Publication date: April 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 4
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Τρίτη 13 Μαρτίου 2018
Table of Contents
I pledge to prescribe ethically
Publication date: April 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 4
Author(s): Andrew Kelsey, Justin Finch, Jane M. Grant-Kels
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Information for Readers
Publication date: April 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 4
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Comorbidities in rosacea: A systematic review and update
Publication date: April 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 4
Author(s): Roger Haber, Maria El Gemayel
BackgroundRosacea is linked to abnormalities of cutaneous vasculature and dysregulation of the inflammatory response. Recent reports on rosacea have shown a significant association with cardiovascular, gastrointestinal, and psychiatric diseases, all of which may affect morbidity and mortality among these patients.ObjectiveTo review available data regarding comorbidities associated with rosacea, discuss their pathogenesis, and highlight the evaluation of affected patients.MethodsWe performed a complete and systematic literature review in PubMed/Medline, Embase, and the Cochrane Collaboration databases, searching for all articles on possible associated diseases that have been reported with rosacea, with no limits on publication date, participant age, sex, or nationality.ResultsA total of 29 studies were included in this systematic review, including 14 case-control, 8 cross-sectional, and 7 cohort studies. Statistically significant association with rosacea has been mostly demonstrated with depression (n = 117,848 patients), hypertension (n = 18,176), cardiovascular diseases (n = 9739), anxiety disorder (n = 9079), dyslipidemia (n = 7004), diabetes mellitus (n = 6306), migraine (n = 6136), rheumatoid arthritis (n = 4192), Helicobacter pylori infection (n = 1722), ulcerative colitis (n = 1424), and dementia (n = 1194).LimitationsLimitations included the accuracy of the published data, potential patient selection, and possible confounding factors. The true nature of the drawn correlations is uncertain, and causality cannot be established.ConclusionsRosacea is associated with a number of systemic disorders. Recognition of these conditions is critical to providing appropriate screening and management of affected patients.
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Journal Based CME Instructions and Information
Publication date: April 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 4
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Alopecia areata is a medical disease
Publication date: April 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 4
Author(s): Dorota Z. Korta, Angela M. Christiano, Wilma Bergfeld, Madeleine Duvic, Abby Ellison, Jennifer Fu, John E. Harris, Maria K. Hordinsky, Brett King, Dory Kranz, Julian Mackay-Wiggan, Amy McMichael, David A. Norris, Vera Price, Jerry Shapiro, Natasha Atanaskova Mesinkovska
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Editorial Board
Publication date: April 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 4
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Answers to CME examination
Publication date: April 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 4
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Topical calcipotriol before ablative fractional laser-assisted photodynamic therapy enhances treatment outcomes for actinic keratosis in Fitzpatrick grades III-V skin: A prospective randomized clinical trial
Publication date: April 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 4
Author(s): Jeong-Wan Seo, Ki-Hoon Song
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CME examination
Publication date: April 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 4
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Recommendations for improving the patient experience in specialty encounters
Publication date: April 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 4
Author(s): Nicholas Golda, Stephen Beeson, Nita Kohli, Brandon Merrill
The relationship between patient experience and health care quality has generated significant interest in the patient experience measure. However, it is challenging to find information on how to improve one's patient experience score because scientific data on this topic are weak or lacking, and suggestions provided by scoring vendors are often overgeneralized and not specialty-specific. This review will focus on the current state of evidence supporting factors influencing patient experience (both positive and negative) in outpatient specialist encounters that are applicable to general and surgical dermatology. The literature review includes research from multiple medical specialties. Identified studies were based on title and abstract and sourced from Medline, PubMed, and Scopus databases. Medical subject headings terms in PubMed and Ovid Medline included "dermatology/standards," "patient satisfaction," "surgery/standards," "physician-patient relations," "surgery," "practice management," "practice management, medical," "office management," "patient experience," "practice guidelines," "best practice," and "outpatient surgery." During this review, three main themes affecting the patient experience emerged: communication, time, and access. Of the three, communication appears to be the dominant theme affecting the patient experience measure.
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Prescribing to save patients money: Ethical considerations
Publication date: April 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 4
Author(s): Shridat A. Jadoo, Jules B. Lipoff
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Answers to CME examination
Publication date: April 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 4
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All-cause mortality in patients with basal and squamous cell carcinoma: A systematic review and meta-analysis
Publication date: April 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 4
Author(s): Mackenzie R. Wehner, Wilmarie Cidre Serrano, Adi Nosrati, Patrick Michael Schoen, Mary-Margaret Chren, John Boscardin, Eleni Linos
BackgroundThere are varying reports of the association of basal cell carcinoma (BCC) and cutaneous squamous cell carcinoma (SCC) with mortality.ObjectiveTo synthesize the available information on all-cause mortality after a diagnosis of BCC or SCC in the general population.MethodsWe searched PubMed (1966-present), Web of Science (1898-present), and Embase (1947-present) and hand-searched to identify additional records. All English articles that reported all-cause mortality in patients with BCC or SCC were eligible. We excluded case reports, case series, and studies in subpopulations of patients. Random effects model meta-analyses were performed separately for BCC and SCC.ResultsThe searches yielded 6538 articles, and 156 were assessed in a full-text review. Twelve studies met the inclusion criteria, and 4 were included in the meta-analysis (encompassing 464,230 patients with BCC and with 175,849 SCC), yielding summary relative mortalities of 0.92 (95% confidence interval, 0.83-1.02) in BCC and 1.25 (95% confidence interval, 1.17-1.32) in SCC.LimitationsOnly a minority of studies controlled for comorbidities. There was significant heterogeneity in meta-analysis (χ2P < .001, I2 > 98%), but studies of SCC were qualitatively concordant: all showed statistically significant increased relative mortality.ConclusionsWe found that patients with SCC are at higher risk for death from any cause compared with the general population.
