Background: Development of a universal cancer vaccine for the prevention of all cancers has been under development for many years. Antiangiogenic cancer vaccines elicit immune responses with the potential of destroying tumor vasculature endothelial cells without affecting vasculature integrity in normal tissues. The methods used in the development of antigen compositions comprising these vaccines have been recently improved and described in this report in the context of SANTAVAC ™ development - the first cancer vaccine based on endothelial cell heterogeneity. <p></p> Methods: The present report summarizes data related to SANTAVAC™ development, including technical key points associated with optimal SANTAVAC™ production, a description of the composition required for preparing cancer vaccines with the highest predicted efficacy and safety, and a strategy for SANTAVAC™ large-scale implementation. Patents related to SANTAVAC™ and other universal cancer vaccines are also described. <p></p> Results: SANTAVAC ™ was shown to be the most promising antigen composition for anti-cancer vaccination, allowing for immune targeting of the tumor vasculature in experimental models with a high predicted efficacy (up to 60), where efficacy represents the fold decrease in the number of endothelial cells with a tumor-induced phenotype and directly related to predicted arrest of tumor growth. <p></p> Conclusion: The use of SANTAVAC ™ as a universal antigenic composition may spur vaccine development activities resulting in a set of therapeutic or prophylactic vaccines against different types of solid cancers. <p></p>
http://ift.tt/2lYCgLH
Τετάρτη 8 Μαρτίου 2017
SANTAVAC ™: A Novel Universal Antigen Composition for Developing Cancer Vaccines
Exploring Strategies to Improve Cardiac Arrest Survival: Proceedings of a Workshop.
Cardiac arrest often strikes seemingly healthy individuals without warning and without regard to age, gender, race, or health status. Representing the third leading cause of death in the United States, cardiac arrest is defined as "a severe malfunction or cessation of the electrical and mechanical activity of the heart ... [which] results in almost instantaneous loss of consciousness and collapse". Although the exact number of cardiac arrests is unknown, conservative estimates suggest that approximately 600,000 individuals experience a cardiac arrest in the United States each year.
http://ift.tt/2mYw7nx
Review of NASA's Evidence Reports on Human Health Risks: 2016 Letter Report.
This is the fourth in a series of five letter reports that provide an independent review of the more than 30 evidence reports that NASA has compiled on human health risks for long-duration and exploration spaceflights. This letter report reviews eight evidence reports and examines the quality of the evidence, analysis, and overall construction of each report; identifies existing gaps in report content; and provides suggestions for additional sources of expert input.
http://ift.tt/2m2zeH7
Using 21st Century Science to Improve Risk-Related Evaluations.
Over the last decade, several large-scale United States and international programs have been initiated to incorporate advances in molecular and cellular biology, -omics technologies, analytical methods, bioinformatics, and computational tools and methods into the field of toxicology. Similar efforts are being pursued in the field of exposure science with the goals of obtaining more accurate and complete exposure data on individuals and populations for thousands of chemicals over the lifespan; predicting exposures from use data and chemical-property information; and translating exposures between test systems and humans.
http://ift.tt/2mYwA9q
Permanent alopecia in patients with breast cancer after taxane chemotherapy and adjuvant hormonal therapy: Clinicopathologic findings in a cohort of 10 patients
Publication date: Available online 8 March 2017
Source:Journal of the American Academy of Dermatology
Author(s): Athina Fonia, Carlo Cota, Jane F. Setterfield, Lynne J. Goldberg, David A. Fenton, Catherine M. Stefanato
BackgroundAnagen effluvium with reversible scalp alopecia is a known side effect of chemotherapy. However, there are an increasing number of reports in the literature documenting permanent alopecia in patients treated with taxanes.ObjectiveWe sought to describe the clinicopathologic features in breast cancer patients who underwent treatment with taxanes and adjuvant hormonal chemotherapy.MethodsWe reviewed the clinical and histopathologic information of a cohort of 10 patients treated with taxanes and adjuvant hormonal chemotherapy.ResultsWe have observed 3 types of clinical patterns of alopecia (types A, B, and C), and have validated the histopathologic features showing alopecia areata–like and female pattern hair loss.LimitationsThe study was based on a small sample size and retrospective retrieval of clinical information and histopathologic review of posttreatment slides.ConclusionsWe hypothesize a clinicopathologic model of hair follicle cycle disruption in response to the chemoinflammatory and hormonal insults to the hair follicles resulting in permanent alopecia. Clinicopathologic correlation is paramount to the understanding of the morphobiologic pathways in chemotherapy-induced alopecia caused by taxanes and adjuvant hormonal treatment.
http://ift.tt/2mYxi6F
Actin Waves: Origin of Cell Polarization and Migration?
Publication date: Available online 7 March 2017
Source:Trends in Cell Biology
Author(s): Naoyuki Inagaki, Hiroko Katsuno
Actin filaments and associated proteins undergo wave-like movement in various cell types. Recent studies with cutting-edge analyses, including live-cell imaging, biophysical monitoring and manipulation, and mathematical modeling, have highlighted roles of 'actin waves' in cellular protrusion, polarization, and migration. The prevailing models to explain the wave-like dynamics of actin filaments involve an activator–inhibitor mechanism. In addition, axonal actin waves migrate by means of directional assembly and disassembly of membrane-anchored actin filaments, and thus represent a new type of machinery that translocates their component molecules to the cell edge. Here, we review recent advances in our understanding of the generation, mobility, and functions of actin waves, and discuss how actin waves may self-organize into the molecular machinery underlying cell morphogenesis.
http://ift.tt/2lYpBby
Minor Injury Crashes: Prevalence of Driver-Related Risk Factors and Outcome
Source:The Journal of Emergency Medicine
Author(s): Jeffrey R. Brubacher, Herbert Chan, Elizabeth Purssell, Benjamin J. Tuyp, Daniel K. Ting, Vahid Mehrnoush
BackgroundThe majority of crashes cause "minor" injuries (i.e., treated and released from the emergency department [ED]). Minor injury crashes are poorly studied.ObjectivesThis study aims to determine the prevalence of driver-related risk factors and subsequent outcome in drivers involved in minor crashes.MethodsWe interviewed a convenience sample of injured drivers, aged over 17 years, who were treated and released from the ED. Follow-up interviews were conducted 6 months after the crash.ResultsWe approached 123 injured drivers; baseline interviews were completed in 69 and follow-up interviews in 45. Prior to the index crash, 1.4% of drivers drank alcohol, 1.4% used illicit drugs, and 7.2% used sedating prescription medications. Nine drivers (13%) were distracted. In this sample, 5.8% met criteria for being aggressive drivers, 7.2% were risky drivers, and 11.6% drove while experiencing negative emotions. At 6-month follow-up, many drivers were still having health problems, 53.3% were not fully recovered, 46.7% had not returned to usual activities, and 28.9% were off work. Of the 42 participants who resumed driving, 16.7% had a near miss and 4.8% had another crash. Nine (21.4%) reported drinking and driving, and 9.5% reported driving after cannabis use. Cell phone use (16.7%) and use of other electronics while driving (23.8%) were also common.ConclusionsDriver-related risk factors are common in drivers involved in minor injury crashes, and drivers persist in taking risks after being involved in a crash. Despite their name, minor injury crashes are often associated with slow recovery and prolonged absenteeism from work.
http://ift.tt/2m2u2D0
International therapeutic guidelines for patients with HCV-related extrahepatic disorders. A multidisciplinary expert statement
Source:Autoimmunity Reviews
Author(s): Anna Linda Zignego, Manuel Ramos-Casals, Clodoveo Ferri, David Saadoun, Luca Arcaini, Dario Roccatello, Alessandro Antonelli, Anne Claire Desbois, Cloe Commarmond, Laura Gragnani, Milvia Casato, Peter Lamprecht, Alessandra Mangia, Athanasios G Tzioufas, Zobair M Younossi, Patrice Cacoub
Hepatitis C virus (HCV) is both hepatotrophic and lymphotropic virus that causes liver as well extrahepatic manifestations including cryoglobulinemic vasculitis, the most frequent and studied condition, lymphoma, and neurologic, cardiovascular, endocrine-metabolic or renal diseases.HCV-extrahepatic manifestations (HCV-EHMs) may severely affect the overall prognosis, while viral eradication significantly reduces non-liver related deaths.Different clinical manifestations may coexist in the same patient. Due to the variety of HCV clinical manifestations, a multidisciplinary approach along with appropriate therapeutic strategies are required. In the era of interferon-free anti-HCV treatments, international recommendations for the therapeutic management of HCV-EHMs are needed. This implies the need to define the best criteria to use antivirals and/or other therapeutic approaches. The present recommendations, based on qualified expert experience and specific literature, will focus on etiological (antiviral) therapies and/or traditional pathogenetic treatments that still maintain their therapeutic utility.
http://ift.tt/2mYo8H4
Bullous pemphigoid
Source:Autoimmunity Reviews
Author(s): Işın Sinem Bağcı, Orsolya N. Horváth, Thomas Ruzicka, Miklós Sárdy
Bullous pemphigoid (BP) is the most common autoimmune bullous disorder which is characterized by autoantibodies against hemidesmosomal proteins of the skin and mucous membranes. Collagen XVII and dystonin-e have been identified as target antigens. BP affects mostly the elderly. The incidence of the disease is increasing gradually and is associated with high morbidity and mortality. Clinically, BP is characterized by an intensely pruritic eruption with widespread bullous lesions. The clinical diagnosis can be challenging in the setting of atypical presentations. Diagnosis of BP relies on the integration of clinical, histological, immunopathological, and serological findings. The treatment is mainly based on topical and/or systemic glucocorticoids, but anti-inflammatory antibiotics and steroid sparing adjuvants are useful alternatives. Localised and mild BP can be treated with topical corticosteroids alone.
http://ift.tt/2lYq7GH
Animal models in idiopathic inflammatory myopathies: How to overcome a translational roadblock?
