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Showing 100 Latest Publications
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Advances in understanding the mechanisms of erythropoiesis in homeostasis and disease.Thursday, July 21, 2016
Liang R, Ghaffari S,
British journal of haematology. 21-Jul-2016
Anaemia or decreased blood haemoglobin is the most common blood disorder often characterized by reduced red blood cell (RBC) numbers. RBCs are produced from differentiation and commitment of haematopoietic stem cells to the erythroid lineage by a process called erythropoiesis. Coordination of erythropoietin receptor signalling with several erythroid transcription factors including GATA1 is essential for this process. A number of additional players that are critical for RBC production have been identified in recent years. Major technological advances, such as the development of RNA interference, genetically modified animals, including zebrafish, and imaging flow cytometry have led to these discoveries; the emergence of -omics approaches in combination with the optimization of ex vivo erythroid cultures have also produced a more comprehensive understanding of erythropoiesis. Here we summarize studies describing novel regulators of erythropoiesis that modulate erythroid cell production in the context of human erythroid disorders involving hypoxia, iron regulation, immune-related molecules, and the transcription factor FOXO3.
Ex Vivo Assessment of a Parabolic-Tip Inflow Cannula for Pediatric Continuous-Flow VADs.Thursday, July 21, 2016
Griffin MT, Grzywinksi MF, Voorhees HJ, Kameneva MV, Olia SE,
ASAIO journal (American Society for Artificial Internal Organs : 1992). 20-Jul-2016
To address the challenge of unloading the left ventricle during pediatric mechanical circulatory support using next-generation rotary blood pumps, a novel inflow cannula was developed. This unique inflow cannula for pediatric, continuous-flow, left ventricular assist devices (VADs) with a parabolic-shaped inlet entrance was evaluated alongside a bevel-tip and fenestrated-tip cannula via an ex vivo, isolated-heart experimental setup. Performance was characterized using two clinical scenarios of over-pumping and hypovolemia, created by varying pump speed and filling preload pressure respectively, at ideal and off-axis cannula placement to assess ventricular unloading and positional sensitivity. Quantitative and qualitative assessments were performed through the resulting measured hemodynamics and intra-ventricular boroscopic visualization to classify conditions of non-suction, partial, gradual or severe entrainment, and ventricular collapse. The parabolic-tip cannula was found to be significantly less sensitive to placement position (p-values < 0.001) than the bevel-tip cannula under all conditions, while not statistically different from the fenestrated cannula. Visual analysis of the parabolic-tip cannula showed complete resistance to entrainment whereas the fenestrated-tip had partial entrainment in 90% and 87% of the over-pumping and hypovolemic studies, respectively. We conclude that future pediatric VAD designs may benefit from incorporating the parabolic-tip inflow cannula design in order to maximize unloading of the left ventricle in ideal and non-optimal conditions.
Peripheral blood stem cells collection on spectra optia apheresis system using the continuous mononuclear cell collection protocol: A single center report of 39 procedures.Thursday, July 21, 2016
Sanderson F, Poullin P, Smith R, Nicolino-Brunet C, Philip P, Chaib A, Costello R,
Journal of clinical apheresis. 21-Jul-2016
Spectra Optia CMNC protocol successfully collected CD34+ cells with yields permitting the harvest of sufficient enriched grafts for autologous transplantation. The CD34+ cell yield prediction was excellent. PBSC collection with CMNC protocol had advantages of high processing rate, low product volume, and acceptable contamination by platelets.
Targeting the transforming growth factor-β signaling during pre-implantation development in embryos of cattle, sheep and goats.Thursday, July 21, 2016
Hajian M, Hosseini SM, Ostadhosseini S, Nasr-Esfahani MH,
Growth factors (Chur, Switzerland). 21-Jul-2016
Recently, application of chemical inhibitors against differentiation signaling pathways has improved establishment of mESCs. In this study, we applied inhibitors of TGF-β (SB431542) and BMP4 (Noggin) from cleavage to blastocyst stage in cattle, goat and sheep embryos. SB significantly decreases blastocyst rate and total cell number (TCN) in sheep blastocysts, whereas only TCN was significantly decreased in cattle blastocysts. In contrast to SB, Noggin significantly improved cattle blastocyst development but decreased TCN. However, Noggin treatment led to a significant increase in TCN in sheep blastocysts. Regarding pluripotency triad (OCT4, NANOG, SOX2) and cell lineage commitment (REX1, CDX2, GATA4), SB led to a significant reduction in SOX2 expression in goat and cattle, while Noggin increased at least one or two of pluripotent markers in these species. Taken together, this data suggests that inhibition of TGF-β by Noggin may be more favorable for derivation of stem cells in farm animals.
KCNN2 polymorphisms and cardiac tachyarrhythmias.Friday, July 22, 2016
Yu CC, Chia-Ti T, Chen PL, Wu CK, Chiu FC, Chiang FT, Chen PS, Chen CL, Lin LY, Juang JM, Ho LT, Lai LP, Yang WS, Lin JL,
Medicine. Jul-2016
Potassium calcium-activated channel subfamily N member 2 (KCNN2) encodes an integral membrane protein that forms small-conductance calcium-activated potassium (SK) channels. Recent studies in animal models show that SK channels are important in atrial and ventricular repolarization and arrhythmogenesis. However, the importance of SK channels in human arrhythmia remains unclear. The purpose of the present study was to test the association between genetic polymorphism of the SK2 channel and the occurrence of cardiac tachyarrhythmias in humans. We enrolled 327 Han Chinese, including 72 with clinically significant ventricular tachyarrhythmias (VTa) who had a history of aborted sudden cardiac death (SCD) or unexplained syncope, 98 with a history of atrial fibrillation (AF), and 144 normal controls. We genotyped 12 representative tag single nucleotide polymorphisms (SNPs) across a 141-kb genetic region containing the KCNN2 gene; these captured the full haplotype information. The rs13184658 and rs10076582 variants of KCNN2 were associated with VTa in both the additive and dominant models (odds ratio [OR] 2.89, 95% confidence interval [CI] = 1.505-5.545, P = 0.001; and OR 2.55, 95% CI = 1.428-4.566, P = 0.002, respectively). After adjustment for potential risk factors, the association remained significant. The population attributable risks of these 2 variants of VTa were 17.3% and 10.6%, respectively. One variant (rs13184658) showed weak but significant association with AF in a dominant model (OR 1.91, CI = 1.025-3.570], P = 0.042). There was a significant association between the KCNN2 variants and clinically significant VTa. These findings suggest an association between KCNN2 and VTa; it also appears that KCNN2 variants may be adjunctive markers for risk stratification in patients susceptible to SCD.
Single-cell RNA-sequencing: The future of genome biology is now.Thursday, July 21, 2016
Picelli S,
RNA biology. 21-Jul-2016
Genome-wide single-cell analysis represents the ultimate frontier of genomics research. In particular, single-cell RNA-sequencing (scRNA-seq) studies have been boosted in the last few years by an explosion of new technologies enabling the study of the transcriptomic landscape of thousands of single cells in complex multicellular organisms. More sensitive and automated methods are being continuously developed and promise to deliver better data quality and higher throughput with less hands-on time. The outstanding amount of knowledge that is going to be gained from present and future studies will have a profound impact in many aspects of our society, from the introduction of truly tailored cancer treatments, to a better understanding of antibiotic resistance and host-pathogen interactions; from the discovery of the mechanisms regulating stem cell differentiation to the characterization of the early event of human embryogenesis.
Primary Simple Limbal Epithelial Transplantation Along With Excisional Biopsy in the Management of Extensive Ocular Surface Squamous Neoplasia.Thursday, July 21, 2016
Mittal V, Narang P, Menon V, Mittal R, Honavar S,
Cornea. 20-Jul-2016
Restoration of limbal stem cells using SLET technique in an extensive OSSN in the primary setting may be pertinent to a good outcome.
Mechanism for the Cellular Uptake of Targeted Gold Nanorods of Defined Aspect Ratios.Thursday, July 21, 2016
Yang H, Chen Z, Zhang L, Yung WY, Leung KC, Chan HY, Choi CH,
Small (Weinheim an der Bergstrasse, Germany). 21-Jul-2016
Biomedical applications of non-spherical nanoparticles such as photothermal therapy and molecular imaging require their efficient intracellular delivery, yet reported details on their interactions with the cell remain inconsistent. Here, the effects of nanoparticle geometry and receptor targeting on the cellular uptake and intracellular trafficking are systematically explored by using C166 (mouse endothelial) cells and gold nanoparticles of four different aspect ratios (ARs) from 1 to 7. When coated with poly(ethylene glycol) strands, the cellular uptake of untargeted nanoparticles monotonically decreases with AR. Next, gold nanoparticles are functionalized with DNA oligonucleotides to target Class A scavenger receptors expressed by C166 cells. Intriguingly, cellular uptake is maximized at a particular AR: shorter nanorods (AR = 2) enter C166 cells more than nanospheres (AR = 1) and longer nanorods (AR = 4 or 7). Strikingly, long targeted nanorods align to the cell membrane in a near-parallel manner followed by rotating by ≈90° to enter the cell via a caveolae-mediated pathway. Upon cellular entry, targeted nanorods of all ARs predominantly traffic to the late endosome without progressing to the lysosome. The studies yield important materials design rules for drug delivery carriers based on targeted, anisotropic nanoparticles.
In-situ second harmonic generation by cancer cell targeting ZnO nanocrystals to effect photodynamic action in subcellular space.Thursday, July 21, 2016
Gu B, Pliss A, Kuzmin AN, Baev A, Ohulchanskyy TY, Damasco JA, Yong KT, Wen S, Prasad PN,
Biomaterials. 12-Jul-2016
This paper introduces the concept of in-situ upconversion of deep penetrating near infrared light via second harmonic generation from ZnO nanocrystals delivered into cells to effect photo activated therapies, such as photodynamic therapy, which usually require activation by visible light with limited penetration through biological tissues. We demonstrated this concept by subcellular activation of a photodynamic therapy drug, Chlorin e6, excited within its strong absorption Soret band by the second harmonic (SH) light, generated at 409 nm by ZnO nanocrystals, which were targeted to cancer cells and internalized through the folate-receptor mediated endocytosis. By a combination of theoretical modeling and experimental measurements, we show that SH light, generated in-situ by ZnO nanocrystals significantly contributes to activation of photosensitizer, leading to cell death through both apoptotic and necrotic pathways initiated in the cytoplasm. This targeted photodynamic action was studied using label-free Coherent Anti-Stokes Raman Scattering imaging of the treated cells to monitor changes in the distribution of native cellular proteins and lipids. We found that initiation of photodynamic therapy with upconverted light led to global reduction in the intracellular concentration of macromolecules, likely due to suppression of proteins and lipids synthesis, which could be considered as a real-time indicator of cellular damage from photodynamic treatment. In prospective applications this in-situ photon upconversion could be further extended using ZnO nanocrystals surface functionalized with a specific organelle targeting group, provided a powerful approach to identify and consequently maximize a cellular response to phototherapy, selectively initiated in a specific cellular organelle.
Radially Aligned Electrospun Fibers with Continuous Gradient of SDF1α for the Guidance of Neural Stem Cells.Thursday, July 21, 2016
Li X, Li M, Sun J, Zhuang Y, Shi J, Guan D, Chen Y, Dai J,
Small (Weinheim an der Bergstrasse, Germany). 21-Jul-2016
Repair of spinal cord injury will require enhanced recruitment of endogenous neural stem cells (NSCs) from the central canal region to the lesion site to reestablish neural connectivity. The strategy toward this goal is to provide directional cues, e.g., alignment topography and biological gradients from the rostral and caudal ends toward the center. This study demonstrates a facile method for fabrication of continuous gradients of stromal-cell-derived factor-1α (SDF1α) embedded in the radially aligned electrospun collagen/poly (ε-caprolactone) mats. Gradients can be readily produced in a controllable and reproducible fashion by adjusting the collection time and collector size during electrospinning. To get a long-term gradient, the SDF1α is fused with a unique peptide of collagen-binding domain (CBD), which can bind to collagen specifically. Aligned CBD-SDF1α gradients show stable, sustained, and gradual release during 7 d. Further, the effect of aligned CBD-SDF1α gradients on the guidance of NSCs is investigated. It is found that the CBD-SDF1α gradient scaffolds direct and enhance NSC migration from the periphery to the center along the aligned electrospun fibers. Taken together, the tubular conduits based on radially aligned electrospun fibers with continuous SDF1α gradient show great potential for guiding nerve regeneration.
Phospholipid-chitosan hybrid nanoliposomes promoting cell entry for drug delivery against cervical cancer.Thursday, July 21, 2016
Saesoo S, Bunthot S, Sajomsang W, Gonil P, Phunpee S, Songkhum P, Laohhasurayotin K, Wutikhun T, Yata T, Ruktanonchai UR, Saengkrit N,
Journal of colloid and interface science. 30-Jun-2016
This study emphasizes the development of a novel surface modified liposome as an anticancer drug nanocarrier. Quaternized N,O-oleoyl chitosan (QCS) was synthesized and incorporated into liposome vesicles, generating QCS-liposomes (Lip-QCS). The Lip-QCS liposomes were spherical in shape (average size diameter 171.5±0.8nm), with a narrow size distribution (PDI 0.1±0.0) and zeta potential of 11.7±0.7mV. In vitro mucoadhesive tests indicated that Lip-QCS possesses a mucoadhesive property. Moreover, the presence of QCS was able to induce the cationic charge on the surface of liposome. Cellular internalization of Lip-QCS was monitored over time, with the results revealing that the cell entry level of Lip-QCS was elevated at 24h. Following this, Lip-QCS were then employed to load cisplatin, a common platinum-containing anti-cancer drug, with a loading efficiency of 27.45±0.78% being obtained. The therapeutic potency of the loaded Lip-QCS was investigated using a 3D spheroid cervical cancer model (SiHa) which highlighted their cytotoxicity and apoptosis effect, and suitability as a controllable system for sustained drug release. This approach has the potential to assist in development of an effective drug delivery system against cervical cancer.
Low Oxygen Tension Enhances Expression of Myogenic Genes When Human Myoblasts Are Activated from G0 Arrest.Friday, July 22, 2016
Sellathurai J, Nielsen J, Hejbøl EK, Jørgensen LH, Dhawan J, Nielsen MF, Schrøder HD,
PloS one. 2016
We found an increase in proliferation rate of myoblasts when activated at a low oxygen tension (1% O2) compared to 21% O2. In addition, the gene expression studies showed up regulation of the myogenesis related genes PAX3, PAX7, MYOD, MYOG (myogenin), MET, NCAM, DES (desmin), MEF2A, MEF2C and CDH15 (M-cadherin), however, the fraction of DES and MYOD positive cells was not increased by low oxygen tension, indicating that 1% O2 may not have a functional effect on the myogenic response. Furthermore, the expression of genes involved in the TGFβ, Notch and Wnt signaling pathways were also up regulated in low oxygen tension. The differences in gene expression were most pronounced at day one after activation from G0-arrest, thus the initial activation of myoblasts seemed most sensitive to changes in oxygen tension. Protein expression of HES1 and β-catenin indicated that notch signaling may be induced in 21% O2, while the canonical Wnt signaling may be induced in 1% O2 during activation and proliferation of myoblasts.