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Omalizumab response in patients with chronic idiopathic urticaria: Insights from the XTEND-CIU study
Publication date: April 2018
Source:Journal of the American Academy of Dermatology, Volume 78, Issue 4
Author(s): Thomas B. Casale, Patrick H. Win, Jonathan A. Bernstein, Karin Rosén, Michael Holden, Ahmar Iqbal, Benjamin L. Trzaskoma, Ming Yang, Evgeniya N. Antonova, Thomas Murphy, Mark D. Scarupa, Howard Sofen, Allen Kaplan
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Ultrasound Molecular Imaging of Atherosclerosis Using Small-Peptide Targeting Ligands Against Endothelial Markers of Inflammation and Oxidative Stress
Publication date: Available online 13 March 2018
Source:Ultrasound in Medicine & Biology
Author(s): Federico Moccetti, Craig C. Weinkauf, Brian P. Davidson, J. Todd Belcik, Edmund R. Marinelli, Evan Unger, Jonathan R. Lindner
The aim of this study was to evaluate a panel of endothelium-targeted microbubble (MB) ultrasound contrast agents bearing small peptide ligands as a human-ready approach for molecular imaging of markers of high-risk atherosclerotic plaque. Small peptide ligands with established affinity for human P-selectin, VCAM-1, LOX-1 and von Willebrand factor (VWF) were conjugated to the surface of lipid-stabilized MBs. Contrast-enhanced ultrasound (CEUS) molecular imaging of the thoracic aorta was performed in wild-type and gene-targeted mice with advanced atherosclerosis (DKO). Histology was performed on carotid endarterectomy samples from patients undergoing surgery for unstable atherosclerosis to assess target expression in humans. In DKO mice, CEUS signal for all four targeted MBs was significantly higher than that for control MBs, and was three to sevenfold higher than in wild-type mice, with the highest signal achieved for VCAM-1 and VWF. All molecular targets were present on the patient plaque surface but expression was greatest for VCAM-1 and VWF. We conclude that ultrasound contrast agents bearing small peptide ligands feasible for human use can be targeted against endothelial cell adhesion molecules for inflammatory cells and platelets for imaging advanced atherosclerotic disease.
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HDR Salvage Brachytherapy: Multiple Hypothesis Testing vs Machine Learning Analysis
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Gilmer Valdes, Albert J. Chang, Yannet Interian, Kenton Owen, Shane T. Jensen, Lyle H. Ungar, Adam Cunnan, Timothy D. Solberg, I-Chow Hsu
Teaser
Approximately only 50% of patients benefit from Salvage High Dose Rate Brachytherapy (sHDRB) with the majority of second recurrences occurring distantly. Therefore, a better patient selection before sHDRB is critical. Using Machine learning we found that patients with a Fraction of Positive Cores > 0.35 and a Disease Free Interval < 4.12 years after their initial radiation treatment experienced a higher failure rate after salvage HDRB of 0.75 vs 0.38 for the rest of the population.http://ift.tt/2tPYmJk
Close margin <2mm is not associated with higher risks of 10-year local recurrence and breast cancer mortality compared to negative margins in women treated with breast-conserving therapy
Publication date: Available online 13 March 2018
Source:International Journal of Radiation Oncology*Biology*Physics
Author(s): Susan Tyler, Pauline T. Truong, Mary Lesperance, Alan Nichol, Chris Baliski, Rebecca Warburton, Scott Tyldesley
PurposeThe 2014 SS0/ASTRO consensus suggests "no ink on tumor" is a sufficient surgical margin for invasive breast cancer treated with breast conserving surgery (BCS). Whether close margin <2 mm is associated with inferior outcomes remains controversial. This study evaluates 10-year outcomes by margin status in a population-based cohort treated with BCS and adjuvant radiotherapy (RT).MethodsSubjects were 10,863 women with pT1-T3, any N, M0 invasive cancer referred from 2001-2011, an era in which the institutional policy was to re-excise close or positive margins, except in select cases. All women underwent BCS and whole breast ± boost RT. Local recurrence (LR) and breast cancer-specific survival (BCSS) were examined using competing risk analysis in cohorts with negative (≥2 mm; n=9241, 85%), close (<2 mm; n=1310, 12%), or positive (tumor touching ink; n=312, 3%) margins. Multivariable analysis (MVA) and matched-pair analysis were performed.ResultsMedian follow-up was 8 years. Systemic therapy was used in 87% of patients. Boost RT was used in 34.1%, 76.9% and 79.5% of patients with negative, close, and positive margins, respectively. In the negative, close, and positive margin cohorts, 10-year cumulative incidence of LR were 1.8%, 2.0%, and 1.1%, (p=0.759). Corresponding BCSS estimates were 93.9%, 91.8%, and 87.9%, (p<0.001). On MVA, close margins were not associated with increased LR (HR 1.25, 95% CI 0.79-1.97, p=0.350) or reduced BCSS (HR 1.25, 95% CI 0.98-1.58, p=0.071) relative to negative margins. On matched-pair analysis, close margin cases had similar LR (p=0.114) and BCSS (p=0.100) compared to negative margin controls.ConclusionSelect cases with close or positive margins in this population-based analysis had similar LR and BCSS compared to negative margins. While these findings do not endorse omitting re-excision for all cases, the data support a policy of accepting carefully selected cases with close margins for adjuvant radiation therapy without re-excision.