Source:Autoimmunity Reviews
Author(s): Ali Afzali, Tobias Ruck, Heinz Wiendl, Sven G. Meuth
Idiopathic inflammatory myopathies (IIMs) encompass a heterogenic group of rare muscle diseases with common symptoms including muscle weakness and the presence of certain histological features. Since the pathogenesis remains unclear, therapeutic approaches in general comprise unspecific immunosuppression strategies that have been met with limited success. Therefore, a deeper understanding of the underlying pathophysiological mechanisms is critically required to assist in development of targeted therapies. Animal models have proven to be tremendously helpful in mechanistic studies and allow researchers to overcome the inevitable restrictions of human research. Although the number of different IIM models has drastically increased over the last few decades, a model that exhibits the phenotypical and histopathological hallmarks of IIM is still missing. Recent publications have shown promising results addressing different pathophysiological issues like mechanisms of onset, chronification or relapse in IIM. However, a standardization of the methodology is critically required in order to improve comparability and transferability among different groups. Here we provide an overview of the currently available IIM models including our own C-peptide based small-peptide model, critically discuss their advantages and disadvantages and give perspectives to their future use.
http://ift.tt/2mYlBNa
Streptococcus mutans antigen I/II and autoimmunity in cardiovascular diseases
Source:Autoimmunity Reviews
Author(s): Alberta Lucchese
Infectious pathogens from the oral cavity cause oral diseases such as caries, gingivitis, periodontitis, endodontic infections, and alveolar osteitis, and often are also concomitant to systemic diseases, including cardiovascular disorders, stroke, preterm birth, diabetes, and pneumonia, among others. The relationship(s) between oral infections and systemic diseases are still unclear. Using the bacterial cell surface antigen I/II from S. mutans and cardiovascular diseases as a model, this study analyzes peptide commonalities that might underlie autoimmune crossreactions between the bacterial antigen and human proteins associated with cardiovascular disorders. The study outlines a vast peptide sharing that calls attention on autoimmune crossreactivity as a possible mechanism by which S. mutans infection might contribute to induce cardiovascular diseases, and, more in general, offers a new approach to investigate the still elusive molecular links between focal oral infections and human systemic diseases.
http://ift.tt/2lYthKD
Regulatory immune cells and functions in autoimmunity and transplantation immunology
Source:Autoimmunity Reviews
Author(s): Gabor Papp, Peter Boros, Britt Nakken, Peter Szodoray, Margit Zeher
In physiological circumstances, various tolerogenic mechanisms support the protection of self-structures during immune responses. However, quantitative and/or qualitative changes in regulatory immune cells and mediators can evoke auto-reactive immune responses, and upon susceptible genetic background, along with the presence of other concomitant etiological factors, autoimmune disease may develop. In transplant immunology, tolerogenic mechanisms are also critical, since the balance between of alloantigen-reactive effector cells and the regulatory immune cells will ultimately determine whether a graft is accepted or rejected. Better understanding of the immunological tolerance and the potential modulations of immune regulatory processes are crucial for developing effective therapies in autoimmune diseases as well as in organ transplantation.In this review, we focus on the novel insights regarding the impaired immune regulation and other relevant factors contributing to the development of auto-reactive and graft-reactive immune responses in autoimmune diseases and transplant rejection, respectively. We also address some promising approaches for modification of immune-regulatory processes and tolerogenic mechanisms in autoimmunity and solid organ transplantation, which may be beneficial in future therapeutic strategies.
http://ift.tt/2lYkbxl
Editorial Board
Publication date: March–April 2017
Source:Aggression and Violent Behavior, Volume 33
http://ift.tt/2n68y9s
Effectiveness of a selective alcohol prevention program targeting personality risk factors: Results of interaction analyses
Publication date: August 2017
Source:Addictive Behaviors, Volume 71
Author(s): Jeroen Lammers, Ferry Goossens, Patricia Conrod, Rutger Engels, Reinout W. Wiers, Marloes Kleinjan
AimTo explore whether specific groups of adolescents (i.e., scoring high on personality risk traits, having a lower education level, or being male) benefit more from the Preventure intervention with regard to curbing their drinking behaviour.DesignA clustered randomized controlled trial, with participants randomly assigned to a 2-session coping skills intervention or a control no-intervention condition.SettingFifteen secondary schools throughout The Netherlands; 7 schools in the intervention and 8 schools in the control condition.Participants699 adolescents aged 13–15; 343 allocated to the intervention and 356 to the control condition; with drinking experience and elevated scores in either negative thinking, anxiety sensitivity, impulsivity or sensation seeking.MeasurementsDifferential effectiveness of the Preventure program was examined for the personality traits group, education level and gender on past-month binge drinking (main outcome), binge frequency, alcohol use, alcohol frequency and problem drinking, at 12months post-intervention.Intervention and comparatorPreventure is a selective school-based alcohol prevention programme targeting personality risk factors. The comparator was a no-intervention control.FindingsIntervention effects were moderated by the personality traits group and by education level. More specifically, significant intervention effects were found on reducing alcohol use within the anxiety sensitivity group (OR=2.14, CI=1.40, 3.29) and reducing binge drinking (OR=1.76, CI=1.38, 2.24) and binge drinking frequency (β=0.24, p=0.04) within the sensation seeking group at 12months post-intervention. Also, lower educated young adolescents reduced binge drinking (OR=1.47, CI=1.14, 1.88), binge drinking frequency (β=0.25, p=0.04), alcohol use (OR=1.32, CI=1.06, 1.65) and alcohol use frequency (β=0.47, p=0.01), but not those in the higher education group. Post hoc latent-growth analyses revealed significant effects on the development of binge drinking (β=−0.19, p=0.02) and binge drinking frequency (β=−0.10, p=0.03) within the SS personality trait.ConclusionsThe alcohol selective prevention program Preventure appears to have effect on the prevalence of binge drinking and alcohol use among specific groups in young adolescents in the Netherlands, particularly the SS personality trait and lower educated adolescents.
http://ift.tt/2neqzkT
Fast transdifferentiation of human Wharton’s jelly mesenchymal stem cells into neurospheres and nerve-like cells
Publication date: Available online 8 March 2017
Source:Journal of Neuroscience Methods
Author(s): A.R. Bonilla-Porras, C. Velez-Pardo, M. Jimenez-Del-Rio
BackgroundThe human mesenchymal stem cells derived from Wharton's jelly tissue (hWJ-MSCs) represent a tool for cell-based therapies and regenerative medicine. hWJ-MSCs form neurospheres (NSs) within 3 to 7 days. No data is available to establish the neuro-phenotypic markers and time of formation of nerve-like (NLCs) and glial cells from NSs derived from hWJ-MSCs.New MethodhWJ-MSCs were incubated with Fast-N-Spheres medium for 24 and 72h. The new formed NSs were in turn incubated with forskolin in neurogenic NeuroForsk medium for 1-7 days.ResultshWJ-MSCs cultured with Fast-N-Spheres medium trans-differentiated into NSs in just 24h compared to 72h for hWJ-MSCs cultured with classic growth factor medium. The NSs generated from the Fast-N-Spheres medium expressed reduced levels SOX2, OCT4 and NANOG, as markers of pluripotency compared to undifferentiated hWJ-MSCs. The formed NSs exposed to NeuroForsk medium differentiated into NLCs in 4days as evidenced by high levels of protein expression of the neuronal markers, and no expression of the glial marker GFAP.Comparison with Existing Method(s):Currently, the formation and harvest of NSs is expensive and time consuming. Published protocols require 3–7days to form NSs from whole human umbilical cord MSCs. We report for the first time, to our knowledge, the differentiation of NSs-derived from hWJ-MSCs into NLCs.ConclusionsThe fastest method to obtain NSs and NLCs from hWJ-MSCs takes only five days using the two-step incubation media Fast-N-Spheres and NeuroForsk.
Graphical abstract
http://ift.tt/2neBWcE
Measures of economic advantage associated with HPV-positive head and neck cancers among non-Hispanic black and white males identified through the National Cancer Database
Source:Cancer Epidemiology, Volume 48
Author(s): Caryn E. Peterson, Shaveta Khosla, Gina D. Jefferson, Faith G. Davis, Marian L. Fitzgibbon, Sally Freels, Timothy P. Johnson, Kent Hoskins, Charlotte E. Joslin
BackgroundNational trends show dramatic increases in the incidence of HPV-related head and neck squamous cell carcinomas (HNSCCs) among black and white males. Using cases identified through the National Cancer Data Base, we assessed factors associated with HPV 16- or 16/18 positive HNSCCs among non-Hispanic black and white males diagnosed in the U.S. between 2009 and 2013.MethodsThis sample included 21,524 HNSCCs with known HPV status. Adjusted relative risks (RRs) and 95% confidence intervals (CIs) were estimated using log-binomial regression.ResultsCompared to those with HPV-negative tumors, male patients diagnosed with HPV-positive HNSCCs were non-Hispanic white, younger at diagnosis, lived in zip-code areas with higher median household income and higher educational attainment, had private health insurance and no reported comorbidities at diagnosis. Although the risk of HPV-positive HNSCCs increased with measures of higher area-level socioeconomic status, the effect was stronger for non-Hispanic black males (RRAdjusted=1.76, 95% CI 1.49–2.09) than for whites (RRAdjusted=1.12, 95% CI 1.08–1.16). The peak age for diagnosis of HPV-positive HNSCCs occurred in those diagnosed at 45–49 years (RRAdjusted=1.57, 95% CI 1.42–1.73). Oropharyngeal tumors were strongly associated with HPV-positivity (RRAdjusted=4.32, 95% CI 4.03–4.63). In the analysis restricted to oropharyngeal anatomic sites, similar patterns persisted.ConclusionIn our analysis, measures of economic advantage were associated with an increased risk of HPV-positive HNSCCs. In order to develop effective interventions, greater understanding of the risk factors for HPV-positive HNSCCs is needed among both high-risk males and their healthcare providers.
http://ift.tt/2mBfFJe
Bioprinting for vascular and vascularized tissue biofabrication
Publication date: 15 March 2017
Source:Acta Biomaterialia, Volume 51
Author(s): Pallab Datta, Bugra Ayan, Ibrahim T. Ozbolat
Bioprinting is a promising technology to fabricate design-specific tissue constructs due to its ability to create complex, heterocellular structures with anatomical precision. Bioprinting enables the deposition of various biologics including growth factors, cells, genes, neo-tissues and extra-cellular matrix-like hydrogels. Benefits of bioprinting have started to make a mark in the fields of tissue engineering, regenerative medicine and pharmaceutics. Specifically, in the field of tissue engineering, the creation of vascularized tissue constructs has remained a principal challenge till date. However, given the myriad advantages over other biofabrication methods, it becomes organic to expect that bioprinting can provide a viable solution for the vascularization problem, and facilitate the clinical translation of tissue engineered constructs. This article provides a comprehensive account of bioprinting of vascular and vascularized tissue constructs. The review is structured as introducing the scope of bioprinting in tissue engineering applications, key vascular anatomical features and then a thorough coverage of 3D bioprinting using extrusion-, droplet- and laser-based bioprinting for fabrication of vascular tissue constructs. The review then provides the reader with the use of bioprinting for obtaining thick vascularized tissues using sacrificial bioink materials. Current challenges are discussed, a comparative evaluation of different bioprinting modalities is presented and future prospects are provided to the reader.Statement of SignificanceBiofabrication of living tissues and organs at the clinically-relevant volumes vitally depends on the integration of vascular network. Despite the great progress in traditional biofabrication approaches, building perfusable hierarchical vascular network is a major challenge. Bioprinting is an emerging technology to fabricate design-specific tissue constructs due to its ability to create complex, heterocellular structures with anatomical precision, which holds a great promise in fabrication of vascular or vascularized tissues for transplantation use. Although a great progress has recently been made on building perfusable tissues and branched vascular network, a comprehensive review on the state-of-the-art in vascular and vascularized tissue bioprinting has not reported so far. This contribution is thus significant because it discusses the use of three major bioprinting modalities in vascular tissue biofabrication for the first time in the literature and compares their strengths and limitations in details. Moreover, the use of scaffold-based and scaffold-free bioprinting is expounded within the domain of vascular tissue fabrication.
