Publication date: Available online 24 June 2017
Source:Human Pathology
Author(s): Yamini Krishna, Conni McCarthy, Helen Kalirai, Sarah E. Coupland
Current treatments for metastatic uveal melanoma (mUM) are limited and rarely prolong patient survival. Immunotherapy trials for mUM are few, and to-date have demonstrated only marginal success. High densities of tumour-associated-macrophages (TAMs) and infiltrating T-lymphocytes (TILs) in primary UM are associated with poor prognosis. Little is known about the immune microenvironment of mUM. Our aim was to examine the presence and distribution of TAMs and TILs in mUM within the liver. Whole tissue-sections of liver mUM (n=35) were examined by immunohistochemistry. For TAMs, monoclonal-antibodies (mAbs) against CD68 and CD163 were used. Macrophage density and morphology were scored using previous established systems. Density and spatial-distribution of TILs were highlighted using Abs against CD3 (pan-lymphocyte marker), CD4 (T-helper cells) and CD8 (T-cytotoxic cells). CD68+ and CD163+ TAMs were seen within the tumour in all 35 specimens; their density was 'moderate' in 50% of cases, 'few' in 43% and the majority showed an 'indeterminate' phenotype. CD3+ TILs were noted both within mUMs and surrounding the tumour. Of these CD8+ TILs were 'few' in number within mUM but were predominantly seen peri-tumourally at the tumour/normal liver interface, whilst CD4+ TILs showed a high perivascular density within mUM. CD68+ and CD163+ TAMs of 'indeterminate' morphology were observed in mUM, suggesting a tendency towards the pro-tumourigenic M2-phenotype. CD4+ TILs were seen within the mUM, whereas CD8+ TILs tended to be peri-tumoural. The biological and functional roles of inflammatory cells in mUM requires further investigation, to determine if they represent potential targets for future therapies in mUM.
http://ift.tt/2t3IbWO
Σάββατο 24 Ιουνίου 2017
Inflammatory cell infiltrates in advanced metastatic uveal melanoma
Clinical and pathological factors related to brain relapse–free survival in breast cancer patients
Publication date: Available online 24 June 2017
Source:Human Pathology
Author(s): Kadri Altundag
http://ift.tt/2u18tX9
High tumor budding count is associated with adverse clinicopathologic features and poor prognosis in breast carcinoma
Publication date: Available online 24 June 2017
Source:Human Pathology
Author(s): Xiaoxian Li, Bo Wei, Ceyda Sonmez, Zaibo Li, Limin Peng
This study is to address the significance of tumor budding (TB) in breast carcinoma. Totally 244 estrogen receptor-positive (ER+)/HER2-negative (HER2-) and 131 triple-negative breast carcinoma (TNBC) diagnosed from 2004 to 2014 were analyzed. TB (cluster of up to 5 tumor cells at the invasive front) was evaluated using five 200x high power field (HPF) at the hotspot. The highest TB (H-TB) in 1 HPF and average TB (A-TB) in 5 HPFs were correlated with lymph node and distant metastasis, lymphovascular invasion (LVI), local recurrence, overall survival (OS), disease-free survival (DFS). In ER+/HER2- cancer, H-TB and A-TB were significantly associated with distant metastasis. In TNBC, H-TB was associated with distant metastasis by univariate but not multivariate analysis; H-TB and A-TB were associated with LVI and worse OS (all P<.05). TB is associated with poor prognosis in ER+/HER2- and TNBC cancer. Evaluation of H-TB may be sufficient in breast carcinoma.
http://ift.tt/2t3QbHD
Postprandial hyperinsulinemic hypoglycemia in a child as a late complication of esophageal reconstruction
Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print
http://ift.tt/2s39rWu
Impact of discontinuation of growth hormone treatment on lipids and weight status in adolescents
Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print
http://ift.tt/2sO7zy1
Clinical evaluation and mutational analysis of GALK and GALE genes in patients with galactosemia in Greece: one novel mutation and two rare cases
Journal Name: Journal of Pediatric Endocrinology and Metabolism
Issue: Ahead of print
http://ift.tt/2s3vU5u
Global incidence of oral and oropharynx cancer in patients younger than 45 years versus older patients: A systematic review
Source:European Journal of Cancer, Volume 82
Author(s): Aisha A. Hussein, Marco N. Helder, Jan G. de Visscher, C. René Leemans, Boudewijn J. Braakhuis, Henrica C.W. de Vet, Tymour Forouzanfar
Head and neck squamous cell carcinoma (HNSCC) is typically regarded as a disease of elderly people. However, increasing numbers of patients worldwide with HNSCC at younger age (defined as <45 years old) have been reported in recent years.To assess geographical variations and trends worldwide in incidence of oral and oropharyngeal cancer in young patients, a systematic review was conducted in PubMed and Google scholar databases from 1975 to June 2016. Seventy-eight studies were selected for further study.Nineteen population-based studies on incidence rate were available from 13 countries, showing a prominent increase over time except for the Netherlands. A notable rise of oral (mobile) tongue cancer among white women and oropharyngeal cancer in white men was observed. Data suggest that cancer in young patients may be a distinct clinical entity and characterised by different aetiology and pathogenesis. Additionally, the relative proportion of oral and oropharyngeal cancer in young patients to total incidence revealed a significant difference between estimates from North America (5.5%) and both Africa (17.2%) and Middle East (14.5%).It is concluded that (i) a rising trend in oral and oropharynx cancers is observed in young patients worldwide; (ii) incidence studies should properly define outcomes in age cohorts and use a consensus cut-off for young patients; (iii) more population-based studies should be performed in non-Western regions to get accurate global measures of incidence for these cancers in young subpopulations and (iv) there is an urge to identify new aetiological factors in these young patients.
http://ift.tt/2u1sQ6u
MD-2 regulates LPS-induced NLRP3 inflammasome activation and IL-1beta secretion by a MyD88/NF-κB-dependent pathway in alveolar macrophages cell line
Source:Molecular Immunology, Volume 90
Author(s): Man Luo, Lijuan Hu, Dandan Li, Yanying Wang, Yuting He, Lei Zhu, Weiying Ren
Myeloid differentiation protein 2 (MD-2) is required in the recognition of lipopolysaccharide (LPS) by toll-like receptor 4 (TLR4), and participates in LPS-induced alveolar macrophage (AM) inflammation during acute lung injury (ALI). Activation of the NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome aggravates inflammation in LPS-induced ALI. However, there is currently little known about the relationship between MD-2 signaling and the NLRP3 inflammasome. This study showed that NLRP3 expression, IL-1beta (IL-1β) secretion, and pyroptosis were up-regulated after LPS stimulation in the NR8383 AM cell-line. MD-2 gene knock-down reduced LPS-induced mRNA and protein expression of NLRP3 and IL-1β secretion in NR8383 cells, and inhibited the MyD88/NF-κB signaling pathway. Conversely, over-expression of MD-2 not only heightened NLRP3, MyD88, and NF-κB p65 protein expression, it also aggravated the LPS-induced inflammatory response. Furthermore, the NF-κB inhibitor SN50 had a beneficial role in decreasing NLRP3 and caspase-1 mRNA and protein expression. The observations suggest that MD-2 helps to regulate LPS-induced NLRP3 inflammasome activation and the inflammatory response in NR8383 cells, and likely does so by affecting MyD88/NF-κB signaling.