10. Low-Intensity Pulsed Ultrasound (LIPUS) Stimulation Helps to Maintain the Differentiation Potency of Mesenchymal Stem Cells by Induction in Nanog Protein Transcript Levels and Phosphorylation.Friday, July 22, 2016
Kusuyama J, Hwan Seong C, Ohnishi T, Bandow K, Matsuguchi T,
Journal of orthopaedic trauma. Aug-2016
Mesenchymal Stem Cells (MSCs) are pluripotent cells that can be differentiated as osteoblasts, adipocytes, myocytes or chondrocytes depending on the culture condition. However, MSCs are known to lose their differentiation potency after long-term culture. Development of a new cell culture method to maintain their stemness is required for successful application of MSCs. Here, we revealed that low-intensity pulsed ultrasound (LIPUS) stimulation was useful for maintaining the MSC stemness as LIPUS inhibited the loss of osteogenic differentiation potency of osteo-progenitor cells induced by serial subculture. LIPUS also increased the transcriptional and phosphorylation level of Nanog, a crucial stem cell marker gene in a MSC cell line. We also found that LIPUS induced the secretion of extracellular adenosine triphosphate (ATP) in MSC. The treatments of the conditioned medium from LIPUS-stimulated MSC and exogenous ATP promoted Nanog expression. Thus, LIPUS may maintain the long-term differentiation potency of MSCs and osteo-progenitor cells by induction in Nanog transcript level and phosphorylation.
5. Accelerated Fracture Healing Targeting Periosteal Cells: Possibility of Combined Therapy of Low-Intensity Pulsed Ultrasound (LIPUS), Bone Graft, and Growth Factor (bFGF).Friday, July 22, 2016
Uchida K, Urabe K, Naruse K, Mikuni-Takagaki Y, Inoue G, Takaso M,
Journal of orthopaedic trauma. Aug-2016
We have studied the mechanism of fracture healing, and the effect of LIPUS, bone graft and growth factor on accelerating fracture healing. We present here the results of our research. To examine callus formation cells in fracture healing, we made marrow GFP chimera mice and a fracture model of marrow mesenchymal stem cell GFP chimera mice. It was demonstrated that periosteal cells were essential for callus formation. We focused on periosteal cells and examined the effect of LIPUS. In an in vitro experiment using a cultured part of the femur, LIPUS promoted ossification of the periosteal tissue. Further, LIPUS accelerated VEGF expression in the experiment using the femoral fracture model of mice. From these results, it was suggested that activation of periosteal cells might play a role in the fracture healing mechanism of LIPUS. Next, we discussed the possibility of combined therapy of LIPUS, bone graft and growth factor. Therapy involving the topical administration of bFGF using a controlled release system and bone graft could promote callus formation. In addition, LIPUS was able to promote membranaceous ossification after the bone graft. It was suggested that combined therapy of LIPUS, bone graft and bFGF could be a new option for treating fractures.
2. The Effect of Combined Therapy, Percutaneous Autologous Concentrated Bone Marrow Grafting and Low-Intensity Pulsed Ultrasound (LIPUS), on the Treatment of Non-Unions.Friday, July 22, 2016
Mishima H, Sugaya H, Yoshioka T, Wada H, Aoto K, Hyodo K, Tomaru Y, Kumagai H, Akaogi H, Ochiai N, Yamazaki M,
Journal of orthopaedic trauma. Aug-2016
We discuss the effect of combined therapy of percutaneous autologous concentrated bone graft and LIPUS on complex non-union treatment. Seventeen of 27 treated patients who had received the therapy at least 1 year before were discussed (10 femurs, 5 tibiae, 1 humerus, and 1 ulna). The average age of the patients was 40.7, and atrophic degeneration was observed in all cases. After 12 months of treatment, bone union was recognized in 76% in all cases, and in 87% of lower long bones. It was reported that LIPUS was effective at improving blood flow, accelerating cytokines which induce angiogenesis, promoting the transport of nutrition and enzymes to living cells, developing the differentiation of osteoblast from mesenchymal stem cells (MSC), inhibiting the differentiation and development of osteoclast, and promoting endochondral ossification. In this study, all patients had been treated with LIPUS for more than 3 months before the grafting was conducted, but the bone union seemed to stop. It was thought that this combined therapy provided a bone marrow cell growth factor sufficient to enable new bone formation to re-start bone union, and then LIPUS worked effectively to promote the initial differentiation, contributing to new bone formation. This combination therapy-less invasive, safe, and low cost-was considered one useful treatment option for non-union.
Feasibility of Human Amniotic Fluid Derived Stem Cells in Alleviation of Neuropathic Pain in Chronic Constrictive Injury Nerve Model.Friday, July 22, 2016
Chiang CY, Liu SA, Sheu ML, Chen FC, Chen CJ, Su HL, Pan HC,
PloS one. 2016
Human AFMSCs administration could alleviate the neuropathic pain demonstrated in histomorphological alteration and neurobehavior possibly through the modulation of the inflammatory response.
Accumulation of Extracellular Matrix in Advanced Lesions of Canine Distemper Demyelinating Encephalitis.Friday, July 22, 2016
Seehusen F, Al-Azreg SA, Raddatz BB, Haist V, Puff C, Spitzbarth I, Ulrich R, Baumgärtner W,
PloS one. 2016
In demyelinating diseases, changes in the quality and quantity of the extracellular matrix (ECM) may contribute to demyelination and failure of myelin repair and axonal sprouting, especially in chronic lesions. To characterize changes in the ECM in canine distemper demyelinating leukoencephalitis (DL), histochemical and immunohistochemical investigations of formalin-fixed paraffin-embedded cerebella using azan, picrosirius red and Gomori`s silver stain as well as antibodies directed against aggrecan, type I and IV collagen, fibronectin, laminin and phosphacan showed alterations of the ECM in CDV-infected dogs. A significantly increased amount of aggrecan was detected in early and late white matter lesions. In addition, the positive signal for collagens I and IV as well as fibronectin was significantly increased in late lesions. Conversely, the expression of phosphacan was significantly decreased in early and more pronounced in late lesions compared to controls. Furthermore, a set of genes involved in ECM was extracted from a publically available microarray data set and was analyzed for differential gene expression. Gene expression of ECM molecules, their biosynthesis pathways, and pro-fibrotic factors was mildly up-regulated whereas expression of matrix remodeling enzymes was up-regulated to a relatively higher extent. Summarized, the observed findings indicate that changes in the quality and content of ECM molecules represent important, mainly post-transcriptional features in advanced canine distemper lesions. Considering the insufficiency of morphological regeneration in chronic distemper lesions, the accumulated ECM seems to play a crucial role upon regenerative processes and may explain the relatively small regenerative potential in late stages of this disease.
RNA-binding protein Musashi2 induced by RANKL is critical for osteoclast survival.Friday, July 22, 2016
Fujiwara T, Zhou J, Ye S, Zhao H,
Cell death & disease. 2016
The Musashi family of RNA-binding proteins, Musashi1 and Musashi2, regulate self-renewal and differentiation of neuronal and hematopoietic stem cells by modulating protein translation. It has been recently reported that Musashi2, not Musashi1, regulates hematopoietic stem cells. Although osteoclasts are derived from hematopoietic cells, the expression and functions of Musashi proteins in osteoclast lineage cells remain unknown. In this study, we have uncovered that Musashi2 is the predominant isoform of Musashi proteins in osteoclast precursors and its expression is upregulated by receptor activator of NF-κB ligand (RANKL) during osteoclast differentiation. Knocking down the expression of Musashi2 in osteoclast lineage cells by shRNAs attenuates nuclear factor of activated T cells 1 (NFATc1) expression and osteoclast formation in vitro. Mechanistically, loss of Musashi2 inhibits Notch signaling during osteoclast differentiation and induces apoptosis in pre-osteoclasts. In contrast, depletion of Musashi2 has no effects on cell cycle progression and p21(WAF-1) protein expression in macrophages. Furthermore, depletion of Notch2 and its downstream target Hes1 in osteoclast precursors by shRNAs abrogates osteoclastogenesis by inhibiting NFATc1. Finally, absence of Musashi2 in osteoclast precursors promotes apoptosis and inhibits RANKL-induced nuclear factor-κB (NF-κB) activation, which is essential for osteoclast survival, Thus, Musashi2 is required for cell survival and optimal osteoclastogenesis by affecting Notch signaling and NF-κB activation.
Activation of salt-inducible kinase 2 promotes the viability of peritoneal mesothelial cells exposed to stress of peritoneal dialysis.Friday, July 22, 2016
Wang HH, Lin CY, Su SH, Chuang CT, Chang YL, Lee TY, Lee SC, Chang CJ,
Cell death & disease. 2016
Maintaining mesothelial cell viability is critical to long-term successful peritoneal dialysis (PD) treatment. To clarify the viability mechanism of peritoneal mesothelial cells under PD solutions exposure, we examined the mechanisms of cellular response to this stress conditions. Here we report that the proteasome activity is inhibited when treated with PD solutions. Proteasome inhibition-mediated activation of salt-inducible kinase 2 (SIK2), an endoplasmic reticulum-resident protein, is important for mesothelial cell viability. SIK2 is mobilized to promote autophagy and protect the cells from apoptosis under PD solution or MG132 treatment. Immunofluorescence staining showed that SIK2 is colocalized with LC3B in the autophagosomes of mesothelial cells treated with PD solution or derived from patients undergoing PD treatment. SIK2 activation is likely via a two-step mechanism, upstream kinases relieving the autoinhibitory conformation of SIK2 molecule followed by autophosphorylation of Thr175 and activation of kinase activity. These results suggest that activation of SIK2 is required for the cell viability when proteasome activity is inhibited by PD solutions. Maintaining or boosting the activity of SIK2 may promote peritoneal mesothelial cell viability and evolve as a potential therapeutic target for maintaining or restoring peritoneal membrane integrity in PD therapy.
Improvement of ENU Mutagenesis Efficiency Using Serial Injection and Mismatch Repair Deficiency Mice.Friday, July 22, 2016
Gallego-Llamas J, Timms AE, Pitstick R, Peters J, Carlson GA, Beier DR,
PloS one. 2016
ENU mutagenesis is a powerful method for generating novel lines of mice that are informative with respect to both fundamental biological processes and human disease. Rapid developments in genomic technology have made the task of identifying causal mutations by positional cloning remarkably efficient. One limitation of this approach remains the mutation frequency achievable using standard treatment protocols, which currently generate approximately 1-2 sequence changes per megabase when optimized. In this study we used two strategies to attempt to increase the number of mutations induced by ENU treatment. One approach employed mice carrying a mutation in the DNA repair enzyme Msh6. The second strategy involved injection of ENU to successive generations of mice. To evaluate the number of ENU-induced mutations, single mice or pooled samples were analyzed using whole exome sequencing. The results showed that there is considerable variability in the induced mutation frequency using these approaches, but an overall increase in ENU-induced variants from one generation to another was observed. The analysis of the mice deficient for Msh6 also showed an increase in the ENU-induced variants compared to the wild-type ENU-treated mice. However, in both cases the increase in ENU-induced mutation frequency was modest.
Generation of Two Noradrenergic-Specific Dopamine-Beta-Hydroxylase-FLPo Knock-In Mice Using CRISPR/Cas9-Mediated Targeting in Embryonic Stem Cells.Friday, July 22, 2016
Sun JJ, Ray R,
PloS one. 2016
CRISPR/Cas9 mediated DNA double strand cutting is emerging as a powerful approach to increase rates of homologous recombination of large targeting vectors, but the optimization of parameters, equipment and expertise required remain barriers to successful mouse generation by single-step zygote injection. Here, we sought to apply CRISPR/Cas9 methods to traditional embryonic stem (ES) cell targeting followed by blastocyst injection to overcome the common issues of difficult vector construction and low targeting efficiency. To facilitate the study of noradrenergic function, which is implicated in myriad behavioral and physiological processes, we generated two different mouse lines that express FLPo recombinase under control of the noradrenergic-specific Dopamine-Beta-Hydroxylase (DBH) gene. We found that by co-electroporating a circular vector expressing Cas9 and a locus-specific sgRNA, we could target FLPo to the DBH locus in ES cells with shortened 1 kb homology arms. Two different sites in the DBH gene were targeted; the translational start codon with 6-8% targeting efficiency, and the translational stop codon with 75% targeting efficiency. Using this approach, we established two mouse lines with DBH-specific expression of FLPo in brainstem catecholaminergic populations that are publically available on MMRRC (MMRRC_041575-UCD and MMRRC_041577-UCD). Altogether, this study supports simplified, high-efficiency Cas9/CRISPR-mediated targeting in embryonic stem cells for production of knock-in mouse lines in a wider variety of contexts than zygote injection alone.
Pathogenic shifts in endogenous microbiota impede tissue regeneration via distinct activation of TAK1/MKK/p38.Thursday, July 21, 2016
Arnold CP, Merryman MS, Harris-Arnold A, McKinney SA, Seidel CW, Loethen S, Proctor KN, Sánchez Alvarado A,
eLife. 21-Jul-2016
The interrelationship between endogenous microbiota, the immune system, and tissue regeneration is an area of intense research due to its potential therapeutic applications. We investigated this relationship in Schmidtea mediterranea, a model organism capable of regenerating any and all of its adult tissues. Microbiome characterization revealed a high Bacteroidetes to Proteobacteria ratio in healthy animals. Perturbations eliciting an expansion of Proteobacteria coincided with ectopic lesions and tissue degeneration. Culture of these bacteria yielded a strain of Pseudomonas capable of inducing progressive tissue degeneration. RNAi screening uncovered a TAK1 innate immune signaling module underlying compromised tissue homeostasis and regeneration during infection. TAK1/MKK/p38 signaling mediated opposing regulation of apoptosis during infection versus normal tissue regeneration. Given the complex role of inflammation in either hindering or supporting reparative wound healing and regeneration, this invertebrate model provides a basis for dissecting the duality of evolutionarily conserved inflammatory signaling in complex, multi-organ adult tissue regeneration.