Graphical abstract
http://ift.tt/2miR5dP
Covalently immobilized VEGF-mimicking peptide with gelatin methacrylate enhances microvascularization of endothelial cells
Publication date: 15 March 2017
Source:Acta Biomaterialia, Volume 51
Author(s): S. Prakash Parthiban, Deepti Rana, Esmaiel Jabbari, Nadia Benkirane-Jessel, Murugan Ramalingam
Clinically usable tissue-engineered constructs are currently limited due to their inability of forming microvascular networks necessary for adequate cellular oxygen and nutrient supply upon implantation. The aim of this study is to investigate the conditions necessary for microvascularization in a tissue-engineered construct using vascular endothelial growth factor (VEGF). The construct was made of gelatin methacrylate (GelMA) based cell-laden hydrogel system, which was then covalently linked with VEGF-mimicking peptide (AcQK), using human umbilical vein endothelial cells (HUVECs) as the model cell. The results of the mechanics and gene expression analysis indicated significant changes in mechanical properties and upregulation of vascular-specific genes. The major finding of this study is that the increased expression of vascular-specific genes could be achieved by employing AcQK in the GelMA based hydrogel system, leading to accelerated microvascularization. We conclude that GelMA with covalently-linked angiogenic peptide is a useful tissue engineered construct suitable for microvascularization.Statement of Significance(1) This study reports the conditions necessary for microvascularization in a tissue-engineered construct using vascular endothelial growth factor (VEGF). (2) The construct was made of gelatin methacrylate based cell-laden hydrogel system. (3) There is a significant change observed in mechanical properties and upregulation of vascular-specific genes, in particular CD34, when AcQK is used. (4) The major finding of this study is that the increased expression of vascular-specific genes, i.e., CD34 could be achieved by employing AcQK in the GelMA based hydrogel system, leading to accelerated microvascularization.
Graphical abstract
http://ift.tt/2mizrHi
Inhibition of bacterial adhesion and biofilm formation by dual functional textured and nitric oxide releasing surfaces
Publication date: 15 March 2017
Source:Acta Biomaterialia, Volume 51
Author(s): Li-Chong Xu, Yaqi Wo, Mark E. Meyerhoff, Christopher A. Siedlecki
In separate prior studies, physical topographic surface modification or nitric oxide (NO) release has been demonstrated to each be an effective approach to inhibit and control bacterial adhesion and biofilm formation on polymeric surfaces. Such approaches can prevent biomaterial-associated infection without causing the antibiotic resistance of the strain. In this work, both techniques were successfully integrated and applied to a polyurethane (PU) biomaterial surface that bears ordered pillar topographies (400/400nm and 500/500nm patterns) at the top surface and a S-nitroso-N-acetylpenicillamine (SNAP, NO donor) doped sub-layer in the middle, via a soft lithography two-stage replication process. Upon placing the SNAP textured PU films into PBS at 37°C, the decomposition of SNAP within polymer film initiates NO release with a lifetime of up to 10days at flux levels >0.5×10−10molmin−1cm−2 for a textured polyurethane layer containing 15wt% SNAP. The textured surface reduces the accessible surface area and the opportunity of bacteria-surface interaction, while the NO release from the same surface further inhibits bacterial growth and biofilm formation. Such dual functionality surfaces are shown to provide a synergistic effect on inhibition of Staphylococcus epidermidis bacterial adhesion that is significantly greater than the inhibition of bacterial adhesion achieved by either single treatment approach alone. Longer term experiments to observe biofilm formation demonstrate that the SNAP doped-textured PU surface can inhibit the biofilm formation for >28d and provide a practical approach to improve the biocompatibility of current biomimetic biomaterials and thereby reduce the risk of pathogenic infection.Statement of SignificanceMicrobial infection remains a significant barrier to development and implementation of advanced blood-contacting medical devices. Clearly, determining how to design and control material properties that can reduce microbial infection is a central question to biomaterial researchers. In separate prior studies, physical topographic surface modification or nitric oxide (NO) release has been demonstrated to each be an effective approach to inhibit and control bacterial adhesion and biofilm formation on polymeric surfaces. Such approaches can prevent biomaterial-associated infection without causing antibiotic resistance of the bacterial strain. However, efficiency of antimicrobial properties of each approach is still limited and far from sufficient for widespread clinical use. This work successfully integrates both techniques and applies them to a polyurethane (PU) biomaterial surface that bears dual functions, surface topographic modification and NO release. The former reduces the surface contact area and changes surface wettability, resulting in reduction of bacterial adhesion, and NO release further inhibits bacteria growth. Such dual functionalized surfaces provide a synergistic effect on inhibition of Staphylococcus epidermidis bacterial adhesion that is significantly greater than the inhibition of bacterial adhesion achieved by either single treatment approach alone. Furthermore, longer-term experiments demonstrate that the dual functionalized surfaces can inhibit biofilm formation for >28days. The success of this work provides a practical approach to improve the biocompatibility of current biomaterials and thereby reduce the risk of pathogenic infection.
Graphical abstract
http://ift.tt/2miPvsu
The potential of isotopically enriched magnesium to study bone implant degradation in vivo
Publication date: 15 March 2017
Source:Acta Biomaterialia, Volume 51
Author(s): Johannes Draxler, Elisabeth Martinelli, Annelie M. Weinberg, Andreas Zitek, Johanna Irrgeher, Martin Meischel, Stefanie E. Stanzl-Tschegg, Bernhard Mingler, Thomas Prohaska
This pilot study highlights the substantial potential of using isotopically enriched (non-radioactive) metals to study the fate of biodegradable metal implants. It was possible to show that magnesium (Mg) release can be observed by combining isotopic mass spectrometry and isotopic pattern deconvolution for data reduction, even at low amounts of Mg released a from slowly degrading 26Mg enriched (>99%) Mg metal. Following implantation into rats, structural in vivo changes were monitored by μCT. Results showed that the applied Mg had an average degradation rate of 16±5μmyear−1, which corresponds with the degradation rate of pure Mg. Bone and tissue extraction was performed 4, 24, and 52weeks after implantation. Bone cross sections were analyzed by laser ablation inductively coupled plasma mass spectrometry (ICP-MS) to determine the lateral 26Mg distribution. The 26Mg/24Mg ratios in digested tissue and excretion samples were analyzed by multi collector ICP-MS. Isotope pattern deconvolution in combination with ICP-MS enabled detection of Mg pin material in amounts as low as 200ppm in bone tissues and 20ppm in tissues up to two fold increased Mg levels with a contribution of pin-derived Mg of up to 75% (4weeks) and 30% (24weeks) were found adjacent to the implant. After complete degradation, no visual bone disturbance or residual pin-Mg could be detected in cortical bone. In organs, increased Δ26Mg/24Mg values up to 16‰ were determined compared to control samples. Increased Δ26Mg/24Mg values were detected in serum samples at a constant total Mg level. In contrast to urine, feces did not show a shift in the 26Mg/24Mg ratios. This investigation showed that the organism is capable of handling excess Mg well and that bones fully recover after degradation.Statement of SignificanceMagnesium alloys as bone implants have faced increasing attention over the past years. In vivo degradation and metabolism studies of these implant materials have shown the promising application in orthopaedic trauma surgery. With advance in Mg research it has become increasingly important to monitor the fate of the implant material in the organism. For the first time, the indispensible potential of isotopically enriched materials is documented by applying 26Mg enriched Mg implants in an animal model. Therefore, the spatial distribution of pin-Mg in bone and the pin-Mg migration and excretion in the organism could be monitored to better understand metal degradation as well as Mg turn over and excretion.
Graphical abstract
http://ift.tt/2miLlka
Enhanced articular cartilage by human mesenchymal stem cells in enzymatically mediated transiently RGDS-functionalized collagen-mimetic hydrogels
Publication date: 15 March 2017
Source:Acta Biomaterialia, Volume 51
Author(s): Paresh A. Parmar, Jean-Philippe St-Pierre, Lesley W. Chow, Christopher D. Spicer, Violet Stoichevska, Yong Y. Peng, Jerome A. Werkmeister, John A.M. Ramshaw, Molly M. Stevens
Recapitulation of the articular cartilage microenvironment for regenerative medicine applications faces significant challenges due to the complex and dynamic biochemical and biomechanical nature of native tissue. Towards the goal of biomaterial designs that enable the temporal presentation of bioactive sequences, recombinant bacterial collagens such as Streptococcal collagen-like 2 (Scl2) proteins can be employed to incorporate multiple specific bioactive and biodegradable peptide motifs into a single construct. Here, we first modified the backbone of Scl2 with glycosaminoglycan-binding peptides and cross-linked the modified Scl2 into hydrogels via matrix metalloproteinase 7 (MMP7)-cleavable or non-cleavable scrambled peptides. The cross-linkers were further functionalized with a tethered RGDS peptide creating a system whereby the release from an MMP7-cleavable hydrogel could be compared to a system where release is not possible. The release of the RGDS peptide from the degradable hydrogels led to significantly enhanced expression of collagen type II (3.9-fold increase), aggrecan (7.6-fold increase), and SOX9 (5.2-fold increase) by human mesenchymal stem cells (hMSCs) undergoing chondrogenesis, as well as greater extracellular matrix accumulation compared to non-degradable hydrogels (collagen type II; 3.2-fold increase, aggrecan; 4-fold increase, SOX9; 2.8-fold increase). Hydrogels containing a low concentration of the RGDS peptide displayed significantly decreased collagen type I and X gene expression profiles, suggesting a major advantage over either hydrogels functionalized with a higher RGDS peptide concentration, or non-degradable hydrogels, in promoting an articular cartilage phenotype. These highly versatile Scl2 hydrogels can be further manipulated to improve specific elements of the chondrogenic response by hMSCs, through the introduction of additional bioactive and/or biodegradable motifs. As such, these hydrogels have the possibility to be used for other applications in tissue engineering.Statement of SignificanceRecapitulating aspects of the native tissue biochemical microenvironment faces significant challenges in regenerative medicine and tissue engineering due to the complex and dynamic nature of the tissue. The ability to take advantage of, mimic, and modulate cell-mediated processes within novel naturally-derived hydrogels is of great interest in the field of biomaterials to generate constructs that more closely resemble the biochemical microenvironment and functions of native biological tissues such as articular cartilage. Towards this goal, the temporal presentation of bioactive sequences such as RGDS on the chondrogenic differentiation of human mesenchymal stem cells is considered important as it has been shown to influence the chondrogenic phenotype. Here, a novel and versatile platform to recreate a high degree of biological complexity is proposed, which could also be applicable to other tissue engineering and regenerative medicine applications.
Graphical abstract
http://ift.tt/2miXBkU
Editorial Board
Publication date: 15 March 2017
Source:Acta Biomaterialia, Volume 51
http://ift.tt/2miRVYd
Living nano-micro fibrous woven fabric/hydrogel composite scaffolds for heart valve engineering
Publication date: 15 March 2017
Source:Acta Biomaterialia, Volume 51
Author(s): Shaohua Wu, Bin Duan, Xiaohong Qin, Jonathan T. Butcher
Regeneration and repair of injured or diseased heart valves remains a clinical challenge. Tissue engineering provides a promising treatment approach to facilitate living heart valve repair and regeneration. Three-dimensional (3D) biomimetic scaffolds that possess heterogeneous and anisotropic features that approximate those of native heart valve tissue are beneficial to the successful in vitro development of tissue engineered heart valves (TEHV). Here we report the development and characterization of a novel composite scaffold consisting of nano- and micro-scale fibrous woven fabrics and 3D hydrogels by using textile techniques combined with bioactive hydrogel formation. Embedded nano-micro fibrous scaffolds within hydrogel enhanced mechanical strength and physical structural anisotropy of the composite scaffold (similar to native aortic valve leaflets) and also reduced its compaction. We determined that the composite scaffolds supported the growth of human aortic valve interstitial cells (HAVIC), balanced the remodeling of heart valve ECM against shrinkage, and maintained better physiological fibroblastic phenotype in both normal and diseased HAVIC over single materials. These fabricated composite scaffolds enable the engineering of a living heart valve graft with improved anisotropic structure and tissue biomechanics important for maintaining valve cell phenotypes.Statement of SignificanceHeart valve-related disease is an important clinical problem, with over 300,000 surgical repairs performed annually. Tissue engineering offers a promising strategy for heart valve repair and regeneration. In this study, we developed and tissue engineered living nano-micro fibrous woven fabric/hydrogel composite scaffolds by using textile technique combined with bioactive hydrogel formation. The novelty of our technique is that the composite scaffolds can mimic physical structure anisotropy and the mechanical strength of natural aortic valve leaflet. Moreover, the composite scaffolds prevented the matrix shrinkage, which is major problem that causes the failure of TEHV, and better maintained physiological fibroblastic phenotype in both normal and diseased HAVIC. This work marks the first report of a combination composite scaffold using 3D hydrogel enhanced by nano-micro fibrous woven fabric, and represents a promising tissue engineering strategy to treat heart valve injury.