http://ift.tt/2sCWh13
Chronometric investigations of the Middle to Upper Paleolithic transition in the Zagros Mountains using AMS radiocarbon dating and Bayesian age modelling
Source:Journal of Human Evolution, Volume 109
Author(s): Lorena Becerra-Valdivia, Katerina Douka, Daniel Comeskey, Behrouz Bazgir, Nicholas J. Conard, Curtis W. Marean, Andreu Ollé, Marcel Otte, Laxmi Tumung, Mohsen Zeidi, Thomas F.G. Higham
The Middle to Upper Paleolithic transition is often linked with a bio-cultural shift involving the dispersal of modern humans outside of Africa, the concomitant replacement of Neanderthals across Eurasia, and the emergence of new technological traditions. The Zagros Mountains region assumes importance in discussions concerning this period as its geographic location is central to all pertinent hominin migration areas, pointing to both east and west. As such, establishing a reliable chronology in the Zagros Mountains is crucial to our understanding of these biological and cultural developments. Political circumstance, coupled with the poor preservation of organic material, has meant that a clear chronological definition of the Middle to Upper Paleolithic transition for the Zagros Mountains region has not yet been achieved. To improve this situation, we have obtained new archaeological samples for AMS radiocarbon dating from three sites: Kobeh Cave, Kaldar Cave, and Ghār-e Boof (Iran). In addition, we have statistically modelled previously published radiocarbon determinations for Yafteh Cave (Iran) and Shanidar Cave (Iraqi Kurdistan), to improve their chronological resolution and enable us to compare the results with the new dataset. Bayesian modelling results suggest that the onset of the Upper Paleolithic in the Zagros Mountains dates to 45,000–40,250 cal BP (68.2% probability). Further chronometric data are required to improve the precision of this age range.
http://ift.tt/2t344FV
MLC tracking for lung SABR reduces planning target volumes and dose to organs at risk
Source:Radiotherapy and Oncology
Author(s): Vincent Caillet, Paul J. Keall, Emma Colvill, Nicholas Hardcastle, Ricky O'Brien, Kathryn Szymura, Jeremy T. Booth
PurposeAssess the dosimetric impact of multi-leaf collimator (MLC) tracking and mid-ventilation (midV) planning compared with the internal target volume (ITV)-based planning approach for lung Stereotactic Ablative Body Radiotherapy (SABR).MethodTen lung SABR patients originally treated with an ITV-based plan were re-planned according to MLC tracking and midV planning schemes. All plans were delivered on a linac to a motion phantom in a simulated treatment with real lung motions. Delivered dose was reconstructed in patient planning scans. ITV-based, tracking and midV regimes were compared at the planning and delivered stages based on PTV volume and dose metrics for the GTV and OAR.ResultsMLC tracking and midV schemes yielded favourable outcomes compared with ITV-based plans. Average reduction in PTV volume was (MLC tracking/MidV) 33.9%/22%. GTV dose coverage performed better with MLC tracking than the other regimes. Reduction in dose to OAR were for the lung (mean lung dose, 0.8Gy/0.2Gy), oesophagus (D3cc, 1.9Gy/1.4Gy), great vessels (D10cc, 3.2Gy/1.3Gy), trachea (D4cc, 1.1Gy/0.9Gy), heart (D1cc, 2.0Gy/0.5Gy) and spinal cord (D0.03cc, 0.5Gy/−0.1Gy).ConclusionMLC tracking showed reduction in PTV volume, superior GTV dose coverage and organ dose sparing than MidV and ITV-based strategies.
http://ift.tt/2sCoC7s
Progesterone-Mediated Non-Classical Signaling
Publication date: Available online 23 June 2017
Source:Trends in Endocrinology & Metabolism
Author(s): Deepika Garg, Sinnie Sin Man Ng, K. Maravet Baig, Paul Driggers, James Segars
Progesterone is essential for pregnancy maintenance and menstrual cycle regulation. Hormone action has been primarily ascribed to the well-characterized classical signaling pathway involving ligand binding, activation of nuclear progesterone receptors (PRs), and subsequent activation of genes containing progesterone response elements (PREs). Recent studies have revealed progesterone actions via non-classical signaling pathways, often mediated by non-genomic signaling. Progesterone signaling, in conjunction with growth factor signaling, impacts on the function of growth factors and regulates important physiological actions such as cell growth and remodeling, as well as apoptosis. This review focuses on non-classical progesterone signaling pathways, both including and excluding PR, and highlights how research in this area will provide a better understanding of progesterone actions and may inform novel therapeutic strategies.
http://ift.tt/2sNttkG
Novel Structural Insights into GPCR–β-Arrestin Interaction and Signaling
Source:Trends in Cell Biology
Author(s): Ravi Ranjan, Hemlata Dwivedi, Mithu Baidya, Mohit Kumar, Arun K. Shukla
G protein-coupled receptors (GPCRs) are major signal recognition and transmission units in the plasma membrane. The interaction of activated and phosphorylated GPCRs with the multifunctional adaptor proteins β-arrestins (βarrs) is crucial for regulation of their signaling and functional outcomes. Over the past few years, a range of structural, biochemical, and cellular studies have revealed novel insights into GPCR–βarr interaction and signaling. Some of these findings have come as a surprise and therefore have the potential to significantly refine the conceptual framework of the GPCR–βarr system. Here we discuss these recent advances with particular emphasis on biphasic GPCR–βarr interaction, the formation of GPCR–G-protein–βarr supercomplexes, and receptor-specific conformational signatures in βarrs. We also underline the emerging research areas that are likely to be at the center stage of investigations in the coming years.
http://ift.tt/2sNmbNN
Local anaesthesia and nerve damage
Abstract
In a series of 5 lectures to dental practitioners in 2010-11 in New Zealand and Australia given by the Australian Dental Association's Dental Therapeutics Committee, course delegates were asked if they had experienced, or knew of others who had, patient(s) sustaining nerve damage after local anaesthetic injections. Of a total of 253 attendees at these courses, there were 18 instances, reported by a show of hands.
This article is protected by copyright. All rights reserved.
http://ift.tt/2t3b4mk
The course and distribution of the buccal nerve: clinical relevance in dentistry
Abstract
Background
The buccal branch of the mandibular division of the trigeminal nerve is commonly anaesthetised for dental procedures and may be damaged during surgery. Descriptions of the distribution of the buccal nerve (BN) in anatomical texts are generally lacking in detail and do not provide information about the extent of its variation between individuals. There are also commonly-held clinical beliefs about the BN that lack support from anatomical dissections.
Methods
Detailed dissections of the course and distribution of the BN were performed in a sample of 12 hemi-heads from 11 edentulous and partially dentate human adult cadavers.
Results
A broader distribution of the BN was found than described previously, with innervation extending to the lips in all cases. Approximately half of the lateral sides of the lips were innervated by the BN in two cases and approximately one-third of their lateral sides in the other 10 cases. Distribution of the BN to the lower lips was wider than to the upper lips.
Conclusions
Our findings provide a stronger anatomical basis to underpin clinical procedures involving the BN and indicate that some commonly-held clinical views about this nerve are not supported by anatomical evidence.
This article is protected by copyright. All rights reserved.
http://ift.tt/2u0MKi1
Characteristics and effects of dissolved organic phosphorus from different sources on the water quality of Erhai Lake in Southwest China
Abstract
To establish the influence of dissolved organic phosphorus (DOP) from different sources on the water quality of Erhai Lake in August 2014, enzymatic hydrolysis technology was used to characterize enzymatically hydrolyzable phosphorus (EHP). The results indicate that the DOP represents a significant source of the bioavailable P in the lake water and its different sources of Erhai Lake, and the bioavailability of the P pool may be underestimated by up to 55% if DOP is ignored and only the soluble-reactive phosphorus (SRP) is considered. The significant differences in DOP characteristics from the different sources may be related to the origin of the DOP, regional pollution, and environmental factors. The DOP from the sediment porewater can act as an important source of DOP in the lake water based on its high DOP content and high DOP loads from the sediment release. In addition, the highest EHP loads from the sediment release can threaten the water quality of Erhai Lake and sustain the algal blooms when they occur. Therefore, for the protection of Erhai Lake, the contributions of not only the SRP but also the DOP to the bioavailable P pool should be considered, emphasizing the eutrophication risk caused by DOP from sediments, especially in the middle section of Erhai Lake. The effects of DOP from the inflowing rivers on the water quality should also not be ignored, due to its high bioavailability.
http://ift.tt/2t6S1bD
Keep Them Close: PRC2 Poises Enhancer-Promoter Interactions at Anterior Neuronal Genes
Publication date: 4 May 2017
Source:Cell Stem Cell, Volume 20, Issue 5
Author(s): Giulia Caglio, Elena Torlai Triglia, Ana Pombo
Enhancers exist in different epigenetic states: active, primed, or poised. However, it is not yet understood how the different enhancer states influence gene activation. In this issue of Cell Stem Cell, Cruz-Molina et al. (2017) unravel how poised enhancers activate anterior neural genes and the role of Polycomb proteins in enhancer-promoter contacts.