Microdialysis Sampling from Wound Fluids Enables Quantitative Assessment of Cytokines, Proteins, and Metabolites Reveals Bone Defect-Specific Molecular Profiles.Friday, July 22, 2016
Förster Y, Schmidt JR, Wissenbach DK, Pfeiffer SE, Baumann S, Hofbauer LC, von Bergen M, Kalkhof S, Rammelt S,
PloS one. 2016
Bone healing involves a variety of different cell types and biological processes. Although certain key molecules have been identified, the molecular interactions of the healing progress are not completely understood. Moreover, a clinical routine for predicting the quality of bone healing after a fracture in an early phase is missing. This is mainly due to a lack of techniques to comprehensively screen for cytokines, growth factors and metabolites at their local site of action. Since all soluble molecules of interest are present in the fracture hematoma, its in-depth assessment could reveal potential markers for the monitoring of bone healing. Here, we describe an approach for sampling and quantification of cytokines and metabolites by using microdialysis, combined with solid phase extractions of proteins from wound fluids. By using a control group with an isolated soft tissue wound, we could reveal several bone defect-specific molecular features. In bone defect dialysates the neutrophil chemoattractants CXCL1, CXCL2 and CXCL3 were quantified with either a higher or earlier response compared to dialysate from soft tissue wound. Moreover, by analyzing downstream adaptions of the cells on protein level and focusing on early immune response, several proteins involved in the immune cell migration and activity could be identified to be specific for the bone defect group, e.g. immune modulators, proteases and their corresponding inhibitors. Additionally, the metabolite screening revealed different profiles between the bone defect group and the control group. In summary, we identified potential biomarkers to indicate imbalanced healing progress on all levels of analysis.
Corrigendum to ‘‘Allo-transplantation of mesenchymal stem cells attenuates hepatic injury through IL1Ra dependent macrophage switch in a mouse model of liver disease” [J Hepatol 2015;63:1405–1412].Wednesday, July 20, 2016
Journal of hepatology. Apr-2016
Providing a navigable route for acute medicine nurses to advance their practice: a framework of ascending levels of practice.Thursday, July 21, 2016
Lees-Deutsch L, Christian J, Setchfield I,
Acute medicine. 2016
This article conveys concerns raised by delegates at the International SAM Conference (Manchester, 2015) regarding how to advance nursing practice in acute medicine. It endeavors to capture the essence of 'how to advance practice' and 'how to integrate advanced practice' within the workforce structures of an acute medicine unit (AMU). It addresses the production of tacit knowledge and the recognition and integration of this to developing the nursing workforce. The current context of NHS efficiencies and recruitment issues emphasize the value of retaining tacit knowledge. Uniquely, this article offers an early conceptual framework through which levels of advancement and potential transition points to advance nursing practice in acute medicine are articulated. Determining how to advance requires identification of prior accomplishments such as, tacit knowledge, experiential learning, CPD, specialist courses and management experience. This requires nurses to make judicious decisions to advance their practice and the distinction between 'amassing experience' and 'career progression'. It aims to stimulate thinking around the practicalities of advancement, the value of tacit knowledge and potential realization through the framework trajectory.
HIV - lessons from a late diagnosis.Thursday, July 21, 2016
Chan XH, Onen BL, Raza MM, Mital D, Smith RW,
Acute medicine. 2016
Late HIV diagnosis is the most important predictor of HIV-related morbidity and mortality in the UK and often results from missed testing opportunities during earlier contact with health services. The HPA now recommends routine HIV testing be commissioned as a priority for all general medical admissions in high prevalence areas, such as Milton Keynes. We present the case of a patient admitted to our Medical Admissions Unit (MAU) managed initially for presumed septic complications of metastatic disease who was later found to have terminal HIV disease. In keeping with UK-wide experience which we review, a local audit following this case found MAU HIV test coverage increased after routine testing but not after staff education alone, and resulted in implementation of routine HIV testing in our MAU.
Hypoxia regulates Notch-3 mRNA and receptor activation in prostate cancer cells.Thursday, July 21, 2016
Meunier A, Flores AN, McDermott N, Rivera-Figueroa K, Perry A, Lynch T, Redalen KR, Marignol L,
Heliyon. May-2016
The Notch-3 receptor is a recognized key regulator of vascular responses and is increasingly associated with tumorigenesis. Hypoxia-inducible factors activate specific signaling pathways such as Notch in a number of cellular models. This study aimed to evaluate the regulation of Notch-3 by hypoxia in prostate cancer cells. Notch-3 gene and protein expression was established in a panel of aerobic and hypoxic prostate cell lines in vitro, the CWR22 xenograft model and RNA extracted from low grade (Gleason score < = 6); high grade (Gleason score > = 7); non-hypoxic (low HIF, low VEGF); hypoxic (high HIF, high VEGF) patient FFPE specimens. NOTCH-3 was upregulated in PC3 (3-fold), 22Rv1 (4.1-fold) and DU145 (3.8-fold) but downregulated in LnCaP (12-fold) compared to the normal cell lines. NOTCH-3 expression was modified following hypoxic exposure in these cells. NOTCH-3 was upregulated (2.2-fold) in higher grade and hypoxic tumors, when compared to benign and aerobic pools. In the CWR22 xenograft model, Notch-3 expression was restored in castrate resistant tumors. Nuclear translocation of the Notch-3 intracellular domain was no longer detected following exposure of cells to hypoxia but not associated with a change in expression of HES-1. Our data further identifies Notch-3 as a potentially key hypoxic-responsive member of the Notch pathway in prostate tumorigenesis.
Development of a cell-seeded modified small intestinal submucosa for urethroplasty.Thursday, July 21, 2016
Zhang L, Du A, Li J, Pan M, Han W, Xiao Y,
Heliyon. Mar-2016
A modified 3D porous SIS scaffold seeded with UC and treated with PAA produces better urethroplasty results than cell-seeded untreated SIS scaffolds, or unseeded PAA treated SIS scaffolds.
Immune Cell Isolation from Mouse Femur Bone Marrow.Thursday, July 21, 2016
Liu X, Quan N,
Bio-protocol. 20-Oct-2015
The bone marrow is the site of hematopoesis and contains mixed population of blood cells including erythrocytes, granulocytes, monocytes, dendritic cells, lymphocytes and hematopoietic stem cells. The following protocol provides a simple and fast method for isolation of bone marrow immune cells (no erythrocytes) from mouse femurs with a yield of approximate 8 × 10(7) cells in 5 ml culture media (1.6 × 10(4) cells/μl). Further isolation or flow cytometric analysis might be required for study of specific immune cell types.
Constitutive Expression of GATA4 Dramatically Increases the Cardiogenic Potential of D3 Mouse Embryonic Stem Cells.Thursday, July 21, 2016
Laemmle LL, Cohen JB, Glorioso JC,
The open biotechnology journal. 22-7-2016
The transcription factor GATA binding protein 4 (GATA4) is a vital regulator of cardiac programming that acts by inducing the expression of many different genes involved in cardiomyogenesis. Here we generated a D3 mouse embryonic stem cell line that constitutively expresses high levels of GATA4 and show that these cells have dramatically increased cardiogenic potential compared to an eGFP-expressing control cell line. Embryoid bodies (EB) derived from the D3-GATA4 line displayed increased levels of cardiac gene expression and showed more abundant cardiomyocyte differentiation than control eGFP EB. These cells and two additional lines expressing lower levels of GATA4 provide a platform to screen previously untested cardiac genes and gene combinations for their ability to further increase the efficiency of cardiomyocyte differentiation beyond that achieved by transgenic GATA4 alone. Non-integrative delivery of identified gene combinations will aid in the production of differentiated cells for the treatment of ischemic cardiomyopathy.
In vivo confocal microscopy of the sclerocorneal limbus after limbal stem cell transplantation: Looking for limbal architecture modifications and cytological phenotype correlations.Thursday, July 21, 2016
Mastropasqua L, Calienno R, Lanzini M, Nubile M, Colabelli-Gisoldi RA, De Carlo L, Pocobelli A,
Molecular vision. 2016
After successful ex vivo expanded limbal stem cell transplantation, in the presence of a complete anatomic architecture subversion, documented by support of in vivo confocal microscopy, the sclerocorneal limbus seemed to maintain its primary function. In vivo confocal microscopy confirmed the procedure was a non-invasive, efficacious diagnostic ocular surface procedure in the case of cell therapy reconstructive surgery.
Unmasking stem-specific neutralizing epitopes by abolishing N-linked glycosylation sites of influenza hemagglutinin proteins for vaccine design.Thursday, July 21, 2016
Liu WC, Jan JT, Huang YJ, Chen TH, Wu SC,
Journal of virology. 20-Jul-2016
N-linked glycosylation sites in the stem region of influenza hemagglutinin (HA) proteins are mostly well-conserved among various influenza virus strains. Targeting highly conserved HA stem regions has been proposed as a useful strategy for designing universal influenza vaccines. Our studies indicate that unmasking the HA2-stem N-glycans of recombinant HA proteins from H5N1 and pH1N1 viruses induced more potent neutralizing antibody titers against homologous and heterosubtypic viruses. However, only the immunization with the H5N1 HA2-stem mutant protein can refocus B antibody responses to the helix A epitope for inducing more CR6261-like/FI6v3-like and fusion inhibition antibodies in antisera, resulting in a significant improvement for the protection against lethal H5N1 virus challenges. These results may provide useful information for designing more effective influenza vaccines.
Small-molecule inhibitor sorafenib regulates immunoreactions by inducing survival and differentiation of bone marrow cells.Thursday, July 21, 2016
Zhao X, Cao M, Lu Z, Wang T, Ren Y, Liu C, Nelson D,
Innate immunity. 19-Jul-2016
Sorafenib has been used for the treatment of liver cancer. However, its clinical impact on human immunity system remains poorly known. Our previous study has shown that sorafenib modulates immunosuppressive cell populations in murine liver cancer models. Here, we continue to report that low doses of sorafenib promotes the survival of murine bone marrow cells (BMCs) in a dose-dependent manner by up-regulating the anti-apoptotic protein survivin. Sorafenib induces differentiation of BMCs into suppressive dendritic cells that inhibit autologous T-cell proliferation and stimulate CD4(+) T cells to express increased IL-1β, IL-2, IL-4, IL-10, IFN-γ and TNF-α, and reduced levels of IL-6 and CD25, which indicates that sorafenib-induced dendritic cells represent a distinct cellular subset with unique properties. Taken together, our findings suggest that in addition to its anticancer effects, sorafenib has an immunoregulatory property that is apparent at low doses.
Redefining the origin and evolution of ovarian cancer: A hormonal connection.Thursday, July 21, 2016
Cardenas C, Alvero AB, Yun B, Mor G,
Endocrine-related cancer. 20-Jul-2016
Ovarian cancer has the highest mortality of all female reproductive cancers. Late diagnosis, tumor heterogeneity, and the development of chemoresistance contribute to this statistic and works against patient survival. Current studies have revealed novel concepts that impact our view on how ovarian cancer develops. The greatest impact is on our understanding that as a disease, ovarian cancer has multiple cellular origins and that these malignant precursors are mostly derived from outside of the ovaries. In this review, we propose a new concept of a step-wise developmental process that may underwrite ovarian tumorigenesis and progression: (1) migration to/recruitment of the ovaries; (2) seeding and establishment in the ovaries; (3) induction of a dormant cancer stage; and (4) expansion and tumor progression. We will discuss the relationship of each step with the changing ovarian function and milieu during the reproductive age and subsequent occurrence of menopause. The realization that ovarian cancer development and progression occurs in distinct steps is critical for the search of adequate markers for early detection that will offer personalized strategies for prevention and therapy.
Greener synthesis of indolizine analogues using water as a base and solvent: study for larvicidal activity against Anopheles arabiensis.Thursday, July 21, 2016
Sandeep C, Venugopala KN, Gleiser RM, Chetram A, Padmashali B, Kulkarni RS, Venugopala R, Odhav B,
Chemical biology & drug design. 21-Jul-2016
Greener synthesis of a series of novel indolizine analogues have been achieved by the cyclization of aromatic cycloimmoniumylides with electron deficient alkynes in presence of water as the base and solvent at 80 °C. Yield of the title compounds was good and reactions performed were eco-friendly. The structures of these newly synthesized compounds have been confirmed by spectroscopic techniques such as FTIR, NMR, LC-MS and elemental analysis. Characterized title compounds were evaluated for larvicidal activity against Anopheles arabiensis by standard WHO larvicidal assay using Temephos as standard at 4 μg/mL. Title compounds 2e, 2f and 2g emerged as promising larvicidal agents. This article is protected by copyright. All rights reserved.
Changes in body composition of Indian lactating women: a longitudinal study.Thursday, July 21, 2016
Kajale NA, Khadilkar VV, Mughal Z, Chiplonkar SA, Khadilkar AV,
Asia Pacific journal of clinical nutrition. 2016
These urban relatively sedentary MSC women consumed fat rich food PP with higher android fat retention and partial recovery of BMD at DF and TB at 1-year. Modifications in activity and dietary nutrient intakes may be necessary to prevent cardiovascular and bone health related risks.
A combined approach for the treatment of lateral and posterolateral tibial plateau fractures.Thursday, July 21, 2016
Zhang P, Lian K, Luo D, Huang Z, Li T, Lin D,
Injury. 5-Jul-2016
The combined approach with dual-plate offers direct and complete surgical exposure and provide an effective method for the treatment of lateral and posterolateral tibial plateau fractures.
Islet cell transplantation from Göttingen minipigs to cynomolgus monkeys: analysis of virus safety.Thursday, July 21, 2016
Morozov VA, Ludwig S, Ludwig B, Rotem A, Barkai U, Bornstein SR, Denner J,
Xenotransplantation. 20-Jul-2016
Although the donor islet cells and the recipients were negative for HEV using PCR and Western blot analysis, in one recipient, antibodies against HEV were found, indicating infection in a single case. All recipients were negative for antibodies against PERV, and all were negative for PCMV, indicating absence of infection. As HEV was not detected in the donor pig before transplantation, a more complex and regular screening of the animals using highly sensitive methods is required to avoid virus transmission.
Human mesenchymal stem cell transplantation promote neural differentiation and behavioral performance in the photothrombotic mouse model.Thursday, July 21, 2016
Choi YK, Urnukhsaikhan E, Yoon HH, Seo YK, Park JK,
Biotechnology journal. 21-Jul-2016
Various animal models of stroke have been developed to simulate the human stroke with the development of the ischemic method facilitates preclinical stroke research. The photothrombotic ischemia model, based on the intravascular photochemical reaction, is widely used for in vivo studies. However, this study has limitation, which generated relatively small-sized infarction model on superficial cortex compared to that of MCAO stroke model. In this study, we adapted the photothorombosis mouse model and determined the optimum conditions for generation of cell death and deficits with high reproducibility. The extent of damage within the cortex was assessed by infarct volume and cellular/behavioral analyses. In this model, we detected neural cell death and inflammatory responses; moreover, the degree of behavioral impairment was correlated with the brain infarct volume. Further, to enhance our understanding of neural repair, we analyzed the effect of neural differentiation by transplantation of human BM-MSCs. We demonstrated that BM-MSCs transplantation promoted the neural differentiation and behavioral performance in our photothrombosis model. Therefore, this research was meaningful to provide a stable animal model of stroke with low variability. Moreover, this model will facilitate development of novel MSC-based therapeutics for stroke.
