read more.
Although significant advances have been made in the biologic understanding of graft-versus-host disease (GVHD) and its treatment options, GVHD remains the single most challenging obstacle to the success of allogeneic hematopoietic cell transplantation (HCT) due to high risk of disabling morbidity and mortality. Extracorporeal photopheresis (ECP) has promising effects in controlling steroid-refractory GVHD, both acute and chronic, and it has been studied extensively. Its putative immunomodulatory mechanisms, while not immunosuppressive, position ECP as an attractive treatment strategy for GVHD patients who are already receiving global immunosuppression. However, ECP is relatively underutilized due in part to limited access and time commitment. Here, we review the recent findings on the ECP efficacy in both acute and chronic GVHD, primarily for steroid-refractory status, and we critically appraise its benefits. We also explore salient considerations on the optimal use of ECP in the treatment of refractory GVHD. Full article
(This article belongs to the Special Issue Cell Therapy for the Treatment of GVHD)
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Review
Restoration of DAP Kinase Tumor Suppressor Function: A Therapeutic Strategy to Selectively Induce Apoptosis in Cancer Cells Using Immunokinase Fusion Proteins
by Mehmet Kemal Tur, Adebukola K. Daramola, Stefan Gattenlöhner, Marco Herling, Shivan Chetty and Stefan Barth
Biomedicines 2017, 5(4), 59; https://doi.org/10.3390/biomedicines5040059 - 4 Oct 2017
Cited by 12 | Viewed by 5775
Abstract
Targeted cancer immunotherapy is designed to selectively eliminate tumor cells without harming the surrounding healthy tissues. The death-associated protein kinases (DAPk) are a family of proapoptotic proteins that play a vital role in the regulation of cellular process and have been identified as [...] Read more.
Targeted cancer immunotherapy is designed to selectively eliminate tumor cells without harming the surrounding healthy tissues. The death-associated protein kinases (DAPk) are a family of proapoptotic proteins that play a vital role in the regulation of cellular process and have been identified as positive mediators of apoptosis via extrinsic and intrinsic death-regulating signaling pathways. Tumor suppressor activities have been shown for DAPk1 and DAPk2 and they are downregulated in e.g., Hodgkin’s (HL) and B cell lymphoma (CLL), respectively. Here, we review a targeted therapeutic approach which involves reconstitution of DAPks by the generation of immunokinase fusion proteins. These recombinant proteins consist of a disease-specific ligand fused to a modified version of DAPk1 or DAPk2. HL was targeted via CD30 and B-CLL via CD22 cell surface antigens. Full article
(This article belongs to the Special Issue Immuno-Active Cancer Therapeutics)
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Figure 1
<p>Schematic representation of the multi-domain organization of death associated protein kinase DAPk1 (death-associated protein kinases 1), and ZIPk. The catalytic domain, a death domain, and ankyrin repeats, which may mediate its interaction with other proteins. The cytoskeleton-binding region is responsible for DAPk1 intracellular localization to actin microfilaments. DAPk1 and DAPk2 are activated by a rise in cytosolic calcium concentrations resulting from cellular stresses, through binding of calcium-activated calmodulin [<a href="#B33-biomedicines-05-00059" class="html-bibr">33</a>]. NLS = nuclear localization signal.</p> Full article ">Figure 2
<p>Activation of different DAPk signaling cascade by different stimuli. Based on the signal input and cell context, the DAPk family of genes play a crucial role is deciding the outcome of whether a cell survives or undergoes apoptosis. Activated DAPk proteins may initiate p53-dependent or independent apoptosis or mediate an autophagic programmed cell death [<a href="#B39-biomedicines-05-00059" class="html-bibr">39</a>].</p> Full article ">Figure 3