Teaser
Enhancers exist in different epigenetic states: active, primed, or poised. However, it is not yet understood how the different enhancer states influence gene activation. In this issue of Cell Stem Cell, Cruz-Molina et al. (2017) unravel how poised enhancers activate anterior neural genes and the role of Polycomb proteins in enhancer-promoter contacts.http://ift.tt/2p3vWZA
Direct Reprogramming of Fibroblasts via a Chemically Induced XEN-like State
Publication date: Available online 22 June 2017
Source:Cell Stem Cell
Author(s): Xiang Li, Defang Liu, Yantao Ma, Xiaomin Du, Junzhan Jing, Lipeng Wang, Bingqing Xie, Da Sun, Shaoqiang Sun, Xueqin Jin, Xu Zhang, Ting Zhao, Jingyang Guan, Zexuan Yi, Weifeng Lai, Ping Zheng, Zhuo Huang, Yanzhong Chang, Zhen Chai, Jun Xu, Hongkui Deng
Direct lineage reprogramming, including with small molecules, has emerged as a promising approach for generating desired cell types. We recently found that during chemical induction of induced pluripotent stem cells (iPSCs) from mouse fibroblasts, cells pass through an extra-embryonic endoderm (XEN)-like state. Here, we show that these chemically induced XEN-like cells can also be induced to directly reprogram into functional neurons, bypassing the pluripotent state. The induced neurons possess neuron-specific expression profiles, form functional synapses in culture, and further mature after transplantation into the adult mouse brain. Using similar principles, we were also able to induce hepatocyte-like cells from the XEN-like cells. Cells in the induced XEN-like state were readily expandable over at least 20 passages and retained genome stability and lineage specification potential. Our study therefore establishes a multifunctional route for chemical lineage reprogramming and may provide a platform for generating a diverse range of cell types via application of this expandable XEN-like state.
Graphical abstract
Teaser
In this article, Deng and colleagues show that functional neurons and hepatocytes can be induced from fibroblasts via a chemically induced and highly expandable XEN-like state, bypassing the pluripotent stage. This featured lineage reprogramming strategy would be generalized for generating other functional desirable cell types.http://ift.tt/2sxw5Vw
Hematopoiesis: Reconciling Historic Controversies about the Niche
Publication date: 4 May 2017
Source:Cell Stem Cell, Volume 20, Issue 5
Author(s): Ninib Baryawno, Nicolas Severe, David T. Scadden
The niche, as first conceptualized, was in conflict with the prevailing wisdom that stem cells have internal logic. The niche hypothesis has been indisputably confirmed. Yet, recent findings indicate little plasticity of epigenetically scripted hematopoietic stem/progenitors. Reconciling this conflict requires re-envisioning the niche as an enabler, not designer, of cell fate.
Teaser
The niche, as first conceptualized, was in conflict with the prevailing wisdom that stem cells have internal logic. The niche hypothesis has been indisputably confirmed. Yet, recent findings indicate little plasticity of epigenetically scripted hematopoietic stem/progenitors. Reconciling this conflict requires re-envisioning the niche as an enabler, not designer, of cell fate.http://ift.tt/2pfAiZU
Differentiation of Human Pluripotent Stem Cells into Colonic Organoids via Transient Activation of BMP Signaling
Publication date: Available online 22 June 2017
Source:Cell Stem Cell
Author(s): Jorge O. Múnera, Nambirajan Sundaram, Scott A. Rankin, David Hill, Carey Watson, Maxime Mahe, Jefferson E. Vallance, Noah F. Shroyer, Katie L. Sinagoga, Adrian Zarzoso-Lacoste, Jonathan R. Hudson, Jonathan C. Howell, Praneet Chatuvedi, Jason R. Spence, John M. Shannon, Aaron M. Zorn, Michael A. Helmrath, James M. Wells
Gastric and small intestinal organoids differentiated from human pluripotent stem cells (hPSCs) have revolutionized the study of gastrointestinal development and disease. Distal gut tissues such as cecum and colon, however, have proved considerably more challenging to derive in vitro. Here we report the differentiation of human colonic organoids (HCOs) from hPSCs. We found that BMP signaling is required to establish a posterior SATB2+ domain in developing and postnatal intestinal epithelium. Brief activation of BMP signaling is sufficient to activate a posterior HOX code and direct hPSC-derived gut tube cultures into HCOs. In vitro, HCOs express colonic markers and contained colon-specific cell populations. Following transplantation into mice, HCOs undergo morphogenesis and maturation to form tissue that exhibits molecular, cellular, and morphologic properties of human colon. Together these data show BMP-dependent patterning of human hindgut into HCOs, which will be valuable for studying diseases including colitis and colon cancer.
Graphical abstract
Teaser
Múnera et al. report the generation of pluripotent stem cell (PSC)-derived human colonic organoids (HCOs). They first find that a conserved BMP-HOX pathway is required to establish posterior identity and then show that activating BMP signaling in human PSC-derived CDX2+ gut tube spheroids generates HCOs that retain colonic identity after transplantation.http://ift.tt/2sxnYbn
Single-Cell RNA-Seq Analysis Maps Development of Human Germline Cells and Gonadal Niche Interactions
Publication date: 1 June 2017
Source:Cell Stem Cell, Volume 20, Issue 6
Author(s): Li Li, Ji Dong, Liying Yan, Jun Yong, Xixi Liu, Yuqiong Hu, Xiaoying Fan, Xinglong Wu, Hongshan Guo, Xiaoye Wang, Xiaohui Zhu, Rong Li, Jie Yan, Yuan Wei, Yangyu Zhao, Wei Wang, Yixin Ren, Peng Yuan, Zhiqiang Yan, Boqiang Hu, Fan Guo, Lu Wen, Fuchou Tang, Jie Qiao
Human fetal germ cells (FGCs) are precursors to sperm and eggs and are crucial for maintenance of the species. However, the developmental trajectories and heterogeneity of human FGCs remain largely unknown. Here we performed single-cell RNA-seq analysis of over 2,000 FGCs and their gonadal niche cells in female and male human embryos spanning several developmental stages. We found that female FGCs undergo four distinct sequential phases characterized by mitosis, retinoic acid signaling, meiotic prophase, and oogenesis. Male FGCs develop through stages of migration, mitosis, and cell-cycle arrest. Individual embryos of both sexes simultaneously contain several subpopulations, highlighting the asynchronous and heterogeneous nature of FGC development. Moreover, we observed reciprocal signaling interactions between FGCs and their gonadal niche cells, including activation of the bone morphogenic protein (BMP) and Notch signaling pathways. Our work provides key insights into the crucial features of human FGCs during their highly ordered mitotic, meiotic, and gametogenetic processes in vivo.