Transcriptome analyses of inner cell mass and trophectoderm cells isolated by magnetic-activated cell sorting from bovine blastocysts using single cell RNA-seq.Thursday, July 21, 2016
Zhao XM, Cui LS, Hao HS, Wang HY, Zhao SJ, Du WH, Wang D, Liu Y, Zhu HB,
Reproduction in domestic animals = Zuchthygiene. 20-Jul-2016
Research on bovine embryonic stem cells (bESCs) has been hampered because bESCs are cultured in conditions that are based on information obtained from culturing mouse and human inner cell mass (ICM) cells. The aim of this study was to compare gene expression in ICM and trophectoderm (TE) cell lineages of bovine embryos and to discuss the findings relative to information available for mice and humans. We separated a high-purity (>90%) ICM and TE from bovine blastocysts by magnetic-activated cell sorting and analysed their transcriptomes by single cell RNA-seq. Differentially expressed genes (DEGs) were assessed using Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) databases. Finally, qRT-PCR was performed to validate the RNA-seq results. From 207 DEGs identified (adjusted p ≤ .05; fold change ≥2), 159 and 48 had greater expression in the ICM and TE cells respectively. We validated 27 genes using qRT-PCR and found their expression patterns were mostly similar to those of RNA-seq, including 12 novel ICM-dominant (HNF4A, CCL24, FGFR4, IFITM3, PTCHD2, GJB5, FN1, KLK7, PRDM14, GRP, FGF19 and GCM1) and two novel TE-dominant (SLC10A1 and WNT4) genes. Bioinformatics analysis showed that these DEGs are involved in many important pathways, such as MAPK and cancer cell pathways, and these pathways have been shown to play essential roles in mouse and human ESCs in the self-renewal and pluripotent maintenance. As a conclusion, there were sufficient differences to allow us to conclude that the control of pluripotency in bovine ICM cells is species-specific.
Enzymatic Crosslinking of Polymer Conjugates is Superior over Ionic or UV Crosslinking for the On-Chip Production of Cell-Laden Microgels.Thursday, July 21, 2016
Henke S, Leijten J, Kemna E, Neubauer M, Fery A, van den Berg A, van Apeldoorn A, Karperien M,
Macromolecular bioscience. 21-Jul-2016
Cell-laden micrometer-sized hydrogels (microgels) hold great promise for improving high throughput ex-vivo drug screening and engineering biomimetic tissues. Microfluidics is a powerful tool to produce microgels. However, only a limited amount of biomaterials have been reported to be compatible with on-chip microgel formation. Moreover, these biomaterials are often associated with mechanical instability, cytotoxicity, and cellular senescence. To resolve this challenge, dextran-tyramine has been explored as a novel biomaterial for on-chip microgel formation. In particular, dextran-tyramine is compared with two commonly used biomaterials, namely, polyethylene-glycol diacrylate (PEGDA) and alginate, which crosslink through enzymatic reaction, UV polymerization, and ionic interaction, respectively. Human mesenchymal stem cells (hMSCs) encapsulated in dextran-tyramine microgels demonstrate significantly higher (95%) survival as compared to alginate (81%) and PEGDA (69%). Long-term cell cultures demonstrate that hMSCs in PEGDA microgels become senescent after 7 d. Alginate microgels dissolve within 7 d due to Ca(2+) loss. In contrast, dextran-tyramine based microgels remain stable, sustain hMSCs metabolic activity, and permit for single-cell level analysis for at least 28 d of culture. In conclusion, enzymatically crosslinking dextran-tyramine conjugates represent a novel biomaterial class for the on-chip production of cell-laden microgels, which possesses unique advantages as compared to the commonly used UV and ionic crosslinking biomaterials.
MicroRNA-mediated target mRNA cleavage and 3'-uridylation in human cells.Thursday, July 21, 2016
Xu K, Lin J, Zandi R, Roth JA, Ji L,
Scientific reports. 2016
MicroRNAs (miRNAs) play an important role in targeted gene silencing by facilitating posttranscriptional and translational repression. However, the precise mechanism of mammalian miRNA-mediated gene silencing remains to be elucidated. Here, we used a stem-loop array reverse-transcription polymerase chain reaction assay to analyse miRNA-induced mRNA recognition, cleavage, posttranscriptional modification, and degradation. We detected endogenous let-7 miRNA-induced and Argonaute-catalysed endonucleolytic cleavage on target mRNAs at various sites within partially paired miRNA:mRNA sequences. Most of the cleaved mRNA 5'-fragments were 3'-oligouridylated by activities of terminal uridylyl transferases (TUTases) in miRNA-induced silencing complexes and temporarily accumulated in the cytosol for 5'-3' degradation or other molecular fates. Some 3'-5' decayed mRNA fragments could also be captured by the miRNA-induced silencing complex stationed at the specific miRNA:mRNA target site and oligouridylated by other TUTases at its proximity without involving Argonaute-mediated RNA cleavage. Our findings provide new insights into the molecular mechanics of mammalian miRNA-mediated gene silencing by coordinated target mRNA recognition, cleavage, uridylation and degradation.
Mesenchymal stem cells as a double-edged sword in suppression or progression of solid tumor cells.Thursday, July 21, 2016
Norozi F, Ahmadzadeh A, Shahrabi S, Vosoughi T, Saki N,
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 20-Jul-2016
Tumor cells are able to attract mesenchymal stem cells (MSCs) to primary tumor site. On the other hand, MSCs secrete various factors to attract tumor cells towards BM. In this review, in addition to assessment of MSCs function at tumor sites and their impact on growth and metastasis of tumor cells, the importance of MSC in attraction of malignant cells to BM and their involvement in drug resistance of tumor cells have also been studied. Relevant literature was identified by a PubMed search (2000-2015) of English-language literature using the terms mesenchymal stem cells, cancer cell, metastasis, and tumor microenvironment. MSCs migrate towards tumor microenvironment and are involved in both pro-tumorigenic and antitumorigenic functions. The dual function of MSCs at tumor sites is dependent upon a variety of factors, including the type and origin of MSCs, the cancer cell line under study, in vivo or in vitro conditions, the factors secreted by MSCs and interactions between MSCs, host immune cells and cancer cells. Therefore, MSCs can be regarded both as friends and enemies of cancer cells. Although the role of a number of pathways, including IL-6/STAT3 pathway, has been indicated in controlling the interaction between MSCs and tumor cells, other mechanisms by which MSCs can control the tumor cells are not clear yet. A better understanding of these mechanisms through further studies can determine the exact role of MSCs in cancer progression and identify them as important therapeutic agents or targets.
Pet Radiopharmaceuticals for Personalized Medicine.Thursday, July 21, 2016
Sharma SK,
Current drug targets. 19-Jul-2016
Recent advances in the self-shielded cyclotrons, improved targets, video-monitored hot cells design, and automated PET radiopharmaceutical (RPs) synthesis modules, utilizing computer-controlled graphic user interphase (GUI) has revolutionized PET molecular imaging technology for basic biomedical research and theranostics to accomplish the ultimate goal of evidence-based personalized medicine. Particularly, [18F]HX4: (3-[18F]fluoro-2-(4-((2-nitro-1Himidazol-1-yl)methyl)-1H-1,2,3,-triazol-1-yl)-propan-1-ol), 18F-FAZA: 1-(5-[18F]Fluoro-5-deoxy-α-D-arabinofuranosyl)-2-nitroimidazole, and 18F-FMSIO: 18F-Ffluoromisonidazole to assess tumor hypoxia, [18F]FB-VAD-FMK: [18F]4-fluorobenzylcarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone to determine in vivo apoptosis, 64Cu-PTSM: 64Cu-Pyrualdehyde Bis-N-Methylthiosemicarbazone for brain and myocardial perfusion imaging, and 68Ga-DOTATOC: 68Ga-DOTAD-Phy1-Tyr3-octreotide and 68Ga-DOTANOC: 68Ga-(1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid)-1-NaI3-octreotide for neuroendocrine and neural crest tumors have demonstrated great promise in personalized theranostics. Furthermore, multimodality imaging with 124I-PET/CT and 18FDG-PET/CT rationalizes 131I treatment in thyroid cancer patients to prevent cost and morbid toxicity. In addition to 18F-labeled PET-RPs used in clinical practice, novel discoveries of chemical reactions including transition metal-mediated cross-coupling of carbon-carbon, carbon-heterocarbon, and click chemistry at ambient temperature with significantly reduced synthesis times, labeled even with short-lived radionuclides such as 11C, has facilitated development of novel PET-RPs. These innovative approaches to synthesize PET-RPs and efficient image acquisition capabilities have improved the resolution of multimodality imaging and significantly reduced the radiation exposure to patients as well as healthcare professionals. Future developments in novel PET-RPs, utilizing automated microfluidic synthesis modules and multifunctional nanoparticles, will improve biomarker discovery, internal dosimetry, pharmacokinetics, immunotherapy, and stem cell tracking in regenerative medicine. This review provides recent developments in the synthesis of clinically-significant cyclotron and generator-based PET-RPs with potential applications in cardiovascular diseases, neurodegenerative diseases, and cancer to accomplish the ultimate goal of evidence-based personalized theranostics.
Proteomic discovery of host kinase signaling in bacterial infections.Thursday, July 21, 2016
Richter E, Mostertz J, Hochgräfe F,
Proteomics. Clinical applications. 20-Jul-2016
Protein phosphorylation catalyzed by protein kinases acts as a reversible molecular switch in signal transduction, providing a mechanism for the control of protein function in cellular processes. During microbial infection, cellular signaling essentially contributes to immune control to restrict the dissemination of invading pathogens within the host organism. However, pathogenic microbes compete for the control of host signaling to create a beneficial environment for successful invasion and infection. Although efforts to achieve a better understanding of the host-pathogen interaction and its molecular consequences have been made, there is urgent need for a comprehensive characterization of infection-related host signaling processes. System-wide and hypothesis-free analysis of phosphorylation-mediated host signaling during host-microbe interactions by mass spectrometry (MS)-based methods is not only promising in view of a greater understanding of the pathogenesis of the infection but also may result in the identification of novel host targets for preventive or therapeutic intervention. Here, we review state-of-the-art MS-based techniques for the system-wide identification and quantitation of protein phosphorylation and compare them to array-based phosphoprotein analyses. We also provide an overview of how phosphoproteomics and kinomics have contributed to our understanding of protein kinase-driven phosphorylation networks that operate during host-microbe interactions. This article is protected by copyright. All rights reserved.
Clinical impact of early recovery of peripheral blood absolute lymphocyte count after frontline autologous stem cell transplantation for diffuse large B-cell lymphoma.Thursday, July 21, 2016
Kim Y, Kim SJ, Cheong JW, Cho H, Chung H, Lee JY, Jang JE, Min YH, Kim JS,
Hematological oncology. 21-Jul-2016
We conducted a retrospective study to evaluate the clinical impact of an early recovery of posttransplant absolute lymphocyte count (ALC) on the outcome of frontline autologous stem cell transplantation (ASCT) for diffuse large B-cell lymphoma (DLBCL). We reviewed 65 DLBCL patients who underwent frontline ASCT after primary chemotherapy based on cyclophosphamide, doxorubicin, vincristine, and prednisone. A receiver operating characteristic analysis was performed to determine the optimal cut point (0.4 × 10(9) /L) for an ALC at 15 days after ASCT (ALC-15). Both event-free survival and overall survival rates of the higher-ALC-15 group were significantly better than those of the lower-ALC-15 group (event-free survival, P = .008; overall survival, P = .013). The infused CD34(+) cell count was significantly associated with the recovery of ALC-15 (>0.4 × 10(9) /L) after ASCT (P = .028). A multivariate analysis confirmed that a higher infused CD34(+) cell dose (>5.0 × 10(6)  cells/kg) was an independent factor affecting an early recovery of ALC after ASCT (odds ratio, 4.145; 95% confidence interval, 1.106-15.528; P = .035). In conclusion, an early recovery of ALC after ASCT can be regarded as a good prognostic marker in patients with DLBCL who have undergone frontline ASCT. We found that the infused CD34(+) cell dose for ASCT was associated with the recovery of ALC.
IQGAP1 Binds To YAP and Modulates Its Transcriptional Activity.Thursday, July 21, 2016
Sayedyahossein S, Li Z, Hedman AC, Morgan CJ, Sacks DB,
The Journal of biological chemistry. 20-Jul-2016
During development, the Hippo signaling pathway regulates key physiological processes, such as control of organ size, regeneration and stem cell biology. Yes-associated protein (YAP) is a major transcriptional co-activator of the Hippo pathway. The scaffold protein IQGAP1 interacts with more than 100 binding partners to integrate diverse signaling pathways. In this study, we report that IQGAP1 binds to YAP and modulates its activity. IQGAP1 and YAP coimmunoprecipitated from cells. In vitro analysis with pure proteins demonstrated a direct interaction between IQGAP1 and YAP. Analysis with multiple fragments of each protein showed that the interaction occurs via the IQ domain of IQGAP1 and the TEAD-binding domain of YAP. The interaction between IQGAP1 and YAP has functional effects. Knockout of endogenous IQGAP1 significantly increased the formation of nuclear YAP/TEAD complexes. Further analysis showed that YAP/TEAD-mediated transcription in cells lacking IQGAP1 was significantly greater than in control cells. These data reveal that IQGAP1 binds to YAP and modulates its co-transcriptional function, suggesting that IQGAP1 participates in Hippo signaling.
Complex Transfusion Issues in Pediatric Hematopoietic Stem Cell Transplantation.Thursday, July 21, 2016
Webb J, Abraham A,
Transfusion medicine reviews. 18-Jun-2016
Advances in the fields of pediatric transfusion medicine and hematopoietic stem cell transplant have resulted in improved outcomes but also present new questions for research. The diagnostic capabilities involved in transfusion medicine have improved in recent times, now including methods for determination of red blood cell minor antigens, detection of anti-human leukocyte antigen antibodies, and noninvasive iron quantification. At the same time, transplants are being performed for more indications including nonmalignant disease and with less intense conditioning regimens that allow some recipient blood cells to persist after transplant. We are therefore faced with new opportunities to understand the implications of transfusion medicine testing and to develop data-driven guidelines relevant to the current-day approach to transfusion and transplantation.