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Cisplatin suppresses proliferation, migration and invasion of nasopharyngeal carcinoma cells in vitro by repressing the Wnt/β-catenin/Endothelin-1 axis via activating B cell translocation gene 1
Abstract
Purpose
Nasopharyngeal carcinoma (NPC) is one of the most commonly diagnosed cancers worldwide with significantly high prevalence in Southern China. Chemoprevention of cancer with alkylating agent compounds could potentially reverse, suppress, or prevent cancer progression. Cisplatin (CIS) is an antineoplastic or cytotoxic platinum-based drug used for chemotherapy of different types of human cancers such as NPC. Nevertheless, the effects of CIS on the migration and invasion of human NPC cells and the underlying molecular mechanisms have not yet been fully scrutinized.
Methods
In this work, we tested the effect of CIS on the proliferation, migration and invasion of NPC cells. The results exhibited that this drug exerts remarkable inhibitory effects on the proliferation, migration and invasion of NPC cells in a dose-dependent manner. Western blotting and real time RT-PCR were used for expression analyses.
Results
We found that CIS treatment led to a dose-dependent inhibition of Endothelin-1 (ET1) expression, at protein as well as mRNA levels in NPC cells. CIS was also found to activate the expression of BTG1 in NPC cells. Moreover, mechanistic analyses revealed that CIS increased the expression of B cell translocation gene 1 (BTG1) to suppress the expression of ET1. Furthermore, we show that ET1 could not be induced in CIS-resistant cells with suppressed BTG1 expression, and subsequently demote the proliferation, migration and invasion of NPC cells.
Conclusions
These findings provided compelling evidence of the role of CIS in suppressing NPC metastasis and its underlying molecular mechanisms.
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An in vivo evaluation of microbial diversity before and after the photo-activated disinfection in primary endodontic infections: Traditional phenotypic and molecular approaches
Source:Photodiagnosis and Photodynamic Therapy, Volume 22
Author(s): Maryam Pourhajibagher, Abbas Bahador
BackgroundIt is essential to identify the root canal microbial diversity and count. This is due to the polymicrobial nature of the primary endodontic infection that is associated with the microbial diversity and increased resistance to the antimicrobial agents. Photo-activated disinfection (PAD), also known as antimicrobial photodynamic therapy, is a new promising non-antibiotic approach, studied to prevent microbial resistance and treatment failure.Materials and methodsIn this study, we investigated the effect of PAD on reduction of microbial diversity and count, related with primary endodontic infections. Microbial specimens were collected before PAD from patients infected with the primary endodontic infection. PAD with toluidine blue O (TBO), in combination with diode laser, was performed on infected root canals. Resampling was carried out on the root canal after PAD, and microorganisms were identified by classical microbiological tests using biochemical and analytical profile index (API ® 20A) assays and nucleic acid approaches.ResultsFrom the 36 subjects studied before TBO-PAD, 187 cultivable isolates from 14 different genera and 19 various microbial species were retrieved. Of the bacterial isolates, 45.4% were strict anaerobes including Veillonella parvula, Porphyromonas gingivalis, Propionibacterium acnes, Lactobacillus acidophilus, Campylobacter rectus, and Slackia exigua, in order of their frequency; 45.4% were facultative anaerobes; and 9.2% were microaerophilic bacteria (Aggregatibacter actinomycetemcomitans). This in vivo study revealed significant decrease in the microbial diversity and count of the infected root canal after TBO-PAD (P < 0.05); whereas P. gingivalis strains, the most resistance microorganisms, were recovered in 34% of the samples after TBO-mediated PAD (P > 0.05).ConclusionsTBO-mediated PAD is an effective in exhibiting efficient antimicrobial activity due to the substantial reduction of the microbial diversity and count in the primary endodontic infections.
http://ift.tt/2pa7eVt
Superficial resection combined with photodynamic therapy for successful treatment of facial lupus vulgaris with squamous cell carcinoma
Source:Photodiagnosis and Photodynamic Therapy, Volume 22
Author(s): Qian Zhang, Xiulian Xu, Rong Zeng, Wenbo Bu, Fang Fang
Skin squamous cell carcinoma is the second most common non-melanoma skin tumor worldwide. Most skin squamous cell carcinoma patients have underlying diseases. Here, we report a 56 year-old patient diagnosed with skin squamous cell carcinoma and with a 30 year course of neglected lupus vulgaris, which was very rare. In this case, we adopted a treatment strategy involving a small wound: superficial resection combined with photodynamic therapy with a satisfied result.
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The response surface methodology speeds up the search for optimal parameters in the photoinactivation of E. coli by photodynamic therapy
Publication date: June 2018
Source:Photodiagnosis and Photodynamic Therapy, Volume 22
Author(s): Larissa S. Amaral, Eduardo B. Azevedo, Janice R. Perussi
Antimicrobial Photodynamic Inactivation (a-PDI) is based on the oxidative destruction of biological molecules by reactive oxygen species generated by the photo-excitation of a photosensitive molecule. When a-PDT is performed with the use of mathematical models, the optimal conditions for maximum inactivation are found. Experimental designs allow a multivariate analysis of the experimental parameters. This is usually made using a univariate approach, which demands a large number of experiments, being time and money consuming. This paper presents the use of the response surface methodology for improving the search for the best conditions to reduce E. coli survival levels by a-PDT using methylene blue (MB) and toluidine blue (TB) as photosensitizers and white light. The goal was achieved by analyzing the effects and interactions of the three main parameters involved in the process: incubation time (IT), photosensitizer concentration (CPS), and light dose (LD). The optimization procedure began with a full 23 factorial design, followed by a central composite one, in which the optimal conditions were estimated. For MB, CPS was the most important parameter followed by LD and IT whereas, for TB, the main parameter was LD followed by CPS and IT. Using the estimated optimal conditions for inactivation, MB was able to inactivate 99.999999% CFU mL−1 of E. coli with IT of 28 min, LD of 31 J cm−2, and CPS of 32 μmol L−1, while TB required 18 min, 39 J cm−2, and 37 μmol L−1. The feasibility of using the response surface methodology with a-PDT was demonstrated, enabling enhanced photoinactivation efficiency and fast results with a minimal number of experiments.