Graphical abstract
Teaser
Li et al. interrogate the transcriptomes of over 2,000 fetal germ cells (FGCs) and their gonadal niche cells from male and female human embryos using single-cell RNA-seq analysis. They provide insights into the developmental trajectories and heterogeneity in FGCs over a wide range of developmental stages.http://ift.tt/2pagKZg
Integrin α7 Is a Functional Marker and Potential Therapeutic Target in Glioblastoma
Publication date: Available online 9 June 2017
Source:Cell Stem Cell
Author(s): Tobias L. Haas, Maria Rita Sciuto, Lidia Brunetto, Cecilia Valvo, Michele Signore, Micol E. Fiori, Simona di Martino, Stefano Giannetti, Liliana Morgante, Alessandra Boe, Michele Patrizii, Uwe Warnken, Martina Schnölzer, Andrea Ciolfi, Chiara Di Stefano, Mauro Biffoni, Lucia Ricci-Vitiani, Roberto Pallini, Ruggero De Maria
Functionally relevant markers of glioblastoma stem-like cells (GSCs) have potential for therapeutic targeting to treat this aggressive disease. Here we used generation and screening of thousands of monoclonal antibodies to search for receptors and signaling pathways preferentially enriched in GSCs. We identified integrin α7 (ITGA7) as a major laminin receptor in GSCs and in primary high-grade glioma specimens. Analyses of mRNA profiles in comprehensive datasets revealed that high ITGA7 expression negatively correlated with survival of patients with both low- and high-grade glioma. In vitro and in vivo analyses showed that ITGA7 plays a key functional role in growth and invasiveness of GSCs. We also found that targeting of ITGA7 by RNAi or blocking mAbs impaired laminin-induced signaling, and it led to a significant delay in tumor engraftment plus a strong reduction in tumor size and invasion. Our data, therefore, highlight ITGA7 as a glioblastoma biomarker and candidate therapeutic target.
Graphical abstract
Teaser
Haas et al. identify integrin α7 as a functional marker of glioblastoma stem cells by screening a monoclonal antibody library generated against primary glioblastoma (GBM) cells. Functional experiments in culture and in vivo show that the targeting of integrin α7 has potential as a therapeutic avenue for treating this aggressive disease.http://ift.tt/2r5U5f3
Synthetic Embryos: Windows into Mammalian Development
Publication date: 4 May 2017
Source:Cell Stem Cell, Volume 20, Issue 5
Author(s): Aryeh Warmflash
Mammalian embryonic stem cells (ESCs) can self-organize in vitro, but whether they can recreate early embryonic morphogenesis is unclear. Harrison et al. recently demonstrate in Science that 3D co-cultures of mouse ESCs and trophoblast stem cells self-organize into embryo-like structures that recreate many features of early mouse development.
Teaser
Mammalian embryonic stem cells (ESCs) can self-organize in vitro, but whether they can recreate early embryonic morphogenesis is unclear. Harrison et al. recently demonstrate in Science that 3D co-cultures of mouse ESCs and trophoblast stem cells self-organize into embryo-like structures that recreate many features of early mouse development.http://ift.tt/2p3JCnK
Lineage Tracing across 10 Years
Publication date: 1 June 2017
Source:Cell Stem Cell, Volume 20, Issue 6
Author(s): Sheila Chari, Anh Nguyen, Jonathan Saxe, Deborah J. Sweet
http://ift.tt/2slAwjW
Gli-fully Halting the Progression of Fibrosis
Publication date: 1 June 2017
Source:Cell Stem Cell, Volume 20, Issue 6
Author(s): Christian F. Guerrero-Juarez, Maksim V. Plikus
Activating triggers, selective markers, and the residual regenerative potential of scar-forming myofibroblasts are largely determined by their origin. In this issue of Cell Stem Cell, Schneider et al. report that bone marrow myofibroblasts derive from Gli1+ mesenchymal stromal cells and that a Gli inhibitor targets them for elimination in mice and humans, ameliorating fibrosis.
Teaser
Activating triggers, selective markers, and the residual regenerative potential of scar-forming myofibroblasts are largely determined by their origin. In this issue of Cell Stem Cell, Schneider et al. report that bone marrow myofibroblasts derive from Gli1+ mesenchymal stromal cells and that a Gli inhibitor targets them for elimination in mice and humans, ameliorating fibrosis.http://ift.tt/2qNuHtu
Dynamic Reorganization of Chromatin Accessibility Signatures during Dedifferentiation of Secretory Precursors into Lgr5+ Intestinal Stem Cells
Publication date: Available online 22 June 2017
Source:Cell Stem Cell
Author(s): Unmesh Jadhav, Madhurima Saxena, Nicholas K. O'Neill, Assieh Saadatpour, Guo-Cheng Yuan, Zachary Herbert, Kazutaka Murata, Ramesh A. Shivdasani
Replicating Lgr5+ stem cells and quiescent Bmi1+ cells behave as intestinal stem cells (ISCs) in vivo. Disrupting Lgr5+ ISCs triggers epithelial renewal from Bmi1+ cells, from secretory or absorptive progenitors, and from Paneth cell precursors, revealing a high degree of plasticity within intestinal crypts. Here, we show that GFP+ cells from Bmi1GFP mice are preterminal enteroendocrine cells and we identify CD69+CD274+ cells as related goblet cell precursors. Upon loss of native Lgr5+ ISCs, both populations revert toward an Lgr5+ cell identity. While active histone marks are distributed similarly between Lgr5+ ISCs and progenitors of both major lineages, thousands of cis elements that control expression of lineage-restricted genes are selectively open in secretory cells. This accessibility signature dynamically converts to that of Lgr5+ ISCs during crypt regeneration. Beyond establishing the nature of Bmi1GFP+ cells, these findings reveal how chromatin status underlies intestinal cell diversity and dedifferentiation to restore ISC function and intestinal homeostasis.
Graphical abstract
Teaser
Jadhav et al. identify an active enhancer signature that distinguishes Lgr5+ intestinal stem cells (ISCs) from Bmi1GFP+ and other secretory cells, including CD69+CD274+ goblet cell precursors. These specialized cells dedifferentiate into Lgr5+ ISCs in response to stem cell attrition, which is accompanied by dynamic rearrangements in open chromatin signatures.http://ift.tt/2sxkNAy
Surface Markers Guide the Journey toward Naive Pluripotency
Publication date: 1 June 2017
Source:Cell Stem Cell, Volume 20, Issue 6
Author(s): Peter Karagiannis, Yasuhiro Takashima
Several protocols have managed to reset human primed PSCs to the naive state. In this issue of Cell Stem Cell, Collier et al. (2017) report a set of surface markers that identify which cells are susceptible to resetting and suggest a potential roadmap for the acquisition of naive pluripotency.
Teaser
Several protocols have managed to reset human primed PSCs to the naive state. In this issue of Cell Stem Cell, Collier et al. (2017) report a set of surface markers that identify which cells are susceptible to resetting and suggest a potential roadmap for the acquisition of naive pluripotency.http://ift.tt/2slSK58
Single-Cell RNA-Seq Analysis Maps Development of Human Germline Cells and Gonadal Niche Interactions
Publication date: 1 June 2017
Source:Cell Stem Cell, Volume 20, Issue 6
Author(s): Li Li, Ji Dong, Liying Yan, Jun Yong, Xixi Liu, Yuqiong Hu, Xiaoying Fan, Xinglong Wu, Hongshan Guo, Xiaoye Wang, Xiaohui Zhu, Rong Li, Jie Yan, Yuan Wei, Yangyu Zhao, Wei Wang, Yixin Ren, Peng Yuan, Zhiqiang Yan, Boqiang Hu, Fan Guo, Lu Wen, Fuchou Tang, Jie Qiao
http://ift.tt/2rMrCPC
Adipocytes at the Core of Bone Function
Publication date: 1 June 2017
Source:Cell Stem Cell, Volume 20, Issue 6
Author(s): Gerald Grandl, Christian Wolfrum
Marrow adipose tissue (MAT) is a specialized adipose tissue with endocrine function found in bone marrow. In this issue of Cell Stem Cell, Ambrosi et al. (2017) identify a stem cell population in the bone marrow that can give rise to both osteogenic and adipogenic MAT precursors and is regulated by diet and aging and affects bone functionality.