IL-10+ regulatory B cells are enriched in cord blood and may play a role in protection against GVHD after cord blood transplantation.Thursday, July 21, 2016
Sarvaria A, Basar R, Mehta RS, Shaim H, Muftuoglu M, Khoder A, Sekine T, Gokdemir E, Kondo K, Marin D, Daher M, Alousi AM, Alsuliman A, Liu E, Oran B, Olson A, Jones RB, Popat U, Hosing C, Champlin R, Shpall EJ, Rezvani K,
Blood. 20-Jul-2016
Cord blood (CB) offers a number of advantages over other sources of hematopoietic stem cells, including a lower rate of chronic graft-versus-host (cGVHD) in the presence of increased HLA disparity. Recent research in experimental models of autoimmunity and in patients with autoimmune or alloimmune disorders has identified a functional group of IL-10-producing regulatory B cells (Bregs) that negatively regulate T-cell immune responses. At present, however, there is no consensus on the phenotypic signature of Bregs, and their prevalence and functional characteristics in CB remain unclear. Here, we demonstrate that CB contains an abundance of B cells with immunoregulatory function. Bregs were identified in both the naïve and transitional B cell compartments and suppressed T-cell proliferation and effector function through IL-10 production as well as cell-to-cell contact involving CTLA-4. We further show that the suppressive capacity of CB-derived Bregs can be potentiated through CD40-ligand signaling, suggesting that inflammatory environments may induce their function. Finally, there was robust recovery of IL-10-producing Bregs in patients after CB transplantation, to higher frequencies and absolute numbers than seen in the peripheral blood of healthy donors or in patients before transplant. The reconstituting Bregs showed strong in vitro suppressive activity against allogeneic CD4+ T-cells, but were deficient in patients with cGVHD. Together, these findings identify a rich source of Breg cells and suggest a protective role for CB-derived Bregs against cGVHD development in CB recipients. This advance could propel the development of Breg-based strategies to prevent or ameliorate this post-transplant complication.
Tumor regression and delayed onset toxicity following B7-H4 CAR T cell Therapy.Thursday, July 21, 2016
Smith JB, Lanitis E, Dangaj D, Buza E, Poussin M, Stashwick C, Scholler N, Powell DJ,
Molecular therapy : the journal of the American Society of Gene Therapy. 21-Jul-2016
B7-H4 protein is frequently overexpressed in ovarian cancer. Here, we engineered T cells with novel B7-H4-specific chimeric antigen receptors (CAR) that recognized both human and murine B7-H4 to test the hypothesis that B7-H4 CAR T cell therapy can be applied safely in preclinical models. B7-H4 CAR T cells specifically secreted IFN-γ and lysed B7-H4(+) targets. In vivo, B7-H4 CAR T cells displayed anti-tumor reactivity against B7-H4(+) human ovarian tumor xenografts. Unexpectedly, B7-H4 CAR T cell treatment reproducibly showed delayed, lethal toxicity 6-8 weeks after therapy. Comprehensive assessment of murine B7-H4 protein distribution uncovered expression in ductal and mucosal epithelial cells in normal tissues. Postmortem analysis revealed the presence of widespread histologic lesions that correlated with B7-H4(+) expression, and were inconsistent with graft versus host disease (GVHD). Lastly, expression patterns of B7-H4 protein in normal human tissue were comparable to distribution in mice, advancing our understanding of B7-H4. We conclude that B7-H4 CAR therapy mediates control of cancer outgrowth. However, long-term engraftment of B7-H4 CAR T cells mediates lethal, off-tumor toxicity that is likely due to wide expression of B7-H4 in healthy mouse organs. This model system provides a unique opportunity for preclinical evaluation of safety approaches that limit CAR-mediated toxicity after tumor destruction in vivo.
Stem Cell-Based Therapies for Ischemic Stroke: Preclinical Results and the Potential of Imaging-Assisted Evaluation of Donor Cell Fate and Mechanisms of Brain Regeneration.Thursday, July 21, 2016
Gervois P, Wolfs E, Ratajczak J, Dillen Y, Vangansewinkel T, Hilkens P, Bronckaers A, Lambrichts I, Struys T,
Medicinal research reviews. 21-Jul-2016
Stroke is the second most common cause of death and is a major cause of permanent disability. Given the current demographic trend of an ageing population and associated increased risk, the prevalence of and socioeconomic burden caused by stroke will continue to rise. Current therapies are unable to sufficiently ameliorate the disease outcome and are not applicable to all patients. Therefore, strategies such as cell-based therapies with mesenchymal stem cell (MSC) or induced pluripotent stem cell (iPSC) pave the way for new treatment options for stroke. These cells showed great preclinical promise despite the fact that the precise mechanism of action and the optimal administration route are unknown. To gain dynamic insights into the underlying repair processes after stem cell engraftment, noninvasive imaging modalities were developed to provide detailed spatial and functional information on the donor cell fate and host microenvironment. This review will focus on MSCs and iPSCs as types of widely used stem cell sources in current (bio)medical research and compare their efficacy and potential to ameliorate the disease outcome in animal stroke models. In addition, novel noninvasive imaging strategies allowing temporospatial in vivo tracking of transplanted cells and coinciding evaluation of neuronal repair following stroke will be discussed.
Current and emerging vascularization strategies in skin tissue engineering.Thursday, July 21, 2016
Frueh FS, Menger MD, Lindenblatt N, Giovanoli P, Laschke MW,
Critical reviews in biotechnology. 20-Jul-2016
Vascularization is a key process in skin tissue engineering, determining the biological function of artificial skin implants. Hence, efficient vascularization strategies are a major prerequisite for the safe application of these implants in clinical practice. Current approaches include (i) modification of structural and physicochemical properties of dermal scaffolds, (ii) biological scaffold activation with growth factor-releasing systems or gene vectors, and (iii) generation of prevascularized skin substitutes by seeding scaffolds with vessel-forming cells. These conventional approaches may be further supplemented by emerging strategies, such as transplantation of adipose tissue-derived microvascular fragments, 3D bioprinting and microfluidics, miRNA modulation, cell sheet engineering, and fabrication of photosynthetic scaffolds. The successful translation of these vascularization strategies from bench to bedside may pave the way for a broad clinical implementation of skin tissue engineering.
PIN1 Suppresses the Hepatic Differentiation of Pulp Stem Cells via Wnt3a.Thursday, July 21, 2016
Kim HJ, Cho YA, Lee YM, Lee SY, Bae WJ, Kim EC,
Journal of dental research. 20-Jul-2016
This study aimed to investigate the role of PIN1 on the hepatic differentiation of human dental pulp stem cells (hDPSCs) and its signaling pathway, as well as the potential therapeutic effects of hDPSC transplantation and PIN1 inhibition on CCl4 (carbon tetrachloride)-induced liver fibrosis in mice. The in vitro results showed that hepatic differentiation was suppressed by infection with adenovirus-PIN1 and promoted by PIN1 inhibitor juglone via the downregulation of Wnt3a and β-catenin. Compared with treatment with either hDPSC transplantation or juglone alone, the combination of hDPSCs and juglone into CCl4-injured mice significantly suppressed liver fibrosis and restored serum levels of alanine transaminase, aspartate transaminase, and ammonia. Collectively, the present study shows for the first time that PIN1 inhibition promotes hepatic differentiation of hDPSCs through the Wnt/β-catenin pathway. Furthermore, juglone in combination with hDPSC transplantation effectively treats liver fibrosis, suggesting that hDPSC transplantation with PIN1 inhibition may be a novel therapeutic candidate for the treatment of liver injury.
Set7 mediated interactions regulate transcriptional networks in embryonic stem cells.Thursday, July 21, 2016
Tuano NK, Okabe J, Ziemann M, Cooper ME, El-Osta A,
Nucleic acids research. 20-Jul-2016
Histone methylation by lysine methyltransferase enzymes regulate the expression of genes implicated in lineage specificity and cellular differentiation. While it is known that Set7 catalyzes mono-methylation of histone and non-histone proteins, the functional importance of this enzyme in stem cell differentiation remains poorly understood. We show Set7 expression is increased during mouse embryonic stem cell (mESC) differentiation and is regulated by the pluripotency factors, Oct4 and Sox2. Transcriptional network analyses reveal smooth muscle (SM) associated genes are subject to Set7-mediated regulation. Furthermore, pharmacological inhibition of Set7 activity confirms this regulation. We observe Set7-mediated modification of serum response factor (SRF) and mono-methylation of histone H4 lysine 4 (H3K4me1) regulate gene expression. We conclude the broad substrate specificity of Set7 serves to control key transcriptional networks in embryonic stem cells.
MicroRNA-145-based differentiation of human mesenchymal stem cells to smooth muscle cells.Thursday, July 21, 2016
Pajoohesh M, Naderi-Manesh H, Soleimani M,
Biotechnology letters. 20-Jul-2016
Overexpression of microRNA-145 in undifferentiated hBM-MSCs results in functionally mature contractile SMCs that can be used in drug discovery and cell therapy in SMC disorders such as vascular disease.
Cordycepin inhibits Chondrocyte Hypertrophy of Mesenchymal Stem Cells through PI3K/Bapx1 and Notch Signaling Pathway.Thursday, July 21, 2016
Cao Z, Dou C, Li J, Tang X, Xiang J, Zhao C, Zhu L, Bai Y, Xiang Q, Dong S,
BMB reports. 20-Jul-2016
Mesenchymal stem cells (MSCs) are widely used in cartilage tissue engineering to repair articular cartilage defects. However, hypertrophy of chondrocytes derived from MSCs might hinder the stabilization of hyaline cartilage. Thus, it is very important to find out a suitable way to maintain the chondrogenic phenotype of chondrocytes. Cordycepin was reported with anti-inflammatory and anti-tumor functions. However, the role of cordycepin in the chondrocyte hypertrophy remains unclear. We investigated the effect of cordycepin on chondrogenesis and chondrocyte hypertrophy in MSCs and ATDC5 cells. Cordycepin up-regulated chondrogenic markers including Sox9 and collagen type Ⅱ while down-regulated hypertrophic markers including Runx2 and collagen type Ⅹ. Further exploration showed that cordycepin promoted chondrogenesis through inhibiting Nrft and activating BMP signaling. Besides, cordycepin suppressed chondrocyte hypertrophy through PI3K/Bapx1 pathway and Notch signaling. Our results indicated cordycepin was a potential agent in maintaining chondrocyte phenotype and reconstructing engineered cartilage.
In vivo generation of neural stem cells through teratoma formation.Thursday, July 21, 2016
Hong YJ, Kim JS, Choi HW, Song H, Park C, Do JT,
Stem cells and development. 20-Jul-2016
Pluripotent stem cells have the potential to differentiate into all cell types of the body in vitro through embryoid body formation or in vivo through teratoma formation. Here, we attempted to generate in vivo neural stem cells (NSCs) differentiated through teratoma formation using Olig2-GFP transgenic embryonic stem cells (ESCs). After 4 to 6 weeks of injection with Olig2-GFP transgenic ESCs, Olig2-GFP+ NSCs were identified in teratomas formed in immunodeficient mice. Interestingly, 4-week-old teratomas contained higher percentage of Olig2-GFP+ cells (~11%) than 6-week-old teratomas (~3%). These in vivo-derived NSCs expressed common NSC markers (Nestin and Sox2) and differentiated into terminal neuronal and glial lineages. These results suggest that pure NSC populations exhibiting properties similar to those of brain-derived NSCs can be established through teratoma formation.
Resistance to cytotoxicity and sustained release of interleukin-6 and interleukin-8 in the presence of decreased interferon-γ after differentiation of glioblastoma by human natural killer cells.Thursday, July 21, 2016
Kozlowska AK, Tseng HC, Kaur K, Topchyan P, Inagaki A, Bui VT, Kasahara N, Cacalano N, Jewett A,
Cancer immunology, immunotherapy : CII. 20-Jul-2016
Natural killer (NK) cells are functionally suppressed in the glioblastoma multiforme (GBM) tumor microenvironment. We have recently shown that survival and differentiation of cancer stem-like cells (CSCs)/poorly differentiated tumors are controlled through two distinct phenotypes of cytotoxic and non-cytotoxic/split anergized NK cells, respectively. In this paper, we studied the function of NK cells against brain CSCs/poorly differentiated GBM and their NK cell-differentiated counterparts. Brain CSCs/poorly differentiated GBM, differentiated by split anergized NK supernatants (supernatants from NK cells treated with IL-2 + anti-CD16mAb) expressed higher levels of CD54, B7H1 and MHC-I and were killed less by the NK cells, whereas their CSCs/poorly differentiated counterparts were highly susceptible to NK cell lysis. Resistance to NK cells and differentiation of brain CSCs/poorly differentiated GBM by split anergized NK cells were mediated by interferon (IFN)-γ and tumor necrosis factor (TNF)-α. Brain CSCs/poorly differentiated GBM expressed low levels of TNFRs and IFN-γRs, and when differentiated and cultured with IL-2-treated NK cells, they induced increased secretion of pro-inflammatory cytokine interleukin (IL)-6 and chemokine IL-8 in the presence of decreased IFN-γ secretion. NK-induced differentiation of brain CSCs/poorly differentiated GBM cells was independent of the function of IL-6 and/or IL-8. The inability of NK cells to lyse GBM tumors and the presence of a sustained release of pro-inflammatory cytokines IL-6 and chemokine IL-8 in the presence of a decreased IFN-γ secretion may lead to the inadequacy of NK cells to differentiate GBM CSCs/poorly differentiated tumors, thus failing to control tumor growth.
Cell-based Assay System for Predicting Bone Regeneration in Patient Affected by Aseptic Nonunion and Treated with Platelet Rich Fibrin.Thursday, July 21, 2016
Perut F, Dante D, Nicola R, Nicola B, Donatella G,
Current pharmaceutical biotechnology. 19-Jul-2016
BMSC-based assay could be a useful tool to recognize patients who have a low probability to benefit from the use of autologous platelet concentrate to promote the healing of long bone nonunion.
Cancer-Specific Telomerase Reverse Transcriptase (TERT) Promoter Mutations: Biological and Clinical Implications.Thursday, July 21, 2016
Liu T, Yuan X, Xu D,
Genes. 2016
The accumulated evidence has pointed to a key role of telomerase in carcinogenesis. As a RNA-dependent DNA polymerase, telomerase synthesizes telomeric DNA at the end of linear chromosomes, and attenuates or prevents telomere erosion associated with cell divisions. By lengthening telomeres, telomerase extends cellular life-span or even induces immortalization. Consistent with its functional activity, telomerase is silent in most human normal somatic cells while active only in germ-line, stem and other highly proliferative cells. In contrast, telomerase activation widely occurs in human cancer and the enzymatic activity is detectable in up to 90% of malignancies. Recently, hotspot point mutations in the regulatory region of the telomerase reverse transcriptase (TERT) gene, encoding the core catalytic component of telomerase, was identified as a novel mechanism to activate telomerase in cancer. This review discusses the cancer-specific TERT promoter mutations and potential biological and clinical significances.