<p>Percentages of DAPk gene methylation in different tumors. Minimal and maximal percentage of DAPk methylation is represented in dark blue and light blue, respectively, as identified by different studies [<a href="#B64-biomedicines-05-00059" class="html-bibr">64</a>,<a href="#B65-biomedicines-05-00059" class="html-bibr">65</a>,<a href="#B66-biomedicines-05-00059" class="html-bibr">66</a>,<a href="#B67-biomedicines-05-00059" class="html-bibr">67</a>,<a href="#B68-biomedicines-05-00059" class="html-bibr">68</a>,<a href="#B69-biomedicines-05-00059" class="html-bibr">69</a>,<a href="#B70-biomedicines-05-00059" class="html-bibr">70</a>,<a href="#B71-biomedicines-05-00059" class="html-bibr">71</a>,<a href="#B72-biomedicines-05-00059" class="html-bibr">72</a>,<a href="#B73-biomedicines-05-00059" class="html-bibr">73</a>,<a href="#B74-biomedicines-05-00059" class="html-bibr">74</a>]. RCC: renal cell cancer, CXCA: cervical cancer.</p> Full article ">Figure 4
<p>Schematic representation of an expression cassette for a recombinant immunokinase fusion protein. Under the expression of a strong CMV promoter, the N-terminal Igkappa leader sequence allows direction of expressed protein into the media of the expressing cell line. A C-terminal His<sub>6</sub> tag sequence allows for affinity purification of the recombinant protein via an IMAC purification system.</p> Full article ">
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Review
Innovative Disease Model: Zebrafish as an In Vivo Platform for Intestinal Disorder and Tumors
by Jeng-Wei Lu, Yi-Jung Ho, Shih-Ci Ciou and Zhiyuan Gong
Biomedicines 2017, 5(4), 58; https://doi.org/10.3390/biomedicines5040058 - 29 Sep 2017
Cited by 21 | Viewed by 8709
Abstract
Colorectal cancer (CRC) is one of the world’s most common cancers and is the second leading cause of cancer deaths, causing more than 50,000 estimated deaths each year. Several risk factors are highly associated with CRC, including being overweight, eating a diet high [...] Read more.
Colorectal cancer (CRC) is one of the world’s most common cancers and is the second leading cause of cancer deaths, causing more than 50,000 estimated deaths each year. Several risk factors are highly associated with CRC, including being overweight, eating a diet high in red meat and over-processed meat, having a history of inflammatory bowel disease, and smoking. Previous zebrafish studies have demonstrated that multiple oncogenes and tumor suppressor genes can be regulated through genetic or epigenetic alterations. Zebrafish research has also revealed that the activation of carcinogenesis-associated signal pathways plays an important role in CRC. The biology of cancer, intestinal disorders caused by carcinogens, and the morphological patterns of tumors have been found to be highly similar between zebrafish and humans. Therefore, the zebrafish has become an important animal model for translational medical research. Several zebrafish models have been developed to elucidate the characteristics of gastrointestinal diseases. This review article focuses on zebrafish models that have been used to study human intestinal disorders and tumors, including models involving mutant and transgenic fish. We also report on xenograft models and chemically-induced enterocolitis. This review demonstrates that excellent zebrafish models can provide novel insights into the pathogenesis of gastrointestinal diseases and help facilitate the evaluation of novel anti-tumor drugs. Full article
(This article belongs to the Special Issue Cancer Biomarkers and Targets in Digestive Organs)
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<p>Schematic diagram of zebrafish xenograft model. Colorectal cancer (CRC) tumor cells were labeled with 1,1′-dioctadecyl-3,3,3′3′-tetramethylindocarbocyanine (DiI) dye in vitro, and approximately 300 tumor cells are injected into the yolk sac of each two days post-fertilization zebrafish larvae. Tumor invasion, dissemination, metastasis, and angiogenesis can be visualized, and anti-cancer drug screening can be conducted in vivo in a matter of days.</p> Full article ">Figure 2
<p>Roles of zebrafish intestinal disorder and tumor models in present and future research. Zebrafish is an ideal genetic and disease model system which is accessible for rapid screening and experimental manipulation for preclinical studies. In the future, zebrafish models could be used for patient selection in clinical trials.</p> Full article ">
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