Teaser
Marrow adipose tissue (MAT) is a specialized adipose tissue with endocrine function found in bone marrow. In this issue of Cell Stem Cell, Ambrosi et al. (2017) identify a stem cell population in the bone marrow that can give rise to both osteogenic and adipogenic MAT precursors and is regulated by diet and aging and affects bone functionality.http://ift.tt/2rM8Wzh
Gotta Have GATA for Human Pancreas Development
Publication date: 4 May 2017
Source:Cell Stem Cell, Volume 20, Issue 5
Author(s): David S. Lorberbaum, Lori Sussel
Haploinsufficient GATA6 mutations are associated with human pancreatic agenesis. Shi et al. (2017) in this issue of Cell Stem Cell and Tiyaboonchai et al. (2017) in a recent issue of Cell Reports utilize hPSCs to characterize GATA6 function during human pancreas development. One functional copy of GATA6 is sufficient for definitive endoderm development and pancreas formation, but it is inadequate for functional β cell differentiation.
Teaser
Haploinsufficient GATA6 mutations are associated with human pancreatic agenesis. Shi et al. (2017) in this issue of Cell Stem Cell and Tiyaboonchai et al. (2017) in a recent issue of Cell Reports utilize hPSCs to characterize GATA6 function during human pancreas development. One functional copy of GATA6 is sufficient for definitive endoderm development and pancreas formation, but it is inadequate for functional β cell differentiation.http://ift.tt/2p3GJD7
Mitotic Bookmarking: Maintaining the Stem Cell Identity during Mitosis
Publication date: 1 June 2017
Source:Cell Stem Cell, Volume 20, Issue 6
Author(s): Xin Huang, Jianlong Wang
In Cell Reports, Liu et al. (2017) investigate mechanisms for how pluripotent stem cells maintain their identity during cell division. They show that the histone mark H3K27ac and pluripotency transcription factors remain associated with mitotic chromatin in ESCs and during iPSC reprogramming, demonstrating the importance of mitotic bookmarking in pluripotency.
Teaser
In Cell Reports, Liu et al. (2017) investigate mechanisms for how pluripotent stem cells maintain their identity during cell division. They show that the histone mark H3K27ac and pluripotency transcription factors remain associated with mitotic chromatin in ESCs and during iPSC reprogramming, demonstrating the importance of mitotic bookmarking in pluripotency.http://ift.tt/2slHDcg
Do Adipocytes Emerge from Mural Progenitors?
Publication date: 4 May 2017
Source:Cell Stem Cell, Volume 20, Issue 5
Author(s): Lavanya Vishvanath, Jonathan Z. Long, Bruce M. Spiegelman, Rana K. Gupta
Teaser
Gupta and colleagues highlight recent work, including their own, that suggested based on lineage tracing that mural cells are adipogenic, contrasting with the conclusions of a recent Cell Stem Cell paper.http://ift.tt/2pfQfix
The Dynamic Identity of Intestinal Cancer Stem Cells
Publication date: 1 June 2017
Source:Cell Stem Cell, Volume 20, Issue 6
Author(s): Piero Dalerba
Elimination of self-renewing cancer stem cells (CSCs) is necessary to permanently eradicate malignant tissues. In a recent article in Nature, de Sousa e Melo et al. (2017) reveal that intestinal tumors can contain dynamic pools of functionally distinct CSC populations, which seem to interconvert depending on the host tissue microenvironment.
Teaser
Elimination of self-renewing cancer stem cells (CSCs) is necessary to permanently eradicate malignant tissues. In a recent article in Nature, de Sousa e Melo et al. (2017) reveal that intestinal tumors can contain dynamic pools of functionally distinct CSC populations, which seem to interconvert depending on the host tissue microenvironment.http://ift.tt/2rMfMFd
Amitosis of Polyploid Cells Regenerates Functional Stem Cells in the Drosophila Intestine
Publication date: 4 May 2017
Source:Cell Stem Cell, Volume 20, Issue 5
Author(s): Elena M. Lucchetta, Benjamin Ohlstein
Organ fitness depends on appropriate maintenance of stem cell populations, and aberrations in functional stem cell numbers are associated with malignancies and aging. Symmetrical division is the best characterized mechanism of stem cell replacement, but other mechanisms could also be deployed, particularly in situations of high stress. Here, we show that after severe depletion, intestinal stem cells (ISCs) in the Drosophila midgut are replaced by spindle-independent ploidy reduction of cells in the enterocyte lineage through a process known as amitosis. Amitosis is also induced by the functional loss of ISCs coupled with tissue demand and in aging flies, underscoring the generality of this mechanism. However, we also found that random homologous chromosome segregation during ploidy reduction can expose deleterious mutations through loss of heterozygosity. Together, our results highlight amitosis as an unappreciated mechanism for restoring stem cell homeostasis, but one with some associated risk in animals carrying mutations.
Graphical abstract
Teaser
Lucchetta and Ohlstein describe an unexpected mechanism of stem cell replacement in the Drosophila intestine. They found that in some situations where many stem cells are lost, they can be replaced through a process of ploidy reduction, or amitosis, of differentiated polyploid cells to regenerate functional stem cells.http://ift.tt/2ndY2xa
From Cell Stem Cell to Clinical Trials: The Biotech Journey of Two Papers
Publication date: 1 June 2017
Source:Cell Stem Cell, Volume 20, Issue 6
Author(s): Diana Crow
http://ift.tt/2rMmVFq
Racing to Uncover the Link between Zika Virus and Microcephaly
Publication date: 1 June 2017
Source:Cell Stem Cell, Volume 20, Issue 6
Author(s): Guo-li Ming, Hongjun Song, Hengli Tang
Teaser
In this Backstory, Ming, Song, and Tang give a behind-the-scenes account of the collaboration leading to their 2016 paper on Zika virus infection of neural progenitor cells. It was one of the first clues into how ZIKV could be causing birth defects in babies from infected mothers.http://ift.tt/2slBc8Z
Molecular Effects of Doxorubicin on Choline Metabolism in Breast Cancer
Publication date: August 2017
Source:Neoplasia, Volume 19, Issue 8
Author(s): Menglin Cheng, Asif Rizwan, Lu Jiang, Zaver M. Bhujwalla, Kristine Glunde
Abnormal choline phospholipid metabolism is a hallmark of cancer. The magnetic resonance spectroscopy (MRS) detected total choline (tCho) signal can serve as an early noninvasive imaging biomarker of chemotherapy response in breast cancer. We have quantified the individual components of the tCho signal, glycerophosphocholine (GPC), phosphocholine (PC) and free choline (Cho), before and after treatment with the commonly used chemotherapeutic drug doxorubicin in weakly metastatic human MCF7 and triple-negative human MDA-MB-231 breast cancer cells. While the tCho concentration did not change following doxorubicin treatment, GPC significantly increased and PC decreased. Of the two phosphatidylcholine-specific PLD enzymes, only PLD1, but not PLD2, mRNA was down-regulated by doxorubicin treatment. For the two reported genes encoding GPC phosphodiesterase, the mRNA of GDPD6, but not GDPD5, decreased following doxorubicin treatment. mRNA levels of choline kinase α (ChKα), which converts Cho to PC, were reduced following doxorubicin treatment. PLD1 and ChKα protein levels decreased following doxorubicin treatment in a concentration dependent manner. Treatment with the PLD1 specific inhibitor VU0155069 sensitized MCF7 and MDA-MB-231 breast cancer cells to doxorubicin-induced cytotoxicity. Low concentrations of 100 nM of doxorubicin increased MDA-MB-231 cell migration. GDPD6, but not PLD1 or ChKα, silencing by siRNA abolished doxorubicin-induced breast cancer cell migration. Doxorubicin induced GPC increase and PC decrease are caused by reductions in PLD1, GDPD6, and ChKα mRNA and protein expression. We have shown that silencing or inhibiting these genes/proteins can promote drug effectiveness and reduce adverse drug effects. Our findings emphasize the importance of detecting PC and GPC individually.