A Simple Scoring System Predicting the Survival Time of Patients with Bone Metastases after RT.Thursday, July 21, 2016
Zhang WY, Li HF, Su M, Lin RF, Chen XX, Zhang P, Zou CL,
PloS one. 2016
According to this scoring system, the survival time of patients after bone metastasis can be estimated.
Genetic dissection of the Transcription Factor code controlling serial specification of muscle identities in Drosophila.Thursday, July 21, 2016
Dubois L, Frendo JL, Chanut-Delalande H, Crozatier M, Vincent A,
eLife. 2016
Each Drosophila muscle is seeded by one Founder Cell issued from terminal division of a Progenitor Cell (PC). Muscle identity reflects the expression by each PC of a specific combination of identity Transcription Factors (iTFs). Sequential emergence of several PCs at the same position raised the question of how developmental time controlled muscle identity. Here, we identified roles of Anterior Open and ETS domain lacking in controlling PC birth time and Eyes absent, No Ocelli, and Sine oculis in specifying PC identity. The windows of transcription of these and other TFs in wild type and mutant embryos, revealed a cascade of regulation integrating time and space, feed-forward loops and use of alternative transcription start sites. These data provide a dynamic view of the transcriptional control of muscle identity in Drosophila and an extended framework for studying interactions between general myogenic factors and iTFs in evolutionary diversification of muscle shapes.
Economic evaluation of the new oral anticoagulants for the prevention of thromboembolic events: a cost-minimization analysis.Thursday, July 21, 2016
Marcolino MS, Polanczyk CA, Bovendorp AC, Marques NS, Silva LA, Turquia CP, Ribeiro AL,
São Paulo medical journal = Revista paulista de medicina. 18-Jul-2016
In the Brazilian context, from the perspective of society and the public healthcare system, the cumulative costs per patient using warfarin with follow-up in anticoagulation clinics is currently higher than the strategy of prescribing the new oral anticoagulants.
Air pollution and respiratory diseases: ecological time series.Thursday, July 21, 2016
Nascimento LF, Vieira LC, Mantovani KC, Moreira DS,
São Paulo medical journal = Revista paulista de medicina. 18-Jul-2016
The findings from this study provide support for implementing public health policies in this municipality, which is an important steelmaking center.
Impact of Dietary Tomato Juice on Changes in Pulmonary Oxidative Stress, Inflammation and Structure Induced by Neonatal Hyperoxia in Mice (Mus musculus).Thursday, July 21, 2016
Bouch S, Harding R, O'Reilly M, Wood LG, Sozo F,
PloS one. 2016
Many preterm infants require hyperoxic gas for survival, although it can contribute to lung injury. Experimentally, neonatal hyperoxia leads to persistent alterations in lung structure and increases leukocytes in bronchoalveolar lavage fluid (BALF). These effects of hyperoxia on the lungs are considered to be caused, at least in part, by increased oxidative stress. Our objective was to determine if dietary supplementation with a known source of antioxidants (tomato juice, TJ) could protect the developing lung from injury caused by breathing hyperoxic gas. Neonatal mice (C57BL6/J) breathed either 65% O2 (hyperoxia) or room air from birth until postnatal day 7 (P7d); some underwent necropsy at P7d and others were raised in room air until adulthood (P56d). In subsets of both groups, drinking water was replaced with TJ (diluted 50:50 in water) from late gestation to necropsy. At P7d and P56d, we analyzed total antioxidant capacity (TAC), markers of oxidative stress (nitrotyrosine and heme oxygenase-1 expression), inflammation (interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) expression), collagen (COL) and smooth muscle in the lungs; we also assessed lung structure. We quantified macrophages in lung tissue (at P7d) and leukocytes in BALF (at P56d). At P7d, TJ increased pulmonary TAC and COL1α1 expression and attenuated the hyperoxia-induced increase in nitrotyrosine and macrophage influx; however, changes in lung structure were not affected. At P56d, TJ increased TAC, decreased oxidative stress and reversed the hyperoxia-induced increase in bronchiolar smooth muscle. Additionally, TJ alone decreased IL-1β expression, but following hyperoxia TJ increased TNF-α expression and did not alter the hyperoxia-induced increase in leukocyte number. We conclude that TJ supplementation during and after neonatal exposure to hyperoxia protects the lung from some but not all aspects of hyperoxia-induced injury, but may also have adverse side-effects. The effects of TJ are likely due to elevation of circulating antioxidant concentrations.
Current clinical approach to patients with disorders of consciousness.Thursday, July 21, 2016
Amorim RL, Nagumo MM, Paiva WS, Andrade AF, Teixeira MJ,
Revista da Associação Médica Brasileira (1992). Jul-2016
In clinical practice, hospital admission of patients with altered level of consciousness, sleepy or in a non-responsive state is extremely common. This clinical condition requires an effective investigation and early treatment. Performing a focused and objective evaluation is critical, with quality history taking and physical examination capable to locate the lesion and define conducts. Imaging and laboratory exams have played an increasingly important role in supporting clinical research. In this review, the main types of changes in consciousness are discussed as well as the essential points that should be evaluated in the clinical management of these patients.
Overweight and abdominal obesity in adults living with HIV/AIDS.Thursday, July 21, 2016
Castro Ade C, Silveira EA, Falco Mde O, Nery MW, Turchi MD,
Revista da Associação Médica Brasileira (1992). Jul-2016
There was a high prevalence of overweight and abdominal obesity associated with sociodemographic and clinical conditions, and consumption of risk foods. This scenario indicates the need for reorientation of the health care focus in this population.
Exposure to fine particulate matter and hospital admissions due to pneumonia: Effects on the number of hospital admissions and its costs.Thursday, July 21, 2016
Patto NV, Nascimento LF, Mantovani KC, Vieira LC, Moreira DS,
Revista da Associação Médica Brasileira (1992). Jul-2016
A 10 µg/m3 decrease in concentration would imply 256 less hospital admissions and savings of approximately R$ 220,000 in a medium-sized city.
Profile of pediatric eye trauma at Hospital de Base do Distrito Federal (HBDF), Brasília, Brazil.Thursday, July 21, 2016
Rohr JT, Santos PM, Santos RC, Vieira CV, Fé LM, Solano RL, Reis TF, Leão Mde O, Guimarães Vda C,
Revista da Associação Médica Brasileira (1992). Jul-2016
Ocular trauma was more frequent among boys. The mechanisms of injury are the most diverse, and prevail at home. Blunt trauma prevails, but the visual impact is due to open trauma. Programs of prevention and education on child ocular trauma are needed.
Capillary refill time in febrile neutropenia.Thursday, July 21, 2016
Ponte AG, Jácomo RH,
Revista da Associação Médica Brasileira (1992). Jul-2016
CRT higher than three seconds was effective to predict antibiotic escalation.
Prevalence of fungemia in a tertiary hospital: Analysis of the last decade.Thursday, July 21, 2016
Castro LL, Schütze M, Bücker DH, Vasconcellos Lde S,
Revista da Associação Médica Brasileira (1992). Jul-2016
There was an increase in the prevalence of fungemia in the last decade at HC-UFMG. Although candidemias have been responsible for most of the cases, there has been an increase in fungemias caused by other species.
Evaluation of the symptoms and treatment prescribed to hospitalized patients.Thursday, July 21, 2016
Roldi Mda S, Moritz RD,
Revista da Associação Médica Brasileira (1992). Jul-2016
The control of symptoms, especially those considered mild, was unsatisfactory. Drug prescription was inadequate to control pain, and non-existent for some reported symptoms. There was no adequate prioritization of PC. There is a need for optimization and dissemination of PC among health professionals.
Silencing Receptor EphA2 Enhanced Sensitivity to Lipoplatin™ in Lung Tumor and MPM Cells.Wednesday, July 20, 2016
Lee HY, Mohammed KA, Goldberg EP, Kaye F, Nasreen N,
Cancer investigation. 20-Jul-2016
Receptor EphA2 is overexpressed in lung cancer and malignant pleural mesothelioma (MPM) which promote tumorogenesis. Lipoplatin™, a new liposomal cisplatin formulation, is used against resistant tumors. Use of cisplatin-based drugs leads to unacceptable toxicities. To improve the effectiveness of Lipoplatin, enhancing the cellular sensitivity of lung tumor and MPM cells is critical. Therefore, we targeted receptor EphA2 by silencing interference RNA (siRNA) and treated tumor cells with Lipoplatin. The combined effects of siRNA-EphA2 and Lipoplatin were determined. We report that silencing EphA2 significantly enhanced the cellular sensitivity of lung tumor and MPM cells to Lipoplatin and maybe a potential therapy for lung cancer.
Long-Term Outcomes of Hematopoietic Stem Cell Transplantation for ZAP70 Deficiency.Wednesday, July 20, 2016
Cuvelier GD, Rubin TS, Wall DA, Schroeder ML,
Journal of clinical immunology. 20-Jul-2016
ZAP70 deficiency is a rare T + B + NK+ combined immunodeficiency with limited outcome data to help guide decisions around hematopoietic stem cell transplant (HSCT). We sought to understand the long-term clinical and immunologic outcomes of both conditioned and unconditioned HSCT for ZAP70 deficiency following transplant from a variety of graft sources. We performed a retrospective, single center review of all cases of HSCT for genetically confirmed ZAP70 deficiency since 1992. At a median of 13.5-year post-HSCT, 8/8 (100 %) patients are alive. Three received unconditioned bone marrow transplants from human leukocyte antigen (HLA)-matched siblings and achieved stable mixed donor-recipient T cell chimerism but low B cell (4-9 %) and absent to near-absent myeloid donor engraftment. Despite this, all three have normal immunoglobulin levels, have developed specific protective antibody responses to post-HSCT vaccinations, and have discontinued immunoglobulin replacement. Five patients received myeloablative conditioning (three T cell-depleted haploidentical and two unrelated cord blood) and have full donor chimerism for T and B cells and myeloid lineages. One patient experienced primary graft failure after serotherapy only. CD8 T cell count is normal in 5/8, high in 1/8, and low in 2/8. Infectious complications in 5/5 and autoimmune thrombocytopenia in one patient resolved post-HSCT. Mitogen proliferation to phytohemagglutinin was normal after HSCT in 8/8 patients. In total, seven have discontinued immunoglobulin replacement. In conclusion, HSCT using a variety of graft sources and approaches, including unconditioned matched sibling donor transplant, is a life-saving therapy for ZAP70 deficiency, providing excellent long-term immune function and resolution of clinical problems.
Lateral flow biosensor for multiplex detection of nitrofuran metabolites based on functionalized magnetic beads.Wednesday, July 20, 2016
Lu X, Liang X, Dong J, Fang Z, Zeng L,
Analytical and bioanalytical chemistry. 20-Jul-2016
The use of potential mutagenic nitrofuran antibiotic in food animal production has been banned world-wide. Common methods for nitrofuran detection involve complex extraction procedures. In the present study, magnetic beads functionalized with antibody against nitrofuran derivative were used as both the extraction and color developing media in lateral flow biosensor. Derivatization reagent carboxybenzaldehyde is firstly modified with ractopamine. After reaction with nitrofuran metabolites, the resultant molecule has two functional groups: the metabolite moiety and the ractopamine moiety. Metabolite moiety is captured by the antibody that is coated on magnetic beads. This duplex is then loaded onto biosensor and ractopamine moiety is further captured by the antibody immobilized on the test zone of nitrocellulose membrane. Without tedious organic reagent-based extraction procedure, this biosensor was capable of visually detecting four metabolites simultaneously with a detection limit of 0.1 μg/L. No cross-reactivity was observed in the presence of 50 μg/L interferential components. Graphical abstract Derivatization of nitrofuran metabolites (AHD, AOZ, SEM, or AMOZ) and LFA detection of the derivative products.
The dual regulatory role of miR-204 in cancer.Wednesday, July 20, 2016
Li T, Pan H, Li R,
Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine. 20-Jul-2016
MicroRNAs (miRNAs) are a group of endogenous, small (about 22 nucleotides) non-coding RNAs which negatively regulate gene expressions. As one of them, miR-204 originates from the sixth intron of the transient receptor potential melastatin 3 (TRPM3) gene. Therefore, expression of miR-204 is under the control of the TRPM3 promoter and regulated by genetic and epigenetic mechanisms. miR-204 has been found to play the important roles in development of eyes and adipogenesis. Its pathological functions have been observed in a few diseases including pulmonary arterial hypertension, diabetes, and various types of cancers. It is believed that miR-204 acts as a tumor-suppressor via promoting apoptosis, conferring the resistance of cancer cells to chemotherapy, and suppressing the self-renewal of cancer stem cells (CSCs) and the epithelial to mesenchymal transition (EMT). Expression of miR-204 is repressed by its targets XRN1 and TRKB in prostate cancer and endometrial carcinoma, respectively; therefore, they establish an oncogenic feedback loops that play an important role promoting development of cancer. In this review, we summarize our current knowledge regarding miR-204, including its expression, regulation and biological functions, especially focusing our discussion on its role in tumor development and tumor progression.
Long noncoding RNAs in normal and pathological pluripotency.Monday, July 25, 2016
Häfner SJ, Talvard TG, Lund AH,
Seminars in cell & developmental biology. 18-Jul-2016
The striking similarities between pluripotent and cancer cells, such as immortality and increased stress resistance, have long been acknowledged. Numerous studies searched for and successfully identified common molecular players and pathways, thus providing an entirely new challenge and potential therapeutic angle by targeting cancer cells or a specific stem population of the tumor via pluripotency associated processes. However, these strategies have until now mainly been restricted to proteins. Nonetheless, it has become clear over the past decade that the overwhelming majority of the genome produces noncoding transcripts, many of which have proven both functional and crucial for key cellular processes, including stemness maintenance. Moreover, numerous long noncoding RNAs are deregulated in cancer, but little is known concerning their functions and molecular mechanisms. Consequently, it seems essential to integrate the noncoding transcripts into the picture of the stemness-cancer connection. Whereas a number of studies have addressed the expression of lncRNAs in cancer stem cells, no systematic approach has yet been undertaken to identify lncRNAs implicated in the maintenance of the embryonic stemness state that is hijacked by cancer cells. The aim of this review is to highlight long noncoding RNAs with shared functions in stemness and cancer and to outline the current state of a field in its infancy, the search for long noncoding transcripts in cancer stem cells.