Graphical abstract
http://ift.tt/2mFL4KJ
Peptide and nucleic acid-directed self-assembly of cationic nanovehicles through giant unilamellar vesicle modification: Targetable nanocomplexes for in vivo nucleic acid delivery
Publication date: 15 March 2017
Source:Acta Biomaterialia, Volume 51
Author(s): A.D. Tagalakis, R. Maeshima, C. Yu-Wai-Man, J. Meng, F. Syed, L.-P. Wu, A.M. Aldossary, D. McCarthy, S.M. Moghimi, S.L. Hart
One of the greatest challenges for the development of genetic therapies is the efficient targeted delivery of therapeutic nucleic acids. Towards this goal, we have introduced a new engineering initiative in self-assembly of biologically safe and stable nanovesicle complexes (∼90 to 140nm) derived from giant unilamellar vesicle (GUV) precursors and comprising plasmid DNA or siRNA and targeting peptide ligands. The biological performance of the engineered nanovesicle complexes were studied both in vitro and in vivo and compared with cationic liposome-based lipopolyplexes. Compared with cationic lipopolyplexes, nanovesicle complexes did not show advantages in transfection and cell uptake. However, nanovesicle complexes neither displayed significant cytotoxicity nor activated the complement system, which are advantageous for intravenous injection and tumour therapy. On intravenous administration into a neuroblastoma xenograft mouse model, nanovesicle complexes were found to distribute throughout the tumour interstitium, thus providing an alternative safer approach for future development of tumour-specific therapeutic nucleic acid interventions. On oropharyngeal instillation, nanovesicle complexes displayed better transfection efficiency than cationic lipopolyplexes. The technological advantages of nanovesicle complexes, originating from GUVs, over traditional cationic liposome-based lipopolyplexes are discussed.Statement of SignificanceThe efficient targeted delivery of nucleic acids in vivo provides some of the greatest challenges to the development of genetic therapies. Giant unilamellar lipid vesicles (GUVs) have been used mainly as cell and tissue mimics and are instrumental in studying lipid bilayers and interactions. Here, the GUVs have been modified into smaller nanovesicles. We have then developed novel nanovesicle complexes comprising self-assembling mixtures of the nanovesicles, plasmid DNA or siRNA, and targeting peptide ligands. Their biophysical properties were studied and their transfection efficiency was investigated. They transfected cells efficiently without any associated cytotoxicity and with targeting specificity, and in vivo they resulted in very high and tumour-specific uptake and in addition, efficiently transfected the lung. The peptide-targeted nanovesicle complexes allow for the specific targeted enhancement of nucleic acid delivery with improved biosafety over liposomal formulations and represent a promising tool to improve our arsenal of safe, non-viral vectors to deliver therapeutic cargos in a variety of disorders.
Graphical abstract
http://ift.tt/2mFy9bV
A photoresponsive soft interface reversibly controls wettability and cell adhesion by conformational changes in a spiropyran-conjugated amphiphilic block copolymer
Publication date: 15 March 2017
Source:Acta Biomaterialia, Volume 51
Author(s): Di He, Yoshinori Arisaka, Kenichi Masuda, Mitsuya Yamamoto, Naoya Takeda
The functionalities of soft interfaces including cell adhesion can be enhanced by dynamic conversion of polymer properties and movement via external stimuli. Light is a superior stimulus, and various surfaces modified with photoreactive molecules have been prepared. However, in most of these studies, the surface properties are irreversibly changed due to photo-degradation, and reversible adhesion and collection of cells is not feasible. In this study, we developed a photoresponsive polymer soft interface that was able to spatiotemporally control wettability, cell adhesion, and detachment in a reversible manner. Spiropyran molecules were introduced into the hydrophobic block of an amphiphilic diblock copolymer consisting of poly(methyl methacrylate) and polyethylene glycol, and the monomer unit numbers of these components were optimized. The copolymer was immobilized on a glass substrate as a nanofilm. With alternating irradiation using UV and visible light, the surface exhibited reversible changes in hydrophobicity and hydrophilicity, and the direction of change was opposite to the polarity change in photo-isomerization of spiropyran. We also achieved photo-control of effective cell adhesion and detachment with sequential irradiation with UV and visible light. These remarkable functions could be ascribed to conformational changes triggered by photo-isomerization of spiropyran. This photoresponsive polymer soft interface may have applications as a powerful tool in biological studies by facilitating sequential changes in wettability and bioaffinity.Statement of SignificanceWe developed a photoresponsive polymer soft interface, which was able to spatiotemporally control wettability and cell adhesion/detachment in a reversible manner, by introducing spiropyran into the hydrophobic block of an amphiphilic diblock copolymer. With alternating irradiation using UV and visible light, the surface exhibited unique reversible wettability changes; the direction of hydrophobicity and hydrophilicity change was opposite to the polarity change in spiropyran photo-isomerization. Light-dependent reversible control of spatiotemporal cell adhesion and detachment was also achieved with sequential UV (adhesion) and visible light irradiation (detachment). Cell detachment using noncytotoxic visible light was realized for the first time. Cell-patterning capability stably lasted for 25days. This photoresponsive surface could be applied to fabrication of engineered tissues comprised of several cellular species.
Graphical abstract
http://ift.tt/2mFxgQE
Rationally designed dual functional block copolymers for bottlebrush-like coatings: In vitro and in vivo antimicrobial, antibiofilm, and antifouling properties
Publication date: 15 March 2017
Source:Acta Biomaterialia, Volume 51
Author(s): Qiang Gao, Meng Yu, Yajuan Su, Meihua Xie, Xin Zhao, Peng Li, Peter X. Ma
Numerous antimicrobial coatings have been developed for biomedical devices/implants, but few can simultaneously fulfill the requirements for antimicrobial and antifouling ability and biocompatibility. In this study, to develop an antimicrobial and antibiofilm surface coating, diblock amphiphilic molecules with antimicrobial and antifouling segments in a single chain were rationally designed and synthesized. Cationic antimicrobial polypeptides (AMP) were first synthesized by N-carboxyanhydride ring-opening polymerization (NCA-ROP). Heterofunctionalized poly(ethylene glycol) with different lengths (methacrylate-PEGn-tosyl, n=10/45/90) was synthesized and site-specifically conjugated with polypeptides to form diblock amphiphiles. Along with increased PEG chain length, hemolytic activity was considerably improved, and broad-spectrum antimicrobial activity is retained. Three MA-PEGn-b-AMP copolymers were further grafted onto the surface of silicone rubber (a commonly used catheter material) via plasma/UV-induced surface polymerizations to form a bottlebrush-like coating with excellent antimicrobial activity against several pathogenic bacteria (Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus), and effectively prevent biofilm formation. This bottlebrush coating also greatly reduced protein adsorption and platelet adhesion, indicating its excellent antifouling ability. An in vitro cytotoxicity study also demonstrated that this coating is biocompatible with mammalian cells. After subcutaneous implantation of the materials in rats, we demonstrated that the g-PEG45-b-AMP bottlebrush coating exhibits significant anti-infective activity in vivo. Thus, this facilely synthesized PEGylated AMP bottlebrush coating is a feasible method to prevent biomedical devices-associated infections.Statement of SignificanceCurrent antimicrobial coatings are often associated with concerns such as antibiotic resistance, environmental pollution, short-time antimicrobial activity, biofouling, poor blood compatibility and cytotoxicity, etc. To overcome these drawbacks, a robust PEGylated cationic amphiphilic peptides-based bottlebrush-like surface coating is demonstrated here, which fulfil the requirements of antimicrobial and antifouling as well as biocompatibility in the meantime. Briefly, the rational designed g-PEGn-b-AMP block copolymers (n=10/45/90) were synthesized and grafted on silicone surface. This bottlebrush-like coating efficiently kill the contacted bacteria and prevent the biofilm formation, greatly reduced protein and platelet adhesion. It also exhibits excellent blood compatibility and low cytotoxicity in vitro. In particular, g-PEG45-b-AMP coating exhibits significant anti-infection effect in vivo. This coating offering an effective strategy for combating biomedical devices-associated infections.
Graphical abstract
http://ift.tt/2mFsO48
Structuring of composite hydrogel bioadhesives and its effect on properties and bonding mechanism
Publication date: 15 March 2017
Source:Acta Biomaterialia, Volume 51
Author(s): Oded Pinkas, Daniella Goder, Roni Noyvirt, Sivan Peleg, Maayan Kahlon, Meital Zilberman
Bioadhesives are polymeric hydrogels that can adhere to a tissue after crosslinking and are an essential element in nearly all surgeries worldwide. Several bioadhesives are commercially available. However, none of them are ideal. The main limitation of current tissue adhesives is the tradeoff between biocompatibility and mechanical strength, especially in wet hemorrhagic environments. Our novel bioadhesives are based on the natural polymers gelatin (coldwater fish) and alginate, crosslinked by carbodiimide (EDC). Two types of hemostatic agents with a layered silicate structure, montmorillonite (MMT) and kaolin, were loaded in order to improve the sealing ability in a hemorrhagic environment. The effect of the adhesive's components on its mechanical strength was studied by three different methods – burst strength, lap shear and compression. The viscosity, gelation time and structural features of the adhesive were also studied. A qualitative model that describes the effect of the bioadhesive's parameters on the cohesive and adhesive strength was developed. A formulation based on 400mg/mL gelatin, 10mg/mL alginate and 20mg/mL EDC was found as optimal, enabling a burst strength of 387mmHg. Incorporation of kaolin increased the burst strength by 25% due to microcomposite structuring, whereas MMT increased the burst strength by 50% although loaded in a smaller concentration, due to nano-structuring effects. This research clearly shows that the incorporation of kaolin and MMT in gelatin-alginate surgical sealants is a very promising novel approach for improving the bonding strength and physical properties of surgical sealants for use in hemorrhagic environments.Statement of SignificanceThe current manuscript focuses on novel bioadhesives, based on natural polymers and loaded with hemostatic agents with a layered silicate structure, in order to improve the sealing ability in hemorrhagic environment. Such composite bioadhesives have not been developed and studied before.The effect of the adhesive's components on its mechanical strength was studied by three different methods, as well as the physical properties and structural features. Thorough understanding of these unique biomaterials resulted in a qualitative model which describes the effect of the bioadhesive's parameters on the cohesive and adhesive strength. Thus, structure-property-function relationships are presented. Structuring of the composite bioadhesives and its effect of the properties and bonding mechanism, are expected to be of high interest to Acta readership.
Graphical abstract
http://ift.tt/2mFEPXp
Multi-Stimuli-Responsive Biohybrid Nanoparticles with Cross-Linked Albumin Coronae Self-Assembled by a Polymer-Protein Biodynamer
Publication date: Available online 8 March 2017
Source:Acta Biomaterialia
Author(s): Lin Wang, Li Liu, Bingyang Dong, Hanying Zhao, Mingming Zhang, Wenjuan Chen, Yanhang Hong
A thermoresponsive polymer-protein biodynamer was prepared via the bioconjugation of an aliphatic aldehyde-functionalized copolymer to hydrazine-modified bovine serum albumin (BSA) through reversible pyridylhydrazone linkages. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and size exclusion chromatography (SEC) results indicated that the pyridylhydrazone linkages cleaved in an intracellular-mimicking acidic milieu, thus leading to the release of BSA. The dynamic character of the protein biodynamer was demonstrated by exchange reactions with aldehyde-containing molecules. The biodynamer self-assembled into spherical micelles at a temperature above its lower critical solution temperature (LCST). Subsequently, BSA molecules within the hydrophilic coronae of the micelles were readily cross-linked via reaction with cystamine at 45°C, and multi-stimuli-responsive nanoparticles were generated. The biohybrid nanoparticles reversibly swelled and shrank as the cores of the nanoparticles were solvated below the LCST and desolvated above the LCST. The accessible reversibility of the pyridylhydrazone bonds imparts pH-responsive and dynamic characteristics to the nanoparticles. The nanoparticles displayed glutathione (GSH) responsiveness, and the synergistic effects of pH and GSH resulted in complete disintegration of the nanoparticles under the intracellular-mimicking acidic and reductive conditions. The nanoparticles were also enzyme-responsive and disintegrated rapidly in the presence of protease. In vitro cytotoxicity and cell uptake assays demonstrated that the nanoparticles were highly biocompatible and effectively internalized by HepG2 cells, which make them interesting candidates as vehicles for drug delivery application and biomimetic platforms to investigate the biological process in nature.Significance StatementIn this research, we report the synthesis of a temperature and pH dual-responsive polymer-protein biodynamer through reversible pyridylhydrazone formation. The prepared biodynamer can offer a potential platform for intracellular protein delivery. The multi-stimuli-responsive biohybrid nanoparticles containing disulfide functionalities are constructed by cross-linking albumin coronae of the biodynamer micelles. With the combination of a thermoresponsive polymer, protein and reversible covalent bonds, the biohybrid nanoparticles are endowed with highly biocompatible, environmentally responsive and adaptive features. These nanoparticles present the ability to undergo changes in their constitution, hydrodynamic size and nanostructure in response to physical, chemical and biological stimuli, which make them interesting candidates as vehicles for drug delivery application and biomimetic platforms to investigate the biological process in nature.
Graphical abstract
http://ift.tt/2mFLyk2
Sphingosine-1-phosphate improves endothelialization with reduction of thrombosis in recellularized human umbilical vein graft by inhibiting syndecan-1 shedding in vitro
Publication date: 15 March 2017
Source:Acta Biomaterialia, Volume 51
Author(s): Kai Hsia, Ming-Jie Yang, Wei-Min Chen, Chao-Ling Yao, Chih-Hsun Lin, Che-Chuan Loong, Yi-Long Huang, Ya-Ting Lin, Arthur D. Lander, Hsinyu Lee, Jen-Her Lu
Sphingosine-1-phosphate (S1P) has been known to promote endothelial cell (EC) proliferation and protect Syndecan-1 (SDC1) from shedding, thereby maintaining this antithrombotic signal. In the present study, we investigated the effect of S1P in the construction of a functional tissue-engineered blood vessel by using human endothelial cells and decellularized human umbilical vein (DHUV) scaffolds. Both human umbilical vein endothelial cells (HUVEC) and human cord blood derived endothelial progenitor cells (EPC) were seeded onto the scaffold with or without the S1P treatment. The efficacy of re-cellularization was determined by using the fluorescent marker CellTracker CMFDA and anti-CD31 immunostaining. The antithrombotic effect of S1P was examined by the anti-aggregation tests measuring platelet adherence and clotting time. Finally, we altered the expression of SDC1, a major glycocalyx protein on the endothelial cell surface, using MMP-7 digestion to explore its role using platelet adhesion tests in vitro. The result showed that S1P enhanced the attachment of HUVEC and EPC. Based on the anti-aggregation tests, S1P-treated HUVEC recellularized vessels when grafted showed reduced thrombus formation compared to controls. Our results also identified reduced SDC1 shedding from HUVEC responsible for inhibition of platelet adherence. However, no significant antithrombogenic effect of S1P was observed on EPC. In conclusion, S1P is an effective agent capable of decreasing thrombotic risk in engineered blood vessel grafts.Statement of SignificanceSphingosine-1phosphate (S1P) is a low molecular-weight phospholipid mediator that regulates diverse biological activities of endothelial cell, including survival, proliferation, cell barrier integrity, and also influences the development of the vascular system. Based on these characters, we the first time to use it as an additive during the process of a small caliber blood vessel construction by decellularized human umbilical vein and endothelial cell/endothelial progenitor. We further explored the function and mechanism of S1P in promoting revascularization and protection against thrombosis in this tissue engineered vascular grafts. The results showed that S1P could not only accelerate the generation but also reduce thrombus formation of small caliber blood vessel.
Graphical abstract
http://ift.tt/2mFM6X5
Prolonged, acute suppression of cysteinyl leukotriene to reduce capsular contracture around silicone implants
Publication date: 15 March 2017
Source:Acta Biomaterialia, Volume 51
Author(s): Byung Hwi Kim, Min Park, Hyo Jin Park, Seung Ho Lee, Sung Yoon Choi, Chun Gwon Park, Su Min Han, Chan Yeong Heo, Young Bin Choy
We hypothesize that periodically early, local suppression of cysteinyl leukotrienes (CysLTs), which are potent inflammatory mediators, can reduce the fibrotic capsular contracture around silicone implants. We tested this hypothesis with the silicone implants enabled with the sustained release of montelukast, a CysLT receptor antagonist, for 3 and 15days. In this work, we inserted each of the distinct implants into the pocket of the subpanniculus carnosus plane of living rats and performed histological and immunofluorescent (IF) analyses of the tissues biopsied at predetermined periods for 12weeks after implant insertion. The implants with montelukast exhibited significantly reduced polymorphonuclear leukocytes (i.e., PMNs), implying a concurrent reduction of CysLT. This effect was more prominent after long-term local montelukast exposure. Thus, fewer fibroblasts were recruited, thereby reducing transforming growth factor (TGF)-β and myofibroblasts in the tissue around the implant. Therefore, the fibrotic capsule formation, which was assessed using the capsule thickness and collagen density, decreased along with the myofibroblasts. Additionally, the tissue biopsied at the experimental end point exhibited significantly decreased mechanical stiffness.Statement of SignificanceCapsular contracture is troublesome, making the tissues hardened around the silicone implant. This causes serious pain and discomfort to the patients, often leading to secondary surgery for implant replacement. To resolve this, we suggest a strategy of long-term, local suppression of cysteinyl leukotriene, an important mediator present during inflammation. For this, we propose a silicone implant abled to release a drug, montelukast, in a sustained manner. We tested our drug-release implant in living animals, which exhibited a significant decrease in capsule formation compared with the intact silicone implant. Therefore, we conclude that the sustained release of montelukast at the local insertion site represents a promising way to reduce capsular contracture around silicone implants.
Graphical abstract
http://ift.tt/2mFxdEs
Mesoscale porosity at the dentin-enamel junction could affect the biomechanical properties of teeth
Publication date: 15 March 2017
Source:Acta Biomaterialia, Volume 51
Author(s): Elsa Vennat, Wenlong Wang, Rachel Genthial, Bertrand David, Elisabeth Dursun, Aurélien Gourrier
In this paper, the 3D-morphology of the porosity in dentin is investigated within the first 350μm from the dentin-enamel junction (DEJ) by fluorescence confocal laser scanning microscopy (CLSM). We found that the porous microstructure exhibits a much more complex geometry than classically described, which may impact our fundamental understanding of the mechanical behavior of teeth and could have practical consequences for dental surgery.Our 3D observations reveal numerous fine branches stemming from the tubules which may play a role in cellular communication or mechanosensing during the early stages of dentinogenesis. The effect of this highly branched microstructure on the local mechanical properties is investigated by means of numerical simulations. Under simplified assumptions on the surrounding tissue characteristics, we find that the presence of fine branches negatively affects the mechanical properties by creating local stress concentrations. However, this effect is reduced by the presence of peritubular dentin surrounding the tubules.The porosity was also quantified using the CSLM data and compared to this derived from SEM imaging. A bimodal distribution of channel diameters was found near the DEJ with a mean value of 1.5–2μm for the tubules and 0.3–0.5μm for the fine branches which contribute to 30% of the total porosity (∼1.2%). A gradient in the branching density was observed from the DEJ towards the pulp, independently of the anatomical location.Our work constitutes an incentive towards more elaborate multiscale studies of dentin microstructure to better assess the effect of aging and for the design of biomaterials used in dentistry, e.g. to ensure more efficient bonding to dentin. Finally, our analysis of the tubular network structure provides valuable data to improve current numerical models.
Graphical abstract
http://ift.tt/2mFERyv
Role of biphasic calcium phosphate ceramic-mediated secretion of signaling molecules by macrophages in migration and osteoblastic differentiation of MSCs
Publication date: 15 March 2017
Source:Acta Biomaterialia, Volume 51
Author(s): Jing Wang, Dan Liu, Bo Guo, Xiao Yang, Xuening Chen, Xiangdong Zhu, Yujiang Fan, Xingdong Zhang
The inflammatory reaction initiates fracture healing and could play a role in the osteoinductive effect of calcium phosphate (CaP) ceramics, which has been widely confirmed; however, the underlying mechanism has not been fully elucidated. In this study, various signaling molecules from macrophages under the stimulation of osteoinductive biphasic calcium phosphate (BCP) ceramic and its degradation products were examined and evaluated for their influence on the migration and osteoblastic differentiation of mesenchymal stem cells (MSCs). The results of cellular experiments confirmed that the gene expression of most inflammatory factors (IL-1, IL-6 and MCP-1) and growth factors (VEGF, PDGF and EGF) by macrophages were up-regulated to varying degrees by BCP ceramic and its degradation products. Cell migration tests demonstrated that the conditioned media (CMs), which contained abundant signaling molecules secreted by macrophages cultured on BCP ceramic and its degradation products, promoted the migration of MSCs. qRT-PCR analysis indicated that CMs promoted the gene expression of osteogenic markers (ALP, COL-I, OSX, BSP and OPN) in MSCs. ALP activity and mineralization staining further confirmed that CMs promoted the osteoblastic differentiation of MSCs. The present study confirmed the correlation between the inflammatory reaction and osteoinductive capacity of BCP ceramic. The ceramic itself and its degradation products can induce macrophages to express and secrete various signaling molecules, which then recruit and promote the MSCs to differentiate into osteoblasts. Compared with BCP conditioned media, degradation particles played a more substantial role in this process. Thus, inflammation initiated by BCP ceramic and its degradation products could be necessary for osteoinduction by the ceramic.Statement of SignificanceIt is known that the inflammatory reaction initiates fracture healing. The aim of this study was to examine whether osteoinductive BCP ceramics could cause macrophages to change their secretion patterns and whether the secreted cytokines could affect migration and osteoblastic differentiation of MSCs. Moreover, the duration of inflammation could be influenced by the local ionic environment and the degradation products of the implant. Our experimental results revealed the correlation between the inflammatory reaction and osteoinductive capacity of BCP ceramic. The ceramic itself and its degradation products can induce macrophages to express and secrete various signaling molecules, which then recruit and promote the MSCs to differentiate into osteoblasts. Compared with ionic microenvironment, degradation particles played a more substantial role in this process. Therefore, the appropriate inflammation initiated by BCP ceramic and its degradation products could be essential for osteoinduction by the ceramic. We believe that the present study improves the understanding of the effect of biomaterial-mediated inflammation on MSC migration and differentiation and established a preliminary correlation between the immune system and osteoinduction by biomaterials.
Graphical abstract
http://ift.tt/2mFGo7T
Fibrin hydrogels induce mixed dorsal/ventral spinal neuron identities during differentiation of human induced pluripotent stem cells
Publication date: 15 March 2017
Source:Acta Biomaterialia, Volume 51
Author(s): John M. Edgar, Meghan Robinson, Stephanie M. Willerth
We hypothesized that generating spinal motor neurons (sMNs) from human induced pluripotent stem cell (hiPSC)-derived neural aggregates (NAs) using a chemically-defined differentiation protocol would be more effective inside of 3D fibrin hydrogels compared to 2D poly-L-ornithine(PLO)/laminin-coated tissue culture plastic surfaces. We performed targeted RNA-Seq using next generation sequencing to determine the substrate-specific differences in gene expression that regulate cell phenotype. Cells cultured on both substrates expressed sMN genes CHAT and MNX1, though persistent WNT signaling contributed to a higher expression of genes associated with interneurons in NAs cultured in 3D fibrin scaffolds. Cells in fibrin also expressed lower levels of astrocyte progenitor genes and higher levels of the neuronal-specific gene TUBB3, suggesting a purer population of neurons compared to 2D cultures.Statement of SignificanceFibrin scaffolds can support the neuronal differentiation of pluripotent stem cells. This study provides insight into how fibrin hydrogels affect neuronal induction by analyzing of the signaling pathways activated during the differentiation process. These insights can then be used to tailor the properties of these hydrogels to optimize the generation of sMNs for regenerative medicine applications.
Graphical abstract
http://ift.tt/2mFM5lZ
Controlled release of silyl ether camptothecin from thiol-ene click chemistry-functionalized mesoporous silica nanoparticles
Publication date: 15 March 2017
Source:Acta Biomaterialia, Volume 51
Author(s): Yue Yan, Jie Fu, Tianfu Wang, Xiuyang Lu
As efficient drug carriers, stimuli-responsive mesoporous silica nanoparticles are at the forefront of research on drug delivery systems. An acid-responsive system based on silyl ether has been applied to deliver a hybrid prodrug. Thiol-ene click chemistry has been successfully utilized for tethering this prodrug to mesoporous silica nanoparticles. Here, by altering the steric bulk of the substituent on the silicon atom, the release rate of a model drug, camptothecin, was controlled. The synthesized drug delivery system was investigated by analytical methods to confirm the functionalization and conjugation of the mesoporous silica nanoparticles. Herein, trimethyl silyl ether and triethyl silyl ether were selected to regulate the release rate. Under normal plasma conditions (pH 7.4), both types of camptothecin-loaded mesoporous silica nanoparticles (i.e., MSN-Me-CPT and MSN-Et-CPT) did not release the model drug. However, under in vitro acidic conditions (pH 4.0), based on a comparison of the release rates, camptothecin was released from MSN-Me-CPT more rapidly than from MSN-Et-CPT. To determine the biocompatibility of the modified mesoporous silica nanoparticles and the in vivo camptothecin uptake behavior, MTT assays with cancer cells and confocal microscopy observations were conducted, with positive results. These functionalized nanoparticles could be useful in clinical treatments requiring controlled drug release.Statement of SignificanceAs the release rate of drug from drug-carrier plays important role in therapy effects, trimethyl silyl ether (TMS) and triethyl silyl ether (TES) were selected as acid-sensitive silanes to control the release rates of model drugs conjugated from MSNs by thiol-ene click chemistry. The kinetic profiles of TMS and TES materials have been studied. At pH 4.0, the release of camptothecin from MSN-Et-CPT occurred after 2h, whereas MSN-Me-CPT showed immediate drug release. The results showed that silyl ether could be used to control release rates of drugs from MSNs under acid environment, which could be useful in clinical treatments requiring controlled drug release.
Graphical abstract
http://ift.tt/2mFD6l4
Cell number per spheroid and electrical conductivity of nanowires influence the function of silicon nanowired human cardiac spheroids
Publication date: 15 March 2017
Source:Acta Biomaterialia, Volume 51
Author(s): Yu Tan, Dylan Richards, Robert C. Coyle, Jenny Yao, Ruoyu Xu, Wenyu Gou, Hongjun Wang, Donald R. Menick, Bozhi Tian, Ying Mei
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) provide an unlimited cell source to treat cardiovascular diseases, the leading cause of death worldwide. However, current hiPSC-CMs retain an immature phenotype that leads to difficulties for integration with adult myocardium after transplantation. To address this, we recently utilized electrically conductive silicon nanowires (e-SiNWs) to facilitate self-assembly of hiPSC-CMs to form nanowired hiPSC cardiac spheroids. Our previous results showed addition of e-SiNWs effectively enhanced the functions of the cardiac spheroids and improved the cellular maturation of hiPSC-CMs. Here, we examined two important factors that can affect functions of the nanowired hiPSC cardiac spheroids: (1) cell number per spheroid (i.e., size of the spheroids), and (2) the electrical conductivity of the e-SiNWs. To examine the first factor, we prepared hiPSC cardiac spheroids with four different sizes by varying cell number per spheroid (∼0.5k, ∼1k, ∼3k, ∼7k cells/spheroid). Spheroids with ∼3k cells/spheroid was found to maximize the beneficial effects of the 3D spheroid microenvironment. This result was explained with a semi-quantitative theory that considers two competing factors: 1) the improved 3D cell-cell adhesion, and 2) the reduced oxygen supply to the center of spheroids with the increase of cell number. Also, the critical role of electrical conductivity of silicon nanowires has been confirmed in improving tissue function of hiPSC cardiac spheroids. These results lay down a solid foundation to develop suitable nanowired hiPSC cardiac spheroids as an innovative cell delivery system to treat cardiovascular diseases.Statement of SignificanceCardiovascular disease is the leading cause of death and disability worldwide. Due to the limited regenerative capacity of adult human hearts, human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have received significant attention because they provide a patient specific cell source to regenerate damaged hearts. Despite the progress, current human hiPSC-CMs retain an immature phenotype that leads to difficulties for integration with adult myocardium after transplantation. To address this, we recently utilized electrically conductive silicon nanowires (e-SiNWs) to facilitate self-assembly of hiPSC-CMs to form nanowired hiPSC cardiac spheroids. Our previous results showed addition of e-SiNWs effectively enhanced the functions of the cardiac spheroids and improved the cellular maturation of hiPSC-CMs. In this manuscript, we examined the effects of two important factors on the functions of nanowired hiPSC cardiac spheroids: (1) cell number per spheroid (i.e., size of the spheroids), and (2) the electrical conductivity of the e-SiNWs. The results from these studies will allow for the development of suitable nanowired hiPSC cardiac spheroids to effectively deliver hiPSC-CMs for heart repair.
Graphical abstract
http://ift.tt/2mFJMiZ
Dual-mechanism gastroretentive drug delivery system loaded with an amorphous solid dispersion prepared by hot-melt extrusion
Publication date: 1 May 2017
Source:European Journal of Pharmaceutical Sciences, Volume 102
Author(s): Anh Q. Vo, Xin Feng, Manjeet Pimparade, Xinyou Ye, Dong Wuk Kim, Scott T. Martin, Michael A. Repka
In the present study, we aimed to prepare a gastroretentive drug delivery system that would be both highly resistant to gastric emptying via multiple mechanisms and would also potentially induce in situ supersaturation. The bioadhesive floating pellets, loaded with an amorphous solid dispersion, were prepared in a single step of hot-melt extrusion technology. Hydroxypropyl cellulose (Klucel™ MF) and hypromellose (Benecel™ K15M) were used as matrix-forming polymers, and felodipine was used as the model drug. The foam pellets were fabricated based on the expansion of CO2, which was generated from sodium bicarbonate during the melt-extrusion process. A 2n full factorial experimental design was utilized to investigate the effects of formulation compositions to the pellet properties. The melt-extrusion process transformed the crystalline felodipine into an amorphous state that was dispersed and "frozen" in the polymer matrix. All formulations showed high porosity and were able to float immediately, without lag time, on top of gastric fluid, and maintained their buoyancy over 12h. The pellet-specific floating force, which could be as high as 4800μN/g, increased significantly during the first hour, and was relatively stable until 9h. The sodium bicarbonate percentage was found to be most significantly effect to the floating force. The ex vivo bioadhesion force of the pellets to porcine stomach mucosa was approximately 5mN/pellet, which was more than five times higher than the gravitation force of the pellet saturated with water. Drug release was well controlled up to 12h in the sink condition of 0.5% sodium lauryl sulphate in 0.1N HCl. The dissolution at 1, 3, 5, and 8h were 5–12%, 25–45%, 55–80%, and ≥75% respectively for all 11 formulations. In biorelevant dissolution medium, a supersaturated solution was formed, and the concentration was maintained at around 2μg/mL, approximately 10-folds higher than that of the pure felodipine. All input factors significantly affected dissolution in the first 3h, but afterwards, only drug load and hypromellose (HPMC) content had significant effects. The prepared drug delivery system has great potential in overcoming low and fluctuating bioavailability of poorly soluble drugs.ChemicalFelodipine (PubChem CID: 3333); hypromellose (PubChem CID: 57503849), hydroxypropyl cellulose (PubChem CID: 71306830), sodium bicarbonate (PubChem CID: 516892); sodium carbonate (PubChem CID: 10340).
Graphical abstract
http://ift.tt/2mFtPcA
Do flexible inter-injection intervals improve the effects of botulinum toxin A treatment in reducing impairment and disability in patients with spasticity?
Source:Medical Hypotheses
Author(s): Carlo Trompetto, Lucio Marinelli, Laura Mori, Luca Puce, Elisa Pelosin, Carlo Serrati, Francesco Fattapposta, Steno Rinalduzzi, Giovanni Abbruzzese, Antonio Currà
In patients treated with botulinum toxin-A (BoNT-A), toxin-directed antibody formation was related to the dosage and frequency of injections, leading to the empirical adoption of minimum time intervals between injections of 3 months or longer. However, recent data suggest that low immunogenicity of current BoNT-A preparations could allow more frequent injections. Our hypothesis is that a short time interval between injections may be safe and effective in reducing upper limb spasticity and related disability. IncobotulinumtoxinA was injected under ultrasound guidance in spastic muscles of 11 subjects, who were evaluated just before BoNT-A injection (T0), and 1 month (T1), 2 months (T2) and 4 months (T3) after injecting. At T1, in the case of persistent disability related to spasticity interfering with normal activities, patients received an additional toxin dose. Seven subjects received the additional dose at T1 because of persistent disability; 4 of them had a decrease of disability 1 month later (T2). Rethinking the injection scheme for BoNT-A treatment may have a major impact in the management of spasticity and related disability. Future studies with larger sample sizes are warranted to confirm that injection schedules with short time intervals should no longer be discouraged in clinical practice.
http://ift.tt/2mXZGWz
The Hormonal Sensitivity Hypothesis: A Review and New Findings
Source:Medical Hypotheses
Author(s): Carley J. Pope, Kirsten Oinonen, Dwight Mazmanian, Suzanne Stone
Previous women's health practitioners and researchers have postulated that some women are particularly sensitive to hormonal changes occurring during reproductive events. We hypothesize that some women are particularly sensitive to hormonal changes occurring across their reproductive lifespan. To evaluate this hypothesis, we reviewed findings from the existing literature and findings from our own lab. Taken together, the evidence we present shows a recurring pattern of hormonal sensitivity at predictable but different times across the lifespan of some women (i.e., menarche, the premenstrual phase, hormonal contraceptive use, pregnancy, the postpartum period, and menopause). These findings provide support for the hypothesis that there is a subgroup of women who are more susceptible to physical, psychological, and sexual symptoms related to hormonal shifts or abrupt hormonal fluctuations that occur throughout the reproductive lifespan. We propose that this pattern reflects a Hormonal Sensitivity Syndrome.
http://ift.tt/2mXVw0D
The Role of Photodynamic Therapy in Acne: An Evidence-Based Review
Abstract
Background
Acne vulgaris is a highly prevalent skin disorder that affects almost all adolescents and can persist into adulthood. Photodynamic therapy (PDT) is an emerging treatment for acne that involves the use of a photosensitizer in combination with a light source and oxygen.
Methods
We performed a systematic review of the literature and critically evaluated the studies. Sixty-nine clinical trials, four case reports, and two retrospective studies met the inclusion criteria, and seven of the studies were high quality.
Results
The most common photosensitizers used were 5-aminolevulinic acid and methyl aminolevulinate, and both showed similar response. Red light was the most frequently used light source, followed by intense pulsed light, and showed comparable results. Inflammatory and non-inflammatory lesions both responded to treatment, with inflammatory lesions showing greater clearance in most studies. Adverse events associated with PDT for acne were mild and included pain on illumination and post-procedural erythema and edema. PDT has been safely used in higher Fitzpatrick skin types (III–IV), although these patients had a higher risk of transient hyperpigmentation.
Conclusion
This review supports PDT as an efficacious treatment for acne and a good adjunctive treatment for mild to severe acne, especially in patients who have not responded to topical therapy and oral antibacterials, and are not great candidates for isotretinoin. Further studies are warranted to evaluate the optimal photosensitizers, light sources, incubation times, and number of treatments for PDT use in acne.
http://ift.tt/2n5EKd0
Carcinogenesis mechanisms of Fusobacterium nucleatum
Publication date: May 2017
Source:Biomedicine & Pharmacotherapy, Volume 89
Author(s): Pourya Gholizadeh, Hosein Eslami, Hossein Samadi Kafil
Transformed cells of cancers may be related to stromal cells, immune cells, and some bacteria such as Fusobacterium nucleatum. This review aimed to evaluate carcinogenesis mechanisms of Fusobacterium spp. in the oral cavity, pancreatic and colorectal cancers. These cancers are the three of the ten most prevalence cancer in the worldwide. Recent findings demonstrated that F. nucleatum could be considered as the risk factor for these cancers. The most important carcinogenesis mechanisms of F. nucleatum are chronic infection, interaction of cell surface molecules of these bacteria with immune system and stromal cells, immune evasion and immune suppression. However, there are some uncertainty carcinogenesis mechanisms about these bacteria, but this review evaluates almost all the known mechanisms. Well-characterized virulence factors of F. nucleatum such as FadA, Fap2, LPS and cell wall extracts may act as effector molecules in the shift of normal epithelial cells to tumor cells. These molecules may provide new targets, drugs, and strategies for therapeutic intervention.
http://ift.tt/2lXPb0k
Evaluation of serum hepcidin and iron levels in patients with PCOS: a case-control study
Abstract
Purpose
Polycystic ovary syndrome (PCOS) is the most common cause of chronic anovulation with a prevalence of 5–10% in women of reproductive age. The etiology of this disease is not well known, and hepcidin is one of the factors affecting the pathogenesis of the disease. The aim of this study was to evaluate plasma levels of hepcidin in patients with PCOS and its correlation with serum iron level.
Methods
In this case-control study, plasma levels of hepcidin, IL-6, and ferritin using ELISA method and serum iron levels using a spectrophotometric method were tested on 56 women with PCOS (case group) and 41 healthy subjects (control group). The results were analyzed using t test, General Linear Model, Binary logistic regression, and linear regression tests.
Results
The mean hepcidin levels were 1.97 ± 0.53 and 2.40 ± 0.25 pg/ml in the case and control groups, respectively. The t-test results showed significant difference between the two groups (p = 0.0001). The mean serum iron levels were 72.89 ± 28.97 and 70.62 ± 31.18 g/dl in the case and control groups, respectively. The t test analysis indicated no significant difference between the two groups. The serum ferritin and iron levels had no significant relation with serum hepcidin level in two groups.
Conclusion
Despite the differences in the serum levels of hepcidin between the two groups, no significant relation was observed between serum iron levels and hepcidin level in this group of patients. This implies the need for more comprehensive studies on gene expression in hepcidin and iron pathways using real-time and Western techniques to investigate more precisely serum hepcidin level and its relationship with the factors mentioned.
http://ift.tt/2n5GD9u
Publication date: Available online 7 March 2017 Source:Medical Journal Armed Forces India
Publication date: Available online 7 March 2017
Source:Medical Journal Armed Forces India
http://ift.tt/2m1StAN
Publication date: Available online 8 March 2017 Source:Medical Journal Armed Forces India
Publication date: Available online 8 March 2017
Source:Medical Journal Armed Forces India
http://ift.tt/2lDKWvR
Therapeutic Potential for Bone Morphogenetic Protein 4 in Human Malignant Glioma
Publication date: April 2017
Source:Neoplasia, Volume 19, Issue 4
Author(s): Guifa Xi, Benjamin Best, Barbara Mania-Farnell, Charles David James, Tadanori Tomita
Human glioma, in particular, malignant forms such as glioblastoma exhibit dismal survival rates despite advances in treatment strategies. A population of glioma cells with stem-like features, glioma cancer stem-like cells (GCSCs), contribute to renewal and maintenance of the tumor cell population and appear responsible for chemotherapeutic and radiation resistance. Bone morphogenetic protein 4 (BMP4), drives differentiation of GCSCs and thus improves therapeutic efficacy. Based on this observation it is imperative that the clinical merits of BMP4 in treating human gliomas should be addressed. This article reviews BMP4 signaling in central nervous system development and in glioma tumorigenesis, and the potential of this molecule as a treatment target in human gliomas. Further work needs to be done to determine if distinct lineages of GCSCs, associated with different glioma sub-classifications, proneural, neural, classical and mesenchymal, differ in responsiveness to BMP4 treatment. Additionally, interaction among BMP4 and cell matrix, tumor-vascular molecules and microglial immune cells also needs to be investigated, as this will enhance our knowledge about the role of BMP4 in human glioma and lead to the identification and/or development of novel therapeutic approaches that improve treatment outcomes of these devastating tumors.
http://ift.tt/2n5AKsU
Nidogen-1 Degraded by Cathepsin S can be Quantified in Serum and is Associated with Non–Small Cell Lung Cancer
Publication date: April 2017
Source:Neoplasia, Volume 19, Issue 4
Author(s): Nicholas Willumsen, Cecilie L. Bager, Diana J. Leeming, Anne-Christine Bay-Jensen, Morten A. Karsdal
Loss of basement membrane (BM) integrity is typically associated with cancer. Nidogen-1 is an essential component of the BM. Nidogen-1 is a substrate for cathepsin-S (CatS) which is released into the tumor microenvironment. Measuring nidogen-1 degraded by CatS may therefore have biomarker potential in cancer. The aim of this study was to investigate if CatS-degraded nidogen-1 was detectable in serum and a possible biomarker for cancer, a pathology associated with disruption of the BM. A competitive enzyme-linked immunosorbent assay (NIC) was developed with a monoclonal mouse antibody specific for a CatS cleavage site on human nidogen-1. Dilution and spiking recovery, inter- and intravariation, as well as accuracy were evaluated. Serum levels were evaluated in patients with breast cancer, small cell lung cancer (SCLC), and non-SCLC (NSCLC) and in healthy controls. The results indicated that the NIC assay was specific for nidogen-1 cleaved by CatS. Inter- and intraassay variations were 9% and 14%, respectively. NIC was elevated in NSCLC as compared to healthy controls (P<.001), breast cancer (P<.01), and SCLC (P<.5). The diagnostic power (area under the receiver operating characteristics) of NIC for NSCLC as compared to all other samples combined was 0.83 (95% confidence interval: 0.71-0.95), P<.0001. In conclusion, nidogen-1 degraded by CatS can be quantified in serum by the NIC assay. The current data strongly suggest that cathepsin-S degradation of nidogen-1 is strongly associated with NSCLC, which needs validation in larger clinical cohorts.
http://ift.tt/2mAOkGT
Overexpression of the A Disintegrin and Metalloproteinase ADAM15 is linked to a Small but Highly Aggressive Subset of Prostate Cancers
Publication date: April 2017
Source:Neoplasia, Volume 19, Issue 4
Author(s): Christoph Burdelski, Michael Fitzner, Claudia Hube-Magg, Martina Kluth, Asmus Heumann, Ronald Simon, Till Krech, Till Clauditz, Franziska Büscheck, Stefan Steurer, Corinna Wittmer, Andrea Hinsch, Andreas M. Luebke, Frank Jacobsen, Sarah Minner, Maria Christina Tsourlakis, Burkhard Beyer, Thomas Steuber, Imke Thederan, Guido Sauter, Jakob Izbicki, Thorsten Schlomm, Waldemar Wilczak
The A Disintegrin and Metalloproteinase (ADAM) family of endopeptidases plays a role in many solid cancers and includes promising targets for anticancer therapies. Deregulation of ADAM15 has been linked to tumor aggressiveness and cell line studies suggest that ADAM15 overexpression may also be implicated in prostate cancer. To evaluate the impact of ADAM15 expression and its relationship with key genomic alterations, a tissue microarray containing 12,427 prostate cancers was analyzed by immunohistochemistry. ADAM15 expression was compared to phenotype, prognosis and molecular features including TMPRSS2:ERG fusion and frequent deletions involving PTEN, 3p, 5q and 6q. Normal prostate epithelium did not show ADAM15 staining. In prostate cancers, negative, weak, moderate, and strong ADAM15 staining was found in 87.7%, 3.7%, 5.6%, and 3.0% of 9826 interpretable tumors. Strong ADAM15 staining was linked to high Gleason grade, advanced pathological tumor stage, positive nodal stage and resection margin. ADAM15 overexpression was also associated with TMPRSS2:ERG fusions and PTEN deletions (P<.0001) but unrelated to deletions of 3p, 5q and 6q. In univariate analysis, high ADAM15 expression was strongly linked to PSA recurrence (P<.0001). However, in multivariate analyses this association was only maintained if the analysis was limited to preoperatively available parameters in ERG-negative cancers. The results of our study demonstrate that ADAM15 is strongly up regulated in a small but highly aggressive fraction of prostate cancers. In these tumors, ADAM15 may represent a suitable drug target. In a preoperative scenario, ADAM15 expression measurement may assist prognosis assessment, either alone or in combination with other markers
http://ift.tt/2nefQHm
Oxytocin – The Sweet Hormone?
Publication date: Available online 8 March 2017
Source:Trends in Endocrinology & Metabolism
Author(s): Gareth Leng, Nancy Sabatier
Mammalian neurons that produce oxytocin and vasopressin apparently evolved from an ancient cell type with both sensory and neurosecretory properties that probably linked reproductive functions to energy status and feeding behavior. Oxytocin in modern mammals is an autocrine/paracrine regulator of cell function, a systemic hormone, a neuromodulator released from axon terminals within the brain, and a 'neurohormone' that acts at receptors distant from its site of release. In the periphery oxytocin is involved in electrolyte homeostasis, gastric motility, glucose homeostasis, adipogenesis, and osteogenesis, and within the brain it is involved in food reward, food choice, and satiety. Oxytocin preferentially suppresses intake of sweet-tasting carbohydrates while improving glucose tolerance and supporting bone remodeling, making it an enticing translational target.
http://ift.tt/2lXPYyi
Effects of montelukast on tendon healing in a murine model
Abstract
Background
Tendon injury induces a local inflammatory response characterized by the production of pro-inflammatory cytokines. The aim of this study is to investigate the effects of montelukast sodium on the healing of tendons through histological and biomechanical evaluations.
Methods
Forty-eight female Wistar albino rats were randomly assigned to an experimental group that received montelukast sodium (n = 24) and a control group (n = 24) that did not. Tendon injury was created in the Achilles tendon. The experimental group was injected intraperitoneally (IP) with 1 ml of 1 mg/kg montelukast sodium solution once a day prior to the surgery and during the experimental research. The control group was injected with saline solution. Two weeks later, eight rats in each group underwent a histological evaluation. In the fourth week, eight rats underwent a histological evaluation and the other eight rats went through a biomechanical evaluation.
Results
Based on the histological evaluation in the second week, it was observed that the severity of the inflammation was less in the experimental group that received montelukast sodium (p < 0.05). In terms of the formation of collagen, no significant difference was observed between the groups in the second and fourth weeks. Tendon breaking loads were 33.2 ± 10.95 and 38.8 ± 10.90 N for the montelukast group and the control group, respectively. However, the difference between the groups was found to be statistically insignificant (p > 0.05).
Conclusions
There was no negative effect on the healing of tendons due to injection of montelukast sodium. In addition, observing less inflammation in the experimental group in the earlier phase suggests that montelukast sodium may help in preventing tendon adhesion after reconstructive treatment.
Level of Evidence: Not ratable.
http://ift.tt/2necGmQ
Metal/metalloid content in plant parts and soils of Corylus spp. influenced by mining–metallurgical production of copper
Abstract
The town of Bor and its surroundings (Serbia) have been under environmental pollution for more than a century, due to exploitation of large copper deposits. Naturally present Corylus spp. were sampled in the surroundings of the mine and flotation tailings at 12 sites distributed in six zones with different pollution loads, under the assumption that all the zones were endangered except for the background. As, Cd, Co, Cr, Cu, Fe, Mn, Mo, Ni, Pb and Zn inputs from soil and the air were evaluated in plant parts, in terms of absorption, accumulation and indication abilities of Corylus spp. The obtained results showed that As and Cu were the most enriched elements in soil, and their concentration exceeded the limit and remediation values proposed by the regulation. Plant parts (root, branch, leaf and catkin) also showed enrichment of most studied elements in wide ranges. According to the enrichment factor for plant, metal/metalloid inputs, particularly in leaves, were from anthropogenic origin. Plant absorption which occurred at the soil–root interface was low, based on the bioaccumulation factor, which could be indicative of resistance mechanisms of root to abiotic stress induced by a high content of elements in soil substrate. The values of bioaccumulation coefficient suggested weak and intermediate absorption and exclusion abilities of Corylus spp. to the studied elements. Element concentrations differ in unwashed and washed leaves, as well as pollution loads in plant and soil samples from the background, traffic and the sites with clear mining–metallurgical influence. Therefore, Corylus spp. could be promising in biomonitoring studies.
http://ift.tt/2mXAGi2
Imatinib induces sustained progression arrest in RECIST progressive desmoid tumours: Final results of a phase II study of the German Interdisciplinary Sarcoma Group (GISG)
Source:European Journal of Cancer, Volume 76
Author(s): Bernd Kasper, Viktor Gruenwald, Peter Reichardt, Sebastian Bauer, Geraldine Rauch, Ronald Limprecht, Michaela Sommer, Antonia Dimitrakopoulou-Strauss, Lothar Pilz, Florian Haller, Peter Hohenberger
BackgroundDesmoid tumours describe a rare monoclonal, fibroblastic proliferation characterised by an often unpredictable clinical course. Surgery is one therapeutic option for progressing patients, except if mutilating and associated with considerable function loss. Different systemic treatment approaches have been investigated and promising results could be demonstrated using imatinib.Patients and methodsWe initiated a phase II trial within the German Interdisciplinary Sarcoma Group (GISG) evaluating imatinib to induce progression arrest in desmoid tumour patients being Response Evaluation Criteria in Solid Tumours (RECIST) progressive, not amenable to surgical resection with R0 intent or accompanied by unacceptable function loss (NCT01137916). Thirty-eight patients (median age 44 years [range: 19–80]; 68% female; 90% Eastern Cooperative Oncology Group (ECOG) performance status 0) were treated with a daily dose of 800 mg imatinib planned over 2 years. The progression arrest rate after 6 months of imatinib treatment (PAR6mo) was the primary end-point. Patients showing disease progression under imatinib could be treated with nilotinib 800 mg daily. Accrual started in July 2010 in four GISG centres and finalised in September 2013.ResultsThe final analysis for the primary end-point in the evaluable patients of the full analysis set revealed a PAR6mo of 65%. Subsequent progression arrest rates at 9, 12, 15, 18, 21 and 24 months were 65%, 59%, 53%, 53%, 50% and 45%, respectively. None of the patients died within the study observational period. Best reported response was seven partial responses at 21 months revealing an overall response rate of 19%. Eight patients treated with nilotinib demonstrated a PAR at 3 months of 88% (7/8); no more disease progressions occurred until end of study. In general imatinib adverse events were mild to moderate.ConclusionsImatinib induces sustained progression arrest in RECIST progressive desmoid tumour patients. In addition, nilotinib had the potential to stabilise desmoid tumour growth after treatment failure with imatinib.
http://ift.tt/2n5k58P
Long-term outcome of the REMAGUS 02 trial, a multicenter randomised phase II trial in locally advanced breast cancer patients treated with neoadjuvant chemotherapy with or without celecoxib or trastuzumab according to HER2 status
Source:European Journal of Cancer, Volume 75
Author(s): Sylvie Giacchetti, Anne-Sophie Hamy, Suzette Delaloge, Etienne Brain, Frédérique Berger, Brigitte Sigal-Zafrani, Marie-Christine Mathieu, Philippe Bertheau, Jean Marc Guinebretière, Mahasti Saghatchian, Florence Lerebours, chafouny mazouni, Olivier Tembo, Marc Espié, Fabien Reyal, Michel Marty, Bernard Asselain, Jean-Yves Pierga
BackgroundThe REMAGUS-02 multicenter randomised phase II trial showed that the addition to neoadjuvant chemotherapy (NAC) of trastuzumab in patients with localised HER2-positive breast cancer (BC) increased the pathological complete response (pCR) rate and that the addition of celecoxib in HER2-negative cases did not increase the pCR rate. We report here the long-term follow-up results for disease-free survival (DFS) and overall survival (OS).Patients and methodsFrom 2004 to 2007, 340 stage II–III BC patients were randomly assigned to receive neoadjuvant EC-T (four cycles of epirubicin–cyclophosphamide followed by four cycles of docetaxel) +/− celecoxib in HER2-negative cases (n = 220) and ± trastuzumab in HER2-positive cases (n = 120). From September 2005, all patients with HER2-positive BC received adjuvant T (n = 106).ResultsMedian follow-up was nearly 8 years (94.4 months, 20–127 m). In the HER2-negative subgroup, addition of celecoxib was not associated with a DFS benefit. Favourable factors were smaller tumour size, expression of progesterone receptor status (PgR) and pCR. In the HER2-positive population, neoadjuvant trastuzumab was not associated with a DFS benefit. Axillary pCR was the only prognostic factor associated with DFS in this group [HR = 0.44, 95% CI = 0.2–0.97], p = 0.035]. To note, DFS and OS were significantly higher in the HER2-positive than in HER2-negative BC patients (HR = 0.58 [0.36–0.92], p = 0.021).ConclusionCelecoxib combined with NAC provided neither pCR nor survival benefit in patients with HER2-negative BC. Absence of PgR is a major prognostic factor. Neoadjuvant trastuzumab increased pCR rates without translation into a DFS or OS benefit compared with adjuvant trastuzumab only. Axillary pCR could be a more relevant surrogate of survival than in the breast in HER2-positive population. A retrospective comparison shows that patients with HER2-positive tumours have a better outcome than HER2-negative BC patients showing the impact of trastuzumab on the natural history of BC.
Teaser
Key message: Celecoxib, an anti-Cox2, neither improves pCR nor the outcome in HER2-negative BC patients receiving sequential NAC. The long-term outcome of luminal B BC can be worse than triple-negative BC, whereas HER2-positive BC patients have a better prognostic than other subtypes with the addition of trastuzumab in neoadjuvant or adjuvant setting.http://ift.tt/2mAySum
Corrigendum to “Predicting and preventing thromboembolic events in patients receiving cisplatin-based chemotherapy for germ cell tumours” [Eur J Cancer 69 (2016) 151–157]
Source:European Journal of Cancer
Author(s): Marco Gizzi, Lucie Oberic, Christophe Massard, Audrey Poterie, Gwenael Le Teuff, Yohann Loriot, Laurence Albiges, Giulia Baciarello, Judith Michels, Alberto Bossi, Pierre Blanchard, Bernard Escudier, Karim Fizazi
http://ift.tt/2n5nQes
-
Ειδοποίηση Μελετητή:[ ωτα ] [HTML] Gender, identity and material: Film screening C Brand - 2017 ftypM4V *M4V M4A mp42isom*a┌moovlmvhd...
-
Publication date: September 2017 Source: Free Radical Biology and Medicine, Volume 110 Author(s): Lucía Fernández-del-Río, Anish Nag, Elen...