http://ift.tt/2sCj5Oq
Stat6 Promotes Intestinal Tumorigenesis in a Mouse Model of Adenomatous Polyposis by Expansion of MDSCs and Inhibition of Cytotoxic CD8 Response
Publication date: August 2017
Source:Neoplasia, Volume 19, Issue 8
Author(s): Asha Jayakumar, Alfred L.M. Bothwell
Intestinal tumorigenesis in the ApcMin/+ model is initiated by aberrant activation of Wnt pathway. Increased IL-4 expression in human colorectal cancer tissue and growth of colon cancer cell lines implied that IL-4–induced Stat6-mediated tumorigenic signaling likely contributes to intestinal tumor progression in ApcMin/+ mice. Stat6 also appears to promote expansion of myeloid-derived suppressor cells (MDSCs) cells. MDSCs promote polyp formation in the ApcMin/+ model. Hence, Stat6 could have a broad role in coordinating both polyp cell proliferation and MDSC expansion. We found that IL-4–induced Stat6-mediated proliferation of intestinal epithelial cells is augmented by platelet-derived growth factor–BB, a tumor-promoting growth factor. To determine whether polyp progression in ApcMin/+ mice is dependent on Stat6 signaling, we disrupted Stat6 in this model. Total polyps in the small intestine were fewer in ApcMin/+ mice lacking Stat6. Furthermore, proliferation of polyp epithelial cells was reduced, indicating that Stat6 in part controlled polyp formation. Stat6 also promoted expansion of MDSCs in the spleen and lamina propria of ApcMin/+ mice, implying regulation of antitumor T-cell response. More CD8 cells and reduced PD-1 expression on CD4 cells correlated with reduced polyps. In addition, a strong CD8-mediated cytotoxic response led to killing of tumor cells in Stat6-deficient ApcMin/+ mice. Therefore, these findings show that Stat6 has an oncogenic role in intestinal tumorigenesis by promoting polyp cell proliferation and immunosuppressive mediators, and preventing an active cytotoxic process.
http://ift.tt/2s7cgAM
Urétrite à Neisseria meningitidis : deux cas
Publication date: Available online 23 June 2017
Source:Annales de Dermatologie et de Vénéréologie
Author(s): C. Dubois, A.-L. Liegeon, C. Fabbro, F. Truchetet
IntroductionNeisseria meningitidis (NM) est une bactérie commensale présente dans la flore oropharyngée et responsable d'infections invasives. Plus rarement, des localisations génitales ont été décrites. Nous présentons deux cas d'urétrite aiguë à NM.ObservationsDeux hommes de 30 et 31 ans, dont l'un homosexuel séropositif pour le VIH, présentaient un écoulement urétral compatible avec le diagnostic d'urétrite aiguë. Les prélèvements urétraux identifiaient la présence de NM de sérogroupes B et C. L'un des antibiogrammes montrait une sensibilité intermédiaire à la pénicilline G et à l'amoxicilline.DiscussionLa présentation clinique des urétrites aiguës à NM est aspécifique, justifiant la réalisation de prélèvements urétraux devant toute urétrite aiguë. Les urétrites à NM sont peu fréquentes, affectant principalement les hommes ayant des relations sexuelles avec des hommes (HSH). Leur recrudescence s'expliquerait par celle des pratiques sexuelles orogénitales non protégées. L'émergence de résistances de NM impose la réalisation systématique d'un antibiogramme afin d'adapter les stratégies thérapeutiques et prophylactiques. Des cas d'infections invasives à méningocoques de sérogroupe C ont été recensés dans la population HSH avec l'hypothèse d'une porte d'entrée sexuelle. Aussi le Haut conseil de la santé publique recommande-t-il la vaccination contre le méningocoque de sérogroupe C dans cette population.BackgroundNeisseria meningitidis (NM) is a commensal bacteria present in the oropharyngeal flora that causes invasive infections. There have been rarer reports of presence in the genital region. Herein, we present two cases of acute NM urethritis.Patients and methodsTwo men aged 30 and 31years, one of whom is homosexual and seropositive for HIV infection, presented urethral discharge which was diagnosed as acute urethritis. The unit through samples indicated the presence of NM of serogroups B and C. One of the antibiotic sensitivity tests revealed intermediate susceptibility to penicillin G and to amoxicillin.DiscussionThe clinical presentation of acute NM urethritis is non-specific, because of which urethral samples should be taken wherever acute urethritis is suspected. NM urethritis is infrequent and primarily affects men who have sex with men (MSM). Its current increase is due to unprotected oral-genital sexual practices. Due to the emergence of resistance to NM, antibiotic susceptibility testing should be carried out routinely to ensure appropriate therapy and prophylaxis. Cases of invasive serogroup C meningococcal infections have been recorded within the MSM population with hypothetical sexual port of entry. Thus, the French High Public Health Authority recommends vaccination against meningitis C in this population.
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CONTENTS 1
Source:Materials Today, Volume 20, Issue 4
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CONTENTS 2
Source:Materials Today, Volume 20, Issue 4
http://ift.tt/2tZOk3O
Universal secondary relaxation and unusual brittle-to-ductile transition in metallic glasses
Publication date: Available online 23 June 2017
Source:Materials Today
Author(s): Q. Wang, J.J. Liu, Y.F. Ye, T.T. Liu, S. Wang, C.T. Liu, J. Lu, Y. Yang
It has long been recognized that the relaxation spectrum of glassy solids is intrinsically connected to their disordered structural features and deformation behaviors. However, such connections still remain elusive for metallic glasses. Here, through the extensive study of a variety of metallic glasses over a wide range of temperatures, we provide the compelling evidence for the existence of a universal fast secondary relaxation process, which occurs at a temperature far below the glass transition point with a low activation energy (0.3–0.6eV). Furthermore, it is demonstrated that the initiation of plasticity in metallic glasses is strongly correlated with the fast relaxation process. By exciting the fast relaxation process, multiple shear banding is triggered as opposed to single shear banding in the metallic glasses, which leads to an unusual brittle-to-ductile transition in malleability, being fundamentally different from the ordinary one commonly observed in crystalline alloys. Furthermore, our results shed the quantitative insights into the atomistic mechanisms that differentiate brittle from plastic metallic glasses at different temperatures.
Graphical abstract
http://ift.tt/2s2sAYj
Scholar : These new articles for Atmospheric and Oceanic Science Letters are available online
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Scholar : Theatre and Performance Design, Volume 3, Issue 1-2, March - June 2017 is now available online on Taylor & Francis Online
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Patterns of everyday functioning in preschool children born preterm and at term
Source:Research in Developmental Disabilities, Volume 67
Author(s): Anna Karin Andersson, Lene Martin, Katarina Strand Brodd, Lena Almqvist
Background/AimChildren born preterm are at risk of neonatal complications but the long-term consequences for everyday functioning is not well known. The study aimed to identify patterns of everyday functioning in preschool children born preterm and at term in relation to perinatal data, neonatal risk factors, behaviour, and socioeconomic status. Registry data and data from parent rated questionnaires were collected for 331 children.MethodA person-oriented approach with a cluster analysis was used.ResultsA seven cluster solution explained 65.91% of the variance. Most children (n=232) showed patterns of strong everyday functioning. A minority of the children (n=99), showed diverse patterns of weak everyday functioning. Perinatal characteristics, neonatal risk factors and socio-economics did not predict cluster group membership. Children born preterm were represented in all clusters.Conclusion, implicationsMost preschool children are perceived by their parents with strong everyday functioning despite being born preterm. However small groups of children are, for various reasons, perceived with weak functioning, but preterm birth is not the sole contributor to patterns of weak everyday functioning. More critical for all children's everyday functioning is probably the interaction between individual factors, behavioural factors and contextual factors. To gain a broader understanding of children's everyday functioning. Child Health Services need to systematically consider aspects of body function, activity and in addition participation and environmental aspects.
http://ift.tt/2tFoCSG
What is the underlying cause of Type II Diabetes? – Are Cells Protecting Themselves Against the Reactivity of Glucose?