β1 integrin- and JNK-dependent tumor growth upon hypofractionated radiation.Friday, July 22, 2016
Sayeed A, Lu H, Liu Q, Deming Ii D, Duffy A, McCue P, Dicker AP, Davis RJ, Gabrilovich D, Rodeck U, Altieri DC, Languino LR,
Oncotarget. 11-Jul-2016
Radiation therapy is an effective cancer treatment modality although tumors invariably become resistant. Using the transgenic adenocarcinoma of mouse prostate (TRAMP) model system, we report that a hypofractionated radiation schedule (10 Gy/day for 5 consecutive days) effectively blocks prostate tumor growth in wild type (β1wt /TRAMP) mice as well as in mice carrying a conditional ablation of β1 integrins in the prostatic epithelium (β1pc-/- /TRAMP). Since JNK is known to be suppressed by β1 integrins and mediates radiation-induced apoptosis, we tested the effect of SP600125, an inhibitor of c-Jun amino-terminal kinase (JNK) in the TRAMP model system. Our results show that SP600125 negates the effect of radiation on tumor growth in β1pc-/- /TRAMP mice and leads to invasive adenocarcinoma. These effects are associated with increased focal adhesion kinase (FAK) expression and phosphorylation in prostate tumors in β1pc-/- /TRAMP mice. In marked contrast, radiation-induced tumor growth suppression, FAK expression and phosphorylation are not altered by SP600125 treatment of β1wt /TRAMP mice. Furthermore, we have reported earlier that abrogation of insulin-like growth factor receptor (IGF-IR) in prostate cancer cells enhances the sensitivity to radiation. Here we further explore the β1/IGF-IR crosstalk and report that β1 integrins promote cell proliferation partly by enhancing the expression of IGF-IR. In conclusion, we demonstrate that β1 integrin-mediated inhibition of JNK signaling modulates tumor growth rate upon hypofractionated radiation.
Cooperation of imipramine blue and tyrosine kinase blockade demonstrates activity against chronic myeloid leukemia.Wednesday, July 20, 2016
Laidlaw KM, Berhan S, Liu S, Silvestri G, Holyoake TL, Frank DA, Aggarwal B, Bonner MY, Perrotti D, Jørgensen HG, Arbiser JL,
Oncotarget. 12-Jul-2016
The use of tyrosine kinase inhibitors (TKI), including nilotinib, has revolutionized the treatment of chronic myeloid leukemia (CML). However current unmet clinical needs include combating activation of additional survival signaling pathways in persistent leukemia stem cells after long-term TKI therapy. A ubiquitous signaling alteration in cancer, including CML, is activation of reactive oxygen species (ROS) signaling, which may potentiate stem cell activity and mediate resistance to both conventional chemotherapy and targeted inhibitors. We have developed a novel nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitor, imipramine blue (IB) that targets ROS generation. ROS levels are known to be elevated in CML with respect to normal hematopoietic stem/progenitor cells and not corrected by TKI. We demonstrate that IB has additive benefit with nilotinib in inhibiting proliferation, viability, and clonogenic function of TKI-insensitive quiescent CD34+ CML chronic phase (CP) cells while normal CD34+ cells retained their clonogenic capacity in response to this combination therapy in vitro. Mechanistically, the pro-apoptotic activity of IB likely resides in part through its dual ability to block NF-κB and re-activate the tumor suppressor protein phosphatase 2A (PP2A). Combining BCR-ABL1 kinase inhibition with NADPH oxidase blockade may be beneficial in eradication of CML and worthy of further investigation.
Effect of JNK inhibitor SP600125 on hair cell regeneration in zebrafish (Danio rerio) larvae.Wednesday, July 20, 2016
He Y, Cai C, Sun S, Wang X, Li W, Li H,
Oncotarget. 12-Jul-2016
The c-Jun amino-terminal kinase (JNK) proteins are a subgroup of the mitogen-activated protein kinase family. They play a complex role in cell proliferation, survival, and apoptosis. Here, we report a novel role of JNK signalling in hair cell regeneration. We eliminated hair cells of 5-day post-fertilization zebrafish larvae using neomycin followed by JNK inhibition with SP600125. JNK inhibition strongly decreased the number of regenerated hair cells in response to neomycin damage. These changes were associated with reduced proliferation. JNK inhibition also increased cleaved caspase-3 activity and induced apoptosis in regenerating neuromasts. Finally, JNK inhibition with SP600125 decreased the expression of genes related to Wnt. Over-activation of the Wnt signalling pathway partly rescued the hair cell regeneration defects induced by JNK inhibition. Together, our findings provide novel insights into the function of JNK and show that JNK inhibition blocks hair cell regeneration by controlling the Wnt signalling pathway.
Attitudes towards family involvement in cancer treatment decision making: The perspectives of patients, family caregivers, and their oncologists.Wednesday, July 20, 2016
Shin DW, Cho J, Roter DL, Kim SY, Yang HK, Park K, Kim HJ, Shin HY, Kwon TG, Park JH,
Psycho-oncology. 20-Jul-2016
Patients, family caregivers, and to a lesser degree, oncologists expect and valued family involvement in cancer TDM. These findings support a reconsideration of traditional models focused on protection of patient autonomy to a more contextualized form of relational autonomy, whereby the patient and family caregivers can be seen as a unit for autonomous decision.
A cancer specific hypermethylation signature of the TERT promoter predicts biochemical relapse in prostate cancer: A retrospective cohort study.Wednesday, July 20, 2016
Castelo-Branco P, Leão R, Lipman T, Campbell B, Lee D, Price A, Zhang C, Heidari A, Stephens D, Boerno S, Coelho H, Gomes A, Domingos C, Apolonio JD, Schäfer G, Bristow RG, Schweiger MR, Hamilton R, Zlotta A, Figueiredo A, Klocker H, Sültmann H, Tabori U,
Oncotarget. 16-Jul-2016
The identification of new biomarkers to differentiate between indolent and aggressive prostate tumors is an important unmet need. We examined the role of THOR (TERT Hypermethylated Oncological Region) as a diagnostic and prognostic biomarker in prostate cancer (PCa).We analyzed THOR in common cancers using genome-wide methylation arrays. Methylation status of the whole TERT gene in benign and malignant prostate samples was determined by MeDIP-Seq. The prognostic role of THOR in PCa was assessed by pyrosequencing on discovery and validation cohorts from patients who underwent radical prostatectomy with long-term follow-up data.Most cancers (n = 3056) including PCa (n = 300) exhibited hypermethylation of THOR. THOR was the only region within the TERT gene that is differentially methylated between normal and malignant prostate tissue (p < 0.0001). Also, THOR was significantly hypermethylated in PCa when compared to paired benign tissues (n = 164, p < 0.0001). THOR hypermethylation correlated with Gleason scores and was associated with tumor invasiveness (p = 0.0147). Five years biochemical progression free survival (BPFS) for PCa patients in the discovery cohort was 87% (95% CI 73-100) and 65% (95% CI 52-78) for THOR non-hypermethylated and hypermethylated cancers respectively (p = 0.01). Similar differences in BPFS were noted in the validation cohort (p = 0.03). Importantly, THOR was able to predict outcome in the challenging (Gleason 6 and 7 (3 + 4)) PCa (p = 0.007). For this group, THOR was an independent risk factor for BPFS with a hazard-ratio of 3.685 (p = 0.0247). Finally, THOR hypermethylation more than doubled the risk of recurrence across all PSA levels (OR 2.5, p = 0.02).
Combination therapy with copanlisib and ABL tyrosine kinase inhibitors against Philadelphia chromosome-positive resistant cells.Wednesday, July 20, 2016
Okabe S, Tauchi T, Tanaka Y, Sakuta J, Ohyashiki K,
Oncotarget. 14-Jul-2016
ABL tyrosine kinase inhibitor (TKI) therapy has improved the survival of patients with Philadelphia (Ph) chromosome-positive leukemia. However, ABL TKIs cannot eradicate leukemia stem cells. Therefore, new therapeutic approaches for Ph-positive leukemia are needed. Aberrant activation of phosphoinositide 3-kinase (PI3K) signaling is important for the initiation and maintenance of human cancers. Copanlisib (BAY80-6946) is a potent inhibitor of PI3Kα and PI3K-δ. Here we investigated the efficacy of combination therapy of copanlisib with an ABL TKI (imatinib, nilotinib, or ponatinib) using BCR-ABL-positive cells. Although the effects of the ABL TKI treatment were reduced in the presence of the feeder cell line, HS-5, copanlisib inhibited cell growth. Upon combining ABL TKI and copanlisib, cell growth was reduced. Ponatinib and copanlisib combined therapy reduced tumor volume and increased survival in mouse allograft models, respectively. These results indicate that the PI3Kα and -δ inhibitors overcame the chemoprotective effects of the feeder cells and enhanced ABL TKI cytotoxicity. Thus, co-treatment with ABL TKI and copanlisib may be a powerful strategy against ABL TKI-resistant cells, including those harboring the related T315I mutation.
A somitic contribution to the apical ectodermal ridge is essential for fin formation.Monday, July 25, 2016
Masselink W, Cole NJ, Fenyes F, Berger S, Sonntag C, Wood A, Nguyen PD, Cohen N, Knopf F, Weidinger G, Hall TE, Currie PD,
Nature. 20-Jul-2016
The transition from fins to limbs was an important terrestrial adaptation, but how this crucial evolutionary shift arose developmentally is unknown. Current models focus on the distinct roles of the apical ectodermal ridge (AER) and the signalling molecules that it secretes during limb and fin outgrowth. In contrast to the limb AER, the AER of the fin rapidly transitions into the apical fold and in the process shuts off AER-derived signals that stimulate proliferation of the precursors of the appendicular skeleton. The differing fates of the AER during fish and tetrapod development have led to the speculation that fin-fold formation was one of the evolutionary hurdles to the AER-dependent expansion of the fin mesenchyme required to generate the increased appendicular structure evident within limbs. Consequently, a heterochronic shift in the AER-to-apical-fold transition has been postulated to be crucial for limb evolution. The ability to test this model has been hampered by a lack of understanding of the mechanisms controlling apical fold induction. Here we show that invasion by cells of a newly identified somite-derived lineage into the AER in zebrafish regulates apical fold induction. Ablation of these cells inhibits apical fold formation, prolongs AER activity and increases the amount of fin bud mesenchyme, suggesting that these cells could provide the timing mechanism proposed in Thorogood's clock model of the fin-to-limb transition. We further demonstrate that apical-fold-inducing cells are progressively lost during gnathostome evolution; the absence of such cells within the tetrapod limb suggests that their loss may have been a necessary prelude to the attainment of limb-like structures in Devonian sarcopterygian fish.
Dynamics of ribosome scanning and recycling revealed by translation complex profiling.Monday, July 25, 2016
Archer SK, Shirokikh NE, Beilharz TH, Preiss T,
Nature. 20-Jul-2016
Regulation of messenger RNA translation is central to eukaryotic gene expression control. Regulatory inputs are specified by the mRNA untranslated regions (UTRs) and often target translation initiation. Initiation involves binding of the 40S ribosomal small subunit (SSU) and associated eukaryotic initiation factors (eIFs) near the mRNA 5' cap; the SSU then scans in the 3' direction until it detects the start codon and is joined by the 60S ribosomal large subunit (LSU) to form the 80S ribosome. Scanning and other dynamic aspects of the initiation model have remained as conjectures because methods to trap early intermediates were lacking. Here we uncover the dynamics of the complete translation cycle in live yeast cells using translation complex profile sequencing (TCP-seq), a method developed from the ribosome profiling approach. We document scanning by observing SSU footprints along 5' UTRs. Scanning SSU have 5'-extended footprints (up to ~75 nucleotides), indicative of additional interactions with mRNA emerging from the exit channel, promoting forward movement. We visualized changes in initiation complex conformation as SSU footprints coalesced into three major sizes at start codons (19, 29 and 37 nucleotides). These share the same 5' start site but differ at the 3' end, reflecting successive changes at the entry channel from an open to a closed state following start codon recognition. We also observe SSU 'lingering' at stop codons after LSU departure. Our results underpin mechanistic models of translation initiation and termination, built on decades of biochemical and structural investigation, with direct genome-wide in vivo evidence. Our approach captures ribosomal complexes at all phases of translation and will aid in studying translation dynamics in diverse cellular contexts. Dysregulation of translation is common in disease and, for example, SSU scanning is a target of anti-cancer drug development. TCP-seq will prove useful in discerning differences in mRNA-specific initiation in pathologies and their response to treatment.
CD47-blocking antibodies restore phagocytosis and prevent atherosclerosis.Monday, July 25, 2016
Kojima Y, Volkmer JP, McKenna K, Civelek M, Lusis AJ, Miller CL, Direnzo D, Nanda V, Ye J, Connolly AJ, Schadt EE, Quertermous T, Betancur P, Maegdefessel L, Matic LP, Hedin U, Weissman IL, Leeper NJ,
Nature. 20-Jul-2016
Atherosclerosis is the disease process that underlies heart attack and stroke. Advanced lesions at risk of rupture are characterized by the pathological accumulation of diseased vascular cells and apoptotic cellular debris. Why these cells are not cleared remains unknown. Here we show that atherogenesis is associated with upregulation of CD47, a key anti-phagocytic molecule that is known to render malignant cells resistant to programmed cell removal, or 'efferocytosis'. We find that administration of CD47-blocking antibodies reverses this defect in efferocytosis, normalizes the clearance of diseased vascular tissue, and ameliorates atherosclerosis in multiple mouse models. Mechanistic studies implicate the pro-atherosclerotic factor TNF-α as a fundamental driver of impaired programmed cell removal, explaining why this process is compromised in vascular disease. Similar to recent observations in cancer, impaired efferocytosis appears to play a pathogenic role in cardiovascular disease, but is not a fixed defect and may represent a novel therapeutic target.
Structural organization of the inactive X chromosome in the mouse.Monday, July 25, 2016
Giorgetti L, Lajoie BR, Carter AC, Attia M, Zhan Y, Xu J, Chen CJ, Kaplan N, Chang HY, Heard E, Dekker J,
Nature. 18-Jul-2016
X-chromosome inactivation (XCI) involves major reorganization of the X chromosome as it becomes silent and heterochromatic. During female mammalian development, XCI is triggered by upregulation of the non-coding Xist RNA from one of the two X chromosomes. Xist coats the chromosome in cis and induces silencing of almost all genes via its A-repeat region, although some genes (constitutive escapees) avoid silencing in most cell types, and others (facultative escapees) escape XCI only in specific contexts. A role for Xist in organizing the inactive X (Xi) chromosome has been proposed. Recent chromosome conformation capture approaches have revealed global loss of local structure on the Xi chromosome and formation of large mega-domains, separated by a region containing the DXZ4 macrosatellite. However, the molecular architecture of the Xi chromosome, in both the silent and expressed regions, remains unclear. Here we investigate the structure, chromatin accessibility and expression status of the mouse Xi chromosome in highly polymorphic clonal neural progenitors (NPCs) and embryonic stem cells. We demonstrate a crucial role for Xist and the DXZ4-containing boundary in shaping Xi chromosome structure using allele-specific genome-wide chromosome conformation capture (Hi-C) analysis, an assay for transposase-accessible chromatin with high throughput sequencing (ATAC-seq) and RNA sequencing. Deletion of the boundary disrupts mega-domain formation, and induction of Xist RNA initiates formation of the boundary and the loss of DNA accessibility. We also show that in NPCs, the Xi chromosome lacks active/inactive compartments and topologically associating domains (TADs), except around genes that escape XCI. Escapee gene clusters display TAD-like structures and retain DNA accessibility at promoter-proximal and CTCF-binding sites. Furthermore, altered patterns of facultative escape genes in different neural progenitor clones are associated with the presence of different TAD-like structures after XCI. These findings suggest a key role for transcription and CTCF in the formation of TADs in the context of the Xi chromosome in neural progenitors.