Graphical abstract
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Efficacy of Er Cr: YSGG laser therapy at different frequency and power levels on bond integrity of composite to bleached enamel
Source:Photodiagnosis and Photodynamic Therapy, Volume 22
Author(s): Fahad Alkhudhairy, Mustafa Naseem, Mohammed Bin-Shuwaish, Fahim Vohra
The aim was to evaluate the influence of Er, Cr: YSGG laser therapy at different pulse frequency and power levels on the bond strength and microleakage of bleached enamel. One hundred samples were bleached using in-office whitening agent. Bleached samples were divided into six subgroups, four subgroups was based on laser application parameters (pulse frequency 50 and 30 Hz; Power 4.5 & 6 W) one subgroup was treated with bleach (B) and the other was control (no bleaching, no laser application). All specimens including control were etched with 37% phosphoric acid and composite build-ups were performed. Ten specimens from all the groups (B: Bleach only, L1: 50 Hz–4.5 W, L2: 50 Hz–6 W, L3: 30 Hz–4.5 W, L4:50 Hz–6W & C: Control) were assessed for shear bond strength and microleakage scores. Ten samples from all groups were immersed in 2% methylene blue for 24 h and assessed under a digital microscope for microleakage. The lowest mean bond strength was achieved in bleached group (9.49 ± 0.95) and maximum bond strength was observed in control group (33.97 ± 0.86). The highest mean microleakage score was found in bleached specimens (group B) (630.32 ± 156.58) and the lowest in controls (group C) (36.66 ± 27.33). Among assessed laser frequency and power combinations, 4.5 W and 30 Hz frequency showed maximum adhesive bond integrity (high bond strength and low microleakage) for bleached enamel samples.
http://ift.tt/2DpQcao
Photonic technology for the treatments of venous and arterial ulcers: Case report
Source:Photodiagnosis and Photodynamic Therapy, Volume 22
Author(s): Fernanda Mansano Carbinatto, Antonio Eduardo de Aquino, Vitória Helena Maciel Coelho, Vanderlei S. Bagnato
In this report, we report a case study on a 50-year-old male patient with different chronic wounds, such as venous ulcer and arterial ulcer in both legs. These wounds have persisted for more than 10 years, despite the different treatments applied, including, different dressings, hyperbaric camera, as well as the used of several medicines of oral and topical application. The case is addressed with the aim to evaluate if treatment that uses combined techniques such as low level laser therapy (LLLT), photodynamic therapy and cellulose membrane is able to improve healing and reduction of time of treatment in those types of chronic wounds. The results show the clinical protocol is effective for the healing of arterial and venous ulcers and can be considered as a promising possibility.
http://ift.tt/2p9Kk0v
Hypoxic, Toxic, and Acquired Metabolic Encephalopathies at the Emergency Room: The Role of Magnetic Resonance Imaging
Source:Seminars in Ultrasound, CT and MRI
Author(s): Marcos Vieira Godinho, Cíntia Elias Pires, Luiz Celso Hygino da Cruz
Our purpose is to describe typical computed tomography and magnetic resonance imaging findings in encephalopathies in the emergency. The focus of this article are the most frequent toxic and acquired metabolic diseases and their preferential sites of involvement, such as hepatic encephalopathy, hypoglicemia, nonketotic hyperglycemia, osmotic demyelination, posterior reversible encephalopathy syndrome, uremia, illegal drug abuse, carbon monoxide poisoning, and hypoxic-ischemic encephalopathy. The radiologist must be able to identify the most usual patterns of lesion in computed tomography and magnetic resonance imaging in these settings.
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Tissue control of androgen action: The ups and downs of androgen receptor expression
Source:Molecular and Cellular Endocrinology, Volume 465
Author(s): Irene Hunter, Colin W. Hay, Bianca Esswein, Kate Watt, Iain J. McEwan
The hormone testosterone plays crucial roles during male development and puberty and throughout life, as an anabolic regulator of muscle and bone structure and function. The actions of testosterone are mediated, primarily, through the androgen receptor, a member of the nuclear receptor superfamily. The androgen receptor gene is located on the X-chromosome and receptor levels are tightly controlled both at the level of transcription of the gene and post-translationally at the protein level. Sp1 has emerged as the major driver of expression of the androgen receptor gene, while auto-regulation by androgens is associated with both positive and negative regulation in a possible cell-selective manner. Research into the networks of positive and negative regulators of the androgen receptor gene are vital in order to understand the temporal and spatial control of receptor levels and the consequences for healthy aging and disease. A clear understanding of the multiple transcription factors participating in regulation of the androgen receptor gene will likely aid in the development and application of hormone therapies to boast or curb receptor activity.
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Androgens and endometrium: New insights and new targets
Source:Molecular and Cellular Endocrinology, Volume 465
Author(s): Ioannis Simitsidellis, Philippa T.K. Saunders, Douglas A. Gibson
Androgens are synthesised in both the ovary and adrenals in women and play an important role in the regulation of female fertility, as well as in the aetiology of disorders such as polycystic ovarian syndrome, endometriosis and endometrial cancer. The endometrium is an androgen target tissue and the impact of AR-mediated effects has been studied using human endometrial tissue samples and rodent models. In this review we highlight recent evidence that endometrial androgen biosynthesis and intracrine action is important in preparation of a tissue microenvironment that can support implantation and establishment of pregnancy. The impact of androgens on endometrial cell proliferation, in repair of the endometrial wound at the time of menstruation and in endometrial disorders is discussed. Future directions for research focused on AR function as a therapeutic target are considered.
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Editorial Board
Publication date: 15 April 2018
Source:Molecular and Cellular Endocrinology, Volume 465
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Androgens and androgen receptor action in skin and hair follicles
Source:Molecular and Cellular Endocrinology, Volume 465
Author(s): Julieta María Ceruti, Gustavo José Leirós, María Eugenia Balañá
Beyond sexual functions, androgens exert their action in skin physiology and pathophysiology. Skin cells are able to synthesize most active androgens from gonadal or adrenal precursors and the enzymes involved in skin steroidogenesis are implicated both in normal or pathological processes. Even when the role of androgens and androgen receptor (AR) in skin pathologies has been studied for decades, their molecular mechanisms in skin disorders remain largely unknown. Here, we analyze recent studies of androgens and AR roles in several skin-related disorders, focusing in the current understanding of their molecular mechanisms in androgenetic alopecia (AGA). We review the molecular pathophysiology of type 2 5α-reductase, AR coactivators, the paracrine factors deregulated in dermal papillae (such as TGF-β, IGF 1, WNTs and DKK-1) and the crosstalk between AR and Wnt signaling in order to shed some light on new promising treatments.
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Development of selective androgen receptor modulators (SARMs)
Source:Molecular and Cellular Endocrinology, Volume 465
Author(s): Ramesh Narayanan, Christopher C. Coss, James T. Dalton
The Androgen Receptor (AR), a member of the steroid hormone receptor family, plays important roles in the physiology and pathology of diverse tissues. AR ligands, which include circulating testosterone and locally synthesized dihydrotestosterone, bind to and activate the AR to elicit their effects. Ubiquitous expression of the AR, metabolism and cross reactivity with other receptors limit broad therapeutic utilization of steroidal androgens. However, the discovery of selective androgen receptor modulators (SARMs) and other tissue-selective nuclear hormone receptor modulators that activate their cognate receptors in a tissue-selective manner provides an opportunity to promote the beneficial effects of androgens and other hormones in target tissues with greatly reduced unwanted side-effects. In the last two decades, significant resources have been dedicated to the discovery and biological characterization of SARMs in an effort to harness the untapped potential of the AR. SARMs have been proposed as treatments of choice for various diseases, including muscle-wasting, breast cancer, and osteoporosis. This review provides insight into the evolution of SARMs from proof-of-concept agents to the cusp of therapeutic use in less than two decades, while covering contemporary views of their mechanisms of action and therapeutic benefits.
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Cancer Trials Ireland (ICORG) 06-34: A multi-centre clinical trial using three-dimensional conformal radiation therapy to reduce the toxicity of palliative radiation for lung cancer
Source:Radiotherapy and Oncology
Author(s): Ronan L. McDermott, John G. Armstrong, Pierre Thirion, Mary Dunne, Marie Finn, Cormac Small, Mary Byrne, Carmel O'Shea, Lydia O'Sullivan, Aoife Shannon, Emma Kelly, Dayle J. Hacking
TitleCancer Trials Ireland (ICORG) 06-34: A multi-centre clinical trial using three-dimensional conformal radiation therapy to reduce the toxicity of palliative radiation for lung cancer. NCT01176487.Background & purposeTrials of radiation therapy for the palliation of intra-thoracic symptoms from locally advanced non-small cell lung cancer (NSCLC) have concentrated on optimising fractionation and dose schedules. In these trials, the rates of oesophagitis induced by this "palliative" therapy have been unacceptably high. In contrast, this non-randomised, single-arm trial was designed to assess if more technically advanced treatment techniques would result in equivalent symptom relief and reduce the side-effect of symptomatic oesophagitis.Materials & methodsThirty-five evaluable patients with symptomatic locally advanced or metastatic NSCLC were treated using a three-dimensional conformal technique (3-DCRT) and standardised dose regimens of 39 Gy in 13 fractions, 20 Gy in 5 fractions or 17 Gy in 2 fractions. Treatment plans sought to minimise oesophageal dose. Oesophagitis was recorded during treatment, at two weeks, one month and three months following radiation therapy and 3–6 monthly thereafter. Mean dose to the irradiated oesophagus was calculated for all treatment plans.ResultsFive patients (14%) had experienced grade 2 oesophagitis or dysphagia or both during treatment and 2 other patients had these side effects at the 2-week follow-up. At follow-up of one month after therapy, there was no grade two or higher oesophagitis or dysphagia reported. 22 patients were eligible for assessment of late toxicity. Five of these patients reported oesophagitis or dysphagia (one had grade 3 dysphagia, two had grade 2 oesophagitis, one of whom also had grade 2 dysphagia). Quality of Life (QoL) data at baseline and at 1-month follow up were available for 20 patients. At 1-month post radiation therapy, these patients had slightly less trouble taking a short walk, less shortness of breath, did not feel as weak, had better appetite and generally had a better overall quality of life than they did at baseline. They did report being slightly more tired.ConclusionsThis trial is the first of its kind showing that 3-DCRT provides patients with lower rates of oesophageal toxicity whilst yielding acceptable rates of symptom control. (Sponsored by Cancer Trials Ireland (ICORG) Study number 06-34, the Friends of St. Luke's and the St. Luke's Institute of Cancer Research.)
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A prospective cohort study of hepatic toxicity after stereotactic body radiation therapy for hepatocellular carcinoma
Source:Radiotherapy and Oncology
Author(s): Ting-Shi Su, Ren Luo, Ping Liang, Tao Cheng, Ying Zhou, Yong Huang
PurposeTo build and validate multivariate normal tissue complication probability (NTCP) models for radiation-induced hepatic toxicity (RIHT) after stereotactic body radiation therapy (SBRT).MethodsEighty-five patients with hepatocellular carcinoma (HCC) in a phase II clinical trial were enroled. A progression of at least 1 or 2 points in the Child–Pugh (CP) score post-SBRT was classified as RIHT (≥1 or ≥2). NTCP models for RIHT (≥1 or ≥2) were developed using logistic regression. Nomograms for each model were formulated. The cut-off point of each independent dosimetric risk factor was obtained using receiver-operating characteristic (ROC) analysis. We used an independent cohort (101 patients) for model validation.ResultsTwenty (23.5%) and 12 (14.2%) patients experienced RIHT (≥1) and RIHT (≥2), respectively. V15, VS10, and pretreatment CP (pre-CP) were the optimal predictors for RIHT (≥1 and ≥2) modelling. V15 ≤33.1% and VS10 ≥416.2 mL for RIHT (≥1), and V15 ≤21.5% and VS10 ≥621.8 mL for RIHT (≥2), were the cut-off points. Four NTCP models and their nomograms were generated. These models and nomograms showed good prediction performance (area under the curve (AUC), 0.83–0.89). Our NTCP model (RIHT ≥2) based on V15 plus pre-CP performed well (AUC = 0.78) in a validation cohort.ConclusionV15, VS10, and pre-CP are crucial predictors for RIHT (≥1 and ≥2). Our NTCP models and nomograms were conducive to obtain individual constraints for patients with HCC.Registration NumberChiCTR-IIC-16008233.
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Doing the right thing: Quality in radiotherapy, a European perspective
Source:Radiotherapy and Oncology
Author(s): A Vaandering, N Jornet, P Scalliet, M Coffey, Y Lievens
http://ift.tt/2GqRaGy
Influence of inhomogeneous radiosensitivity distributions and intrafractional organ movement on the tumour control probability of focused IMRT in prostate cancer
Source:Radiotherapy and Oncology
Author(s): Benedikt Thomann, Ilias Sachpazidis, Khodor Koubar, Constantinos Zamboglou, Panayiotis Mavroidis, Rolf Wiehle, Anca-Ligia Grosu, Dimos Baltas
PurposeTo evaluate the influence of radioresistance and intrafractional movement on the tumour control probability (TCP) in IMRT prostate treatments using simultaneous integrated boosts to PSMA-PET/CT-delineated GTVs.Materials and methods13 patients had PSMA-PET/CT prior to prostatectomy and histopathological examination. Two GTVs were available: GTV-PET and GTV-histo, which is the true cancer volume. Focused IMRT plans delivering 77 Gy in 35 fractions to the prostate and 95 Gy to PTV-PET were produced. For random portions of the true cancer volume, α and α/β were uniformly changed to represent different radiosensitivity reductions. TCP was calculated (linear quadratic model) for the true cancer volume with and without simulated intrafractional movement.ResultsIntrafractional movement increased the TCP by up to 10.2% in individual cases and 1.2% averaged over all cases for medium radiosensitivity levels. At lower levels of radiosensitivity, movement decreased the TCP. Radiosensitivity reductions of 10–20% led to TCP reductions of 1–24% and 10–68% for 1% and 5% affected cancer volume, respectively. There is no linear correlation but a sudden breakdown of TCPs within a small range of radiosensitivity levels.ConclusionTCP drops significantly within a narrow range of radiosensitivity levels. Intrafractional movement can increase TCP when the boost volume is surrounded by a sufficiently high dose plateau.
http://ift.tt/2tMM7xm
The EPTN consensus-based atlas for CT- and MR-based contouring in neuro-oncology
Source:Radiotherapy and Oncology
Author(s): Daniëlle BP Eekers, Lieke in 't Ven, Erik Roelofs, Alida Postma, Claire Alapetite, Neil G. Burnet, Valentin Calugaru, Inge Compter, Ida E.M. Coremans, Morton Høyer, Maarten Lambrecht, Petra Witt Nyström, Alejandra Méndez Romero, Frank Paulsen, Ana Perpar, Dirk de Ruysscher, Laurette Renard, Beate Timmermann, Pavel Vitek, Damien C. Weber, Hiske L. van der Weide, Gillian A. Whitfield, Ruud Wiggenraad, Esther G.C. Troost
PurposeTo create a digital, online atlas for organs at risk (OAR) delineation in neuro-oncology based on high-quality computed tomography (CT) and magnetic resonance (MR) imaging.MethodsCT and 3 Tesla (3T) MR images (slice thickness 1 mm with intravenous contrast agent) were obtained from the same patient and subsequently fused. In addition, a 7T MR without intravenous contrast agent was obtained from a healthy volunteer. Based on discussion between experienced radiation oncologists, the clinically relevant organs at risk (OARs) to be included in the atlas for neuro-oncology were determined, excluding typical head and neck OARs previously published. The draft atlas was delineated by a senior radiation oncologist, 2 residents in radiation oncology, and a senior neuro-radiologist incorporating relevant available literature. The proposed atlas was then critically reviewed and discussed by European radiation oncologists until consensus was reached.ResultsThe online atlas includes one CT-scan at two different window settings and one MR scan (3T) showing the OARs in axial, coronal and sagittal view. This manuscript presents the three-dimensional descriptions of the fifteen consensus OARs for neuro-oncology. Among these is a new OAR relevant for neuro-cognition, the posterior cerebellum (illustrated on 7T MR images).ConclusionIn order to decrease inter- and intra-observer variability in delineating OARs relevant for neuro-oncology and thus derive consistent dosimetric data, we propose this atlas to be used in photon and particle therapy. The atlas is available online at www.cancerdata.org and will be updated whenever required.
http://ift.tt/2tJaP1J
Seasonal variations in cellular expression of neuropeptide Y (NPY) in testis of the catfish, Clarias batrachus and its potential role in regulation of steroidogenesis
Source:Peptides
Author(s): Priyadarshini Singh, Bechan Lal
The present study demonstrates seasonal variation in the cellular expression of neuropeptide Y (NPY), a known orexigenic neuropeptide, in the testis of the catfish, Clarias batrachus and its relation with testicular steroids. In vitro effects of NPY on androgen production and activities of steroidogenic enzymes were also analyzed to reaffirm the relation between NPY and steroids. NPY-immunoprecipitation was observed in Sertoli cells, interstitial cells and germ cells in recrudescing testis. Intensity of NPY-immunoreaction in the interstitial cells increased steadily with initiation of spermatogenesis and reached maximal in fully grown testes, and then decreased suddenly in the spermiating/spent testis. NPY was also expressed considerably in Sertoli cells in recrudescing testis, but disappeared in the fully grown testis. A moderate NPY-immunoreactivity was also seen in spermatogonial cells in recrudescing testis, but intense NPY-immunoprecipitation was detected in advanced germ cells (spermatids/spermatozoa) in fully mature testis. NPY-immunoreation intensity in interstitial cells showed positive correlation with increasing levels of testicular testosterone and 11-ketotestosterone, and with activities of 3β-HSD & 17β-HSD coinciding with advancing testicular activities. NPY treatment of testicular fragments in vitro stimulated the activities of 3β-HSD & 17β-HSD and increased testosterone & 11-ketotestosterone levels. This study for the first time demonstrates the existence of NPY peptide at cellular levels in fish testis, which stimulates androgen production by acting directly at testicular level.
http://ift.tt/2pdhPOV
Icarus, Blood Pressure, and the Dangers of Flying Too Close to the Sun.
Author: Skolnik, Neil MD
Page: 1097-1099
http://ift.tt/2FyIHDQ
Addressing Acute Coronary Syndromes: New Challenges and Opportunities After the CANTOS Trial (Canakinumab Anti-inflammatory Thrombosis Outcomes Study).
Author: Crea, Filippo MD; Liuzzo, Giovanna MD, PhD
Page: 1100-1102
http://ift.tt/2Do6MHC
Dietary Patterns to Reduce Weight and Optimize Cardiovascular Health: Persuasive Evidence for Promoting Multiple, Healthful Approaches.
Author: Anderson, Cheryl A.M. PhD, MPH, MS
Page: 1114-1116
http://ift.tt/2FERFvm
Efficacy and Safety of the Use of Non-Vitamin K Antagonist Oral Anticoagulants in Patients With Nonvalvular Atrial Fibrillation and Concomitant Aspirin Therapy: A Meta-Analysis of Randomized Trials.
Author: Bennaghmouch, Naoual MD *,; de Veer, Anne J.W.M. MD *,; Bode, Kerstin MD; Mahmoodi, Bakhtawar K. MD, PhD, MPH; Dewilde, Willem J.M. MD, PhD; Lip, Gregory Y.H. MD; Brueckmann, Martina MD; Kleine, Eva MSc; ten Berg, Jurrien M. MD, PhD
Page: 1117-1129
http://ift.tt/2FA0gnb
Non-Vitamin K Antagonist Preferred in Patients With Nonvalvular Atrial Fibrillation and Indication for Aspirin Therapy.
Author: James, Stefan MD, PhD
Page: 1130-1131
http://ift.tt/2DoUuPj
Letter by Jin-shan and Xue-bin Regarding Article, "A Novel [alpha]-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy, and Heart Failure".
Author: Jin-shan, He MD; Xue-bin, Li MD
Page: 1200
http://ift.tt/2GplMYO
Integrative Omics: Harnessing the Proteome to Maximize the Potential of the Genome.
Author: McGarrah, Robert W. MD; Shah, Svati H. MD, MS, MHS
Page: 1173-1175
http://ift.tt/2DoUj6B
Exercise Therapy and Cardiovascular Toxicity in Cancer.
Author: Scott, Jessica M. PhD; Nilsen, Tormod S. PhD; Gupta, Dipti MD, MPH; Jones, Lee W. PhD
Page: 1176-1191
http://ift.tt/2FyIDnA
Alternating Bundle-Branch Block: What Is the Mechanism?.
Author: Saini, Aditya MD; Padala, Santosh K. MD; Koneru, Jayanthi N. MD; Ellenbogen, Kenneth A. MD
Page: 1192-1194
http://ift.tt/2FGLOpa
Widening Racial Differences in Risks for Coronary Heart Disease.
Author: Nadruz, Wilson Jr MD, PhD *,; Claggett, Brian PhD *,; Henglin, Mir BA; Shah, Amil M. MD, MPH; Skali, Hicham MD, MSc; Rosamond, Wayne D. PhD; Folsom, Aaron R. MD, MPH; Solomon, Scott D. MD; Cheng, Susan MD, MMSc, MPH
Page: 1195-1197
http://ift.tt/2FAIjov
Letter by Tsuda Regarding Article, "A Novel [alpha]-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy, and Heart Failure".
Author: Tsuda, Kazushi MD
Page: 1198-1199
http://ift.tt/2FEREaM
Response by Aubdool et al to Letters Regarding Article, "A Novel [alpha]-Calcitonin Gene-Related Peptide Analogue Protects Against End-Organ Damage in Experimental Hypertension, Cardiac Hypertrophy, and Heart Failure".
Author: Aubdool, Aisah A. BSc, MRes, PhD; Argunhan, Fulye BSc, MSc; Thakore, Pratish PhD, BSc, MSc; Brain, Susan D. BSc, PhD
Page: 1201-1202
http://ift.tt/2FG0TYm
Letter by Mutlu and Budinger Regarding Article, "Particulate Matter Exposure and Stress Hormone Levels: A Randomized, Double-Blind, Crossover Trial of Air Purification".
Author: Mutlu, Gokhan M. MD; Budinger, G.R. Scott MD
Page: 1203-1204
http://ift.tt/2Grb1p5
Letter by Jordan and Biaggioni Regarding Article, "Particulate Matter Exposure and Stress Hormone Levels: A Randomized, Double-Blind, Crossover Trial of Air Purification".
Author: Jordan, Jens MD; Biaggioni, Italo MD
Page: 1205-1206
http://ift.tt/2FEhrzW
Letter by Li et al Regarding Article, "Particulate Matter Exposure and Stress Hormone Levels: A Randomized, Double-Blind, Crossover Trial of Air Purification".
Author: Li, Tian MD *,,; Jiang, Shuai MD, PhD *,; Yang, Yang MD, PhD
Page: 1207-1208
http://ift.tt/2GraN1d
Response by Li et al to Letters Regarding Article, "Particulate Matter Exposure and Stress Hormone Levels: A Randomized, Double-Blind, Crossover Trial of Air Purification".
Author: Li, Huichu MS; Cai, Jing PhD; Kan, Haidong PhD
Page: 1209-1210
http://ift.tt/2Dt76VG
Myeloid derived-suppressor cells: their role in cancer and obesity
Source:Current Opinion in Immunology, Volume 51
Author(s): Suzanne Ostrand-Rosenberg
Myeloid-derived suppressor cells (MDSC) are present in most individuals with cancer where they inhibit adaptive and innate antitumor immunity and are an obstacle to cancer immunotherapies. Chronic inflammation is characteristic of adipose tissue and is a risk factor for the onset and progression of cancer in obese individuals. Because MDSC accumulate in response to inflammation, it has been hypothesized that one of the mechanisms by which obesity promotes malignancy is through the induction of MDSC. This article reviews the data supporting this hypothesis, the role of leptin and fatty acid metabolism in the induction of MDSC, and the surprising finding that although MDSC promote tumor progression, they are protective against some of the metabolic dysfunction associated with obesity.
http://ift.tt/2FTGQc7
Evidence of transcranial direct current stimulation-generated electric fields at subthalamic level in human brain in vivo
Source:Brain Stimulation
Author(s): Pratik Y. Chhatbar, Steven A. Kautz, Istvan Takacs, Nathan C. Rowland, Gonzalo J. Revuelta, Mark S. George, Marom Bikson, Wuwei Feng
BackgroundTranscranial direct current stimulation (tDCS) is a promising brain modulation technique for several disease conditions. With this technique, some portion of the current penetrates through the scalp to the cortex and modulates cortical excitability, but a recent human cadaver study questions the amount. This insufficient intracerebral penetration of currents may partially explain the inconsistent and mixed results in tDCS studies to date. Experimental validation of a transcranial alternating current stimulation-generated electric field (EF) in vivo has been performed on the cortical (using electrocorticography, ECoG, electrodes), subcortical (using stereo electroencephalography, SEEG, electrodes) and deeper thalamic/subthalamic levels (using DBS electrodes). However, tDCS-generated EF measurements have never been attempted.Objective/Hypothesis: We aimed to demonstrate that tDCS generates biologically relevant EF as deep as the subthalamic level in vivo.MethodsPatients with movement disorders who have implanted deep brain stimulation (DBS) electrodes serve as a natural experimental model for thalamic/subthalamic recordings of tDCS-generated EF. We measured voltage changes from DBS electrodes and body resistance from tDCS electrodes in three subjects while applying direct current to the scalp at 2 mA and 4 mA over two tDCS montages.ResultsVoltage changes at the level of deep nuclei changed proportionally with the level of applied current and varied with different tDCS montages.ConclusionsOur findings suggest that scalp-applied tDCS generates biologically relevant EF. Incorporation of these experimental results may improve finite element analysis (FEA)-based models.
http://ift.tt/2p9wOtP
Psychological Treatment
Source:Hematology/Oncology Clinics of North America
Author(s): Thomas B. Strouse, Brenda Bursch
Teaser
Psychological approaches to pain management have been demonstrated to be effective for individuals newly diagnosed with cancer, in remission, and/or with progressive or terminal disease. Modalities that have been demonstrated to be most effective are cognitive behavioral approaches that include relaxation skills and/or hypnotherapy.http://ift.tt/2Gqrn17
Scholar : These new articles for Amyloid are available online
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Temporal dynamics of gut microbiota in triclocarban-exposed weaned rats
Abstract
Widely used as an antimicrobial in antibacterial bar soaps, triclocarban (3,4,4′-trichlorocarbanilide