Source:Medical Hypotheses
Author(s): Jacob Z. Dalgaard
Through the last couple of thousands of years, human food sources and availability have changed tremendously. Moving from a diet of hunter-gathers, consisting of nuts, fruits, tubers and meat, to the farmers' diet of vegetables, grains, milk and meat to this and last century, where among other processed foods there is the unlimited availability of refined sugar. This change in diet has been proposed as being the underlying reason for the dramatic increase in the prevalence of type II diabetes that we are observing worldwide in our time. The question is what is the underlying molecular cause of this disease? One possibility proposed here is that type II diabetes might be a consequence of our cells trying to protect themselves from too high intra-cellular concentration of the reactive compound glucose.
http://ift.tt/2sBWT72
Fasting as possible complementary approach for polycystic ovary syndrome: hope or hype?
Source:Medical Hypotheses
Author(s): Benito Chiofalo, Antonio Simone Laganà, Vittorio Palmara, Roberta Granese, Giacomo Corrado, Emanuela Mancini, Salvatore Giovanni Vitale, Helena Ban Frangež, Eda Vrtačnik-Bokal, Onofrio Triolo
Polycystic ovary syndrome (PCOS) is a common endocrine system disorder among women of reproductive age. In several cases, PCOS women show infertility or subfertility and other metabolic alteration, such as insulin resistance (InsR), dyslipidaemia, hyperinsulinemia and obesity. Despite the aetiology of the syndrome is still far from be elucidated, it could be considered the result of concurrent endocrine modifications, lifestyle factors and genetic background. In particular, accumulating evidence suggests that InsR and compensatory hyperinsulinemia play a pivotal pathogenic role in the in the hyperandrogenism of many PCOS phenotypes, which in turn have a clear detrimental effect on chronic anovulation.Different forms of fasting, such as intermittent fasting (IF, including alternate day fasting, or twice weekly fasting, for example) and periodic fasting (PF, lasting several days or longer every 2 or more weeks) are currently being tested in several in vitro and in vivo studies. Changes in the circulating levels of Insulin Growth Factor-1 (IGF-1), Insulin-like Growth Factor-Binding Protein 1 (IGFBP1), glucose and insulin are typical effects of fasting which may play a key role in the modulating aging and metabolic homeostasis.Considering the paramount importance of InsR and compensatory hyperinsulinemia, different fasting regimens can reduce IGF-1, IGFBP1, glucose and insulin levels and consequently have beneficial effects on ovarian function, androgen excess and infertility in PCOS women.
http://ift.tt/2s7bdAR
Scholar : Art Therapy, Volume 34, Issue 2, April 3, 2017 is now available online on Taylor & Francis Online
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Emerging Strategies for Delivering Antiangiogenic Therapies to Primary and Metastatic Brain Tumors
Publication date: Available online 22 June 2017
Source:Advanced Drug Delivery Reviews
Author(s): Vasileios Askoxylakis, Costas D. Arvanitis, Christina S.F. Wong, Gino B. Ferraro, Rakesh K. Jain
Five-years survival rates have not increased appreciably for patients with primary and metastatic brain tumors. Nearly 17,000 patients die from primary brain tumors, whereas approximately 200,000 cases are diagnosed with brain metastasis every year in the US alone. At the same time, with improved control of systemic disease, the incidence of brain metastasis is increasing. Thus novel approaches for improving the treatment outcome for these uniformly fatal diseases are needed urgently. In the review, we summarize the challenges in the treatment of these diseases using antiangiogenic therapies alone or in combination with radio-, chemo- and immuno-therapies. We also discuss the emerging strategies to improve the treatment outcome using both pharmacological approaches to normalize the tumor microenvironment and physical approaches (e.g., focused ultrasound) to modulate the blood-tumor-barrier, along with limitations of each approach. Finally, we offer some new avenues of future research.
Graphical abstract
http://ift.tt/2s6ZOB6
Scholar : These new articles for Acta Odontologica Scandinavica are available online
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Scholar : These new articles for Archives and Records are available online
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Common and diverse elements of ion channels and receptors underlying electrical activity in endocrine pituitary cells
Source:Molecular and Cellular Endocrinology
Author(s): Patrick A. Fletcher, Arthur Sherman, Stanko S. Stojilkovic
The pituitary gland contains six types of endocrine cells defined by hormones they secrete: corticotrophs, melanotrophs, gonadotrophs, thyrotrophs, somatotrophs, and lactotrophs. All these cell types are electrically excitable, and voltage-gated calcium influx is the major trigger for their hormone secretion. Along with hormone intracellular content, G-protein-coupled receptor and ion channel expression can also be considered as defining cell type identity. While many aspects of the developmental and activity dependent regulation of hormone and G-protein-coupled receptor expression have been elucidated, much less is known about the regulation of the ion channels needed for excitation-secretion coupling in these cells. We compare the spontaneous and receptor-controlled patterns of electrical signaling among endocrine pituitary cell types, including insights gained from mathematical modeling. We argue that a common set of ionic currents unites these cells, while differential expression of another subset of ionic currents could underlie cell type-specific patterns. We demonstrate these ideas using a generic mathematical model, showing that it reproduces many observed features of pituitary electrical signaling. Mapping these observations to the developmental lineage suggests possible modes of regulation that may give rise to mature pituitary cell types.
http://ift.tt/2s2hYIU
Oncogene-induced senescence and its evasion in a mouse model of thyroid neoplasia
Source:Molecular and Cellular Endocrinology
Author(s): Roberto Bellelli, Donata Vitagliano, Giorgia Federico, Pina Marotta, Anna Tamburrino, Paolo Salerno, Orlando Paciello, Serenella Papparella, Jeffrey A. Knauf, James A. Fagin, Samuel Refetoff, Giancarlo Troncone, Massimo Santoro
Here we describe a conditional doxycycline-dependent mouse model of RET/PTC3 (NCOA4-RET) oncogene-induced thyroid tumorigenesis. In these mice, after 10 days of doxycycline (dox) administration, RET/PTC3 expression induced mitogen activated protein kinase (MAPK) stimulation and a proliferative response which resulted in the formation of hyperplastic thyroid lesions. This was followed, after 2 months, by growth arrest accompanied by typical features of oncogene-induced senescence (OIS), including upregulation of p16INK4A and p21CIP, positivity at the Sudan black B, activation of the DNA damage response (DDR) markers γH2AX and pChk2 T68, and induction of p53 and p19ARF. After 5 months, about half of thyroid lesions escaped OIS and formed tumors that remained dependent on RET/PTC3 expression. This progression was accompanied by activation of AKT-FOXO1/3a pathway and increased serum TSH levels.
http://ift.tt/2sMCtXd
Scholar : These new articles for Activities, Adaptation & Aging are available online
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Morphological characteristics and HPV genotype predict the treatment response in cutaneous warts
Abstract
Background
Cutaneous warts have a cure rate after therapy of no more than approximately 50%. Recently, we developed and validated a standard assessment tool for warts (CWARTS) based on phenotypical characteristics.
Objectives
To assess whether patient and morphological wart characteristics predict the HPV type in the specific wart and whether these characteristics as well as the HPV type predict a favourable treatment response.
Methods
Photographs were used to score 9 morphological wart characteristics using the newly developed CWARTS tool. Genotyping of 23 wart-associated HPV types was performed using the HSL-PCR/MPG assay. The results were correlated with a favourable response to treatment with monochloroacetic acid, cryotherapy or a combination of cryotherapy and salicylic acid. Odds ratios were calculated using logistic regression in a Generalised Estimating Equations (GEE) model.
Results
Black dots (capillary thrombosis) strongly predicted the presence of any HPV type in a wart. From all characteristics tested, the HPV type most strongly predicted the treatment response when the warts were treated with monochloroacetic acid or the combination of cryotherapy and salicylic acid with a significantly decreased treatment response if the warts contained HPVs of the alpha genus (HPV2, HPV27 or HPV 57). When cryotherapy alone was used for common warts, HPV type did not play a role, but cryotherapy was less effective when the wart showed callus and was located deeper in the skin.
Conclusions
Morphological characteristics of the warts and the HPV genotype influence treatment outcome and thus potentially influence future treatment decisions for common and plantar warts.
This article is protected by copyright. All rights reserved.
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Biosimilars for Psoriasis: Worldwide Overview of Regulatory Guidelines, Uptake and Implications for Dermatology Clinical Practice
Abstract
The introduction of biologic drugs for the treatment of patients with psoriasis has revolutionized treatment paradigms and enabled numerous patients to achieve disease control with an acceptable safety profile. However, the high cost of biologics limits access to these medications for the majority of patients worldwide. In recent years, the introduction of biosimilars for inflammatory diseases has become a fast evolving field. The future use of biosimilars offers the potential for decreased cost and increased access to biologic drugs for patients with psoriasis. For their approval, different regulatory agencies use highly variable methods for definition, production, approval, marketing, and post-marketing surveillance of biosimilars. Due to potential interchangeability between biologics and biosimilars, traceability and pharmacovigilance are required to collect accurate data about adverse events in psoriasis patients; spontaneous reporting, registries, and use of "big data" should facilitate this process on a global basis. The current article describes biosimilar regulatory guidelines and examples of biosimilar uptake in clinical practice in several countries around the world. As it is apparent that biologic treatment decisions may become more physician-independent, the International Psoriasis Council recommends that dermatologists should take an active role in the development of biosimilar prescribing policies with their respective healthcare settings and governmental agencies.
This article is protected by copyright. All rights reserved.
http://ift.tt/2tFhhml
Sebum lipids influence macrophage polarization and activation
Summary
Background
As lipids are known to regulate macrophage functions it is reasonable to suppose that a sebocyte – macrophage axis mediated by sebum lipids may exist.
Objective
To investigate if sebocytes could contribute to the differentiation, polarization and function of macrophages with their secreted lipids.
Methods
Oil-red-O lipid staining and Raman spectroscopy were used to assess the dermal lipid content and penetration. Immunohistochemistry was used to analyse the macrophage subsets. Human peripheral blood monocytes were differentiated in the presence of either supernatant from human SZ95 sebocytes or major sebum lipid components and activated with Propionibacterium acnes. Macrophage surface markers and their capacity to uptake FITC-Propionibacterium acnes were detected by FACS measurements. Cytokine protein levels were evaluated by ELISA and Western blot analysis.
Results
Sebaceous gland rich skin had an increased dermal lipid content compared to sebaceous gland poor skin to which all the tested sebum component lipids could contribute by penetrating through the dermo-epidermal barrier. Of the lipids, oleic and linoleic acids promoted monocyte differentiation into alternatively activated macrophages. Moreover, linoleic acid also had an anti-inflammatory effect in Propionibacterium acnes activated macrophages, inhibiting the secretion of IL-1B, IL-6 and TNF-Α. Squalene, palmitic, stearic and oleic acids augmented the secretion of IL-1B even in the absence of Propionibacterium acnes, while oleic acid had a selective effect of inducing IL-1B, but down-regulating IL-6 and TNF-A secretion.
Conclusions
Our results suggest a role for sebaceous glands in modulating innate immune responses via their secreted lipids that are of possible pathologic and therapeutic relevance.
This article is protected by copyright. All rights reserved.
http://ift.tt/2t5KfyB
A systematic review of pharmacogenetic studies on the response to biologics in psoriasis patients
Abstract
Biologics are indicated for treating moderate to severe psoriasis. As the number of biologics registered for psoriasis increases, so does the need for biomarkers to guide personalized therapeutic decisions. Genetic variants might serve as predictors for treatment response, a field of research known as pharmacogenetics. The aim of this systematic review was to assess which genetic variants are associated with the response to biologics in psoriasis patients. A systematic search was performed in EMBASE, MEDLINE, the Cochrane Library and Web of Science. Twenty-six papers were included in this systematic review: 24 original studies and two meta-analyses. Quality was assessed using a predesigned form. Risk of bias was assessed using the Newcastle-Ottawa Scale. The majority of studies reported a candidate gene approach, focusing on polymorphisms in genes related the therapeutical target or to psoriasis susceptibility. Studied populations were small and results were divergent, especially for studies investigating tumour necrosis factor inhibitors. The evidence for the role of HLA-Cw6 in ustekinumab efficacy shows minimal heterogeneity, with a higher response rate among HLA-Cw6 positive patients reported across three out of five studies. However, replication of these findings in larger cohorts is required. Large scale hypothesis-free searches for genetic biomarkers are needed to uncover the complete genetic background of biologics treatment outcome.
This article is protected by copyright. All rights reserved.
http://ift.tt/2tFOqyi
Clinical experience with infliximab biosimilar in psoriasis
Abstract
biosimilar medicines are biological medicine that have been developed to be highly similar and clinically equivalent to an existing biological medicine. Just as patent expiry for conventional drugs has led to the marketing of generic versions, the expiry of data protection and patents for original biologics has prompted development of biosimilars.
This article is protected by copyright. All rights reserved.
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Malignancies and ustekinumab: an analysis of the FDA Adverse Event Reporting System and the European Union Drug Regulating Authorities Pharmacovigilance database
Abstract
Ustekinumab is a fully human monoclonal antibody that targets the common p40 subunit shared by interleukins (IL)-12 and IL-23, approved in the United States and in Europe on September 2009, for treatment of moderate to severe psoriasis and on September 2016 for moderately to severely active Crohn's disease1. Pre-marketing studies supported an acceptable risk-to-benefit profile2-4.
This article is protected by copyright. All rights reserved.
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Evidence-based practice and the evidence pyramid: A 21st century orthodontic odyssey
Publication date: July 2017
Source:American Journal of Orthodontics and Dentofacial Orthopedics, Volume 152, Issue 1
Author(s): Priti Subhash Mulimani
Organized evidence-based practice is said to have started in the medical field in the late 20th century. Its principles and usage eventually spread to other health sciences, including orthodontics. Although the conceptual foundations and basic tenets of evidence-based orthodontics are based on the classical approach of testing medical interventions, differences unravel as we encounter the ground realities in orthodontics, which are unique due to the length, complexity, and diversity involved in orthodontic treatment and research. How has this led to the evolution of evidence-based orthodontics and changes in its applications? Is it being translated to better clinical answers, treatment strategies, patient satisfaction, and information for orthodontists? What more needs to be done, considering the rapidly changing orthodontic scenario? This article aims to explore these questions to evaluate how evidence-based orthodontics has played itself out so far, so that it can continue to grow strong and stand up to the challenges of 21st century orthodontics.
http://ift.tt/2rNiQ03
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Publication date: September 2017 Source: Free Radical Biology and Medicine, Volume 110 Author(s): Lucía Fernández-del-Río, Anish Nag, Elen...