Factors Affecting Happiness: A Cross-Sectional Study in the Iranian Youth.Wednesday, July 20, 2016
Mehrdadi A, Sadeghian S, Direkvand-Moghadam A, Hashemian A,
Journal of clinical and diagnostic research : JCDR. May-2016
The age groups, type of occupation, physical activity and place of residence were factors associated with happiness in young persons. However, there was not significant relationship between gender, marital status and education level with a happiness score among study participants.
Comparison of Hypnotherapy and Standard Medical Treatment Alone on Quality of Life in Patients with Irritable Bowel Syndrome: A Randomized Control Trial.Wednesday, July 20, 2016
Shahbazi K, Solati K, Hasanpour-Dehkordi A,
Journal of clinical and diagnostic research : JCDR. May-2016
Psychological intervention, particularly hypno-therapy, alongside standard medical therapy could contribute to improving quality of life, pain and fatigue, and psychological disorder in IBS patients resistant to treatment. Also, therapeutic costs, hospital stay and days lost from work could be decreased and patients' efficiency could be increased.
Effect of Triage Training on Concordance of Triage Level between Triage Nurses and Emergency Medical Technicians.Wednesday, July 20, 2016
Ghanbarzehi N, Balouchi A, Sabzevari S, Darban F, Khayat NH,
Journal of clinical and diagnostic research : JCDR. May-2016
It is recommended to train and use common triage system to facilitate transfer or delivery of care between emergency medical technicians and triage nurses.
Structure of a heterogeneous, glycosylated, lipid-bound, in vivo-grown protein crystal at atomic resolution from the viviparous cockroach Diploptera punctata.Wednesday, July 20, 2016
Banerjee S, Coussens NP, Gallat FX, Sathyanarayanan N, Srikanth J, Yagi KJ, Gray JS, Tobe SS, Stay B, Chavas LM, Ramaswamy S,
IUCrJ. 1-Jul-2016
Macromolecular crystals for X-ray diffraction studies are typically grown in vitro from pure and homogeneous samples; however, there are examples of protein crystals that have been identified in vivo. Recent developments in micro-crystallography techniques and the advent of X-ray free-electron lasers have allowed the determination of several protein structures from crystals grown in cellulo. Here, an atomic resolution (1.2 Å) crystal structure is reported of heterogeneous milk proteins grown inside a living organism in their functional niche. These in vivo-grown crystals were isolated from the midgut of an embryo within the only known viviparous cockroach, Diploptera punctata. The milk proteins crystallized in space group P1, and a structure was determined by anomalous dispersion from the native S atoms. The data revealed glycosylated proteins that adopt a lipocalin fold, bind lipids and organize to form a tightly packed crystalline lattice. A single crystal is estimated to contain more than three times the energy of an equivalent mass of dairy milk. This unique storage form of nourishment for developing embryos allows access to a constant supply of complete nutrients. Notably, the crystalline cockroach-milk proteins are highly heterogeneous with respect to amino-acid sequence, glycosylation and bound fatty-acid composition. These data present a unique example of protein heterogeneity within a single in vivo-grown crystal of a natural protein in its native environment at atomic resolution.
Tumorigenicity Evaluation of Umbilical Cord Blood-derived Mesenchymal Stem Cells.Wednesday, July 20, 2016
Park SJ, Kim HJ, Kim W, Kim OS, Lee S, Han SY, Jeong EJ, Park HS, Kim HW, Moon KS,
Toxicological research. Jul-2016
Mesenchymal stem cells (MSCs) have been identified in multiple types of tissue and exhibit characteristic self-renewal and multi-lineage differentiation abilities. However, the possibility of oncogenic transformation after transplantation is concerning. In this study, we investigated the tumorigenic potential of umbilical cord blood-derived MSCs (hUCB-MSCs) relative to MRC-5 and HeLa cells (negative and positive controls, respectively) both in vitro and in vivo. To evaluate tumorigenicity in vitro, anchorage-independent growth was assessed using the soft agar colony formation assay. hUCB-MSCs and MRC-5 cells formed few colonies, while HeLa cells formed a greater number of larger colonies, indicating that hUCB-MSCs and MRC-5 cells do not have anchorage-independent proliferation potential. To detect tumorigenicity in vivo, hUCB-MSCs were implanted as a single subcutaneous injection into BALB/c-nu mice. No tumor formation was observed in mice transplanted with hUCB-MSCs or MRC-5 cells based on macroand microscopic examinations; however, all mice transplanted with HeLa cells developed tumors that stained positive for a human gene according to immunohistochemical analysis. In conclusion, hUCB-MSCs do not exhibit tumorigenic potential based on in vitro and in vivo assays under our experimental conditions, providing further evidence of their safety for clinical applications.
Natural underlying mtDNA heteroplasmy as a potential source of intra-person hiPSC variability.Wednesday, July 20, 2016
Perales-Clemente E, Cook AN, Evans JM, Roellinger S, Secreto F, Emmanuele V, Oglesbee D, Mootha VK, Hirano M, Schon EA, Terzic A, Nelson TJ,
The EMBO journal. 19-Jul-2016
Functional variability among human clones of induced pluripotent stem cells (hiPSCs) remains a limitation in assembling high-quality biorepositories. Beyond inter-person variability, the root cause of intra-person variability remains unknown. Mitochondria guide the required transition from oxidative to glycolytic metabolism in nuclear reprogramming. Moreover, mitochondria have their own genome (mitochondrial DNA [mtDNA]). Herein, we performed mtDNA next-generation sequencing (NGS) on 84 hiPSC clones derived from a cohort of 19 individuals, including mitochondrial and non-mitochondrial patients. The analysis of mtDNA variants showed that low levels of potentially pathogenic mutations in the original fibroblasts are revealed through nuclear reprogramming, generating mutant hiPSCs with a detrimental effect in their differentiated progeny. Specifically, hiPSC-derived cardiomyocytes with expanded mtDNA mutations non-related with any described human disease, showed impaired mitochondrial respiration, being a potential cause of intra-person hiPSC variability. We propose mtDNA NGS as a new selection criterion to ensure hiPSC quality for drug discovery and regenerative medicine.
Age and Human Regenerative Capacity: Impact of Cardiovascular Risk Factors.Wednesday, July 20, 2016
Al Mheid I, Hayek SS, Ko YA, Akbik F, Li Q, Ghasemzadeh N, Martin G, Long Q, Hammadah M, Zafari AM, Vaccarino V, Waller EK, Quyyumi AA,
Circulation research. 19-Jul-2016
Circulating PC levels do not decline with healthy aging; RF exposure at a younger age stimulates PC mobilization whereas continued exposure is associated with lower PC levels in later life. Over the lifespan, exposure to RFs and CVD is associated with an initial stimulation and subsequent decline in circulating PC levels, which reflect endogenous regenerative capacity.
A histological atlas of the tissues and organs of neotenic and metamorphosed axolotl.Wednesday, July 20, 2016
Demircan T, İlhan AE, Aytürk N, Yıldırım B, Öztürk G, Keskin İ,
Acta histochemica. 16-Jul-2016
Axolotl (Ambystoma Mexicanum) has been emerging as a promising model in stem cell and regeneration researches due to its exceptional regenerative capacity. Although it represents lifelong lasting neoteny, induction to metamorphosis with thyroid hormones (THs) treatment advances the utilization of Axolotl in various studies. It has been reported that amphibians undergo anatomical and histological remodeling during metamorphosis and this transformation is crucial for adaptation to terrestrial conditions. However, there is no comprehensive histological investigation regarding the morphological alterations of Axolotl organs and tissues throughout the metamorphosis. Here, we reveal the histological differences or resemblances between the neotenic and metamorphic axolotl tissues. In order to examine structural features and cellular organization of Axolotl organs, we performed Hematoxylin & Eosin, Luxol-Fast blue, Masson's trichrome, Alcian blue, Orcein and Weigart's staining. Stained samples from brain, gallbladder, heart, intestine, liver, lung, muscle, skin, spleen, stomach, tail, tongue and vessel were analyzed under the light microscope. Our findings contribute to the validation of the link between newly acquired functions and structural changes of tissues and organs as observed in tail, skin, gallbladder and spleen. We believe that this descriptive work provides new insights for a better histological understanding of both neotenic and metamorphic Axolotl tissues.
Intestinal regeneration as an insect resistance mechanism to entomopathogenic bacteria.Wednesday, July 20, 2016
Castagnola A, Jurat-Fuentes JL,
Current opinion in insect science. Jun-2016
The intestinal epithelium of insects is exposed to xenobiotics and entomopathogens during the feeding developmental stages. In these conditions, an effective enterocyte turnover mechanism is highly desirable to maintain integrity of the gut epithelial wall. As in other insects, the gut of lepidopteran larvae have stem cells that are capable of proliferation, which occurs during molting and pathogenic episodes. While much is known on the regulation of gut stem cell division during molting, there is a current knowledge gap on the molecular regulation of gut healing processes after entomopathogen exposure. Relevant information on this subject is emerging from studies of the response to exposure to insecticidal proteins from the bacterium Bacillus thuringiensis (Bt) as model intoxicants. In this work we discuss currently available data on the molecular cues involved in gut stem cell proliferation, insect gut healing, and the implications of enhanced healing as a potential mechanism of resistance against Bt toxins.
Deconvoluting the complexity of microRNAs in autophagy to improve potential cancer therapy.Wednesday, July 20, 2016
Yao D, Jiang Y, Gao S, Shang L, Zhao Y, Huang J, Wang J, Yang S, Chen L,
Cell proliferation. 20-Jul-2016
MicroRNAs (miRNAs) (small, non-coding RNAs ∼22 nucleotides [nt] in length), have been estimated to regulate in the region of 30% of human gene expression at the post-transcriptional and translational levels. They are also involved in a series of important cellular processes, such as autophagy. Autophagy is well-known to be an evolutionarily conserved lysosomal degradation process in which a cell degrades long-lived proteins and damaged organelles. Recent evidence has shown that miRNAs can function as either oncogenes or tumour-suppressive genes in human cancers. Also, they are well-characterized to be crucial in tumourigenesis, as either oncogenes or tumour suppressors, by regulating autophagy. However, discovering the intricate mechanism of miRNA-modulated autophagy remains in its infancy. Thus, in this review, we focus on summarizing the dual function of oncogenic or tumour-suppressive miRNAs in regulation of autophagy and their roles in carcinogenesis, thereby revealing the regulatory mechanism of miRNA-modulated autophagy in cancer, to shed light on more novel RNA therapeutic strategies in the future.
Wysoczynski M, Adamiak M, Suszynska M, Abdel-Latif A, Ratajczak J, Ratajczak MZ,
Cell transplantation. 18-Jul-2016
It has been reported that both SCID mice and SCID patients mobilize hematopoietic stem/progenitor cells (HSPCs) poorly in response to granulocyte colony stimulating factor (G-CSF). This defect has been proposed to result from a lack of naturally occurring IgM immunoglobulins to trigger activation of the complement cascade (ComC) and release of C5 cleavage fragments crucial in the mobilization process. However, SCID individuals also have T cell deficiency, and T cells have been shown to modulate trafficking of HSPCs. To learn more about the role of T lymphocytes, we performed mobilization studies in T lymphocyte-deficient nude mice and found that these mice respond poorly to G-CSF and zymosan but are normal mobilizers in response to AMD3100. Since nude mice have normal levels of IgM immunoglobulins in peripheral blood and may activate the ComC, we focused on the potential involvement of Gr1(+) granulocytes and monocytes, which show defective maturation in these animals. Using a nude mouse mobilization model, we found further support for the proposition that proper function of Gr1(+) cells is crucial for optimal mobilization of HSPCs.
Decreased adult neurogenesis in hibernating Syrian hamster.Monday, July 25, 2016
León-Espinosa G, García E, Gómez-Pinedo U, Hernández F, DeFelipe J, Ávila J,
Neuroscience. 18-Jul-2016
Generation of new neurons from adult neural stem cells occurs in the dentate gyrus (DG) of the hippocampus and the lateral walls of the lateral ventricles. In this article, we study the neurogenesis that takes place during the hibernation of the Syrian hamster (Mesocricetus auratus). Using a variety of standard neurogenesis markers and 5-bromo-2-deoxyuridine (BrdU) incorporation, we describe a preferential decrease in the proliferation of newborn neurons in the subventricular zone (SVZ) of the hibernating hamsters (torpor) rather than in the hippocampus. Furthermore, we demonstrate that the proliferative capacity is recovered after 3-4days of torpor when arousal is triggered under natural conditions (i.e., not artificially provoked). In addition, we show that tau3R, a tau isoform with three microtubule-binding domains, is a suitable marker to study neurogenesis both in the SVZ and subgranular zone (SGZ) of the Syrian hamster brain.
Involvement of Luteinizing Hormone in Alzheimer Disease Development in Elderly Women.Wednesday, July 20, 2016
Rao CV,
Reproductive sciences (Thousand Oaks, Calif.). 19-Jul-2016
Alzheimer disease (AD) is a slow progressive neurodegenerative disease that affects more elderly women than elderly men. It impairs memory, typically progresses into multidomain cognitive decline that destroys the quality of life, and ultimately leads to death. About 5.3 million older Americans are now living with this disease, and this number is projected to rise to 14 million by 2050. Annual health-care costs in the United States alone are projected to increase to about US$1.1 trillion by 2050. The initial theory that decreasing estrogen levels leads to AD development in postmenopausal women has been proven inconclusive. For example, Women's Health Research Initiative Memory Study and the population-based nested case-control study have failed to demonstrate that estrogen/progesterone (hormone replacement therapy [HRT]) or estrogen replacement therapy could prevent the cognitive decline or reduce the risk of AD. This led to the realization that AD development could be due to a progressive increase in luteinizing hormone (LH) levels in postmenopausal women. Accordingly, a large number of studies have demonstrated that an increase in LH levels is positively correlated with neuropathological, behavioral, and cognitive changes in AD. In addition, LH has been shown to promote amyloidogenic pathway of precursor protein metabolism and deposition of amyloid β plaques in the hippocampus, a region involved in AD. Cognate receptors that mediate LH effects are abundantly expressed in the hippocampus. Reducing the LH levels by treatment with gonadotropin-releasing hormone agonists could provide therapeutic benefits. Despite these advances, many questions remain and require further research.
Source: NCBI - Disclaimer and Copyright notice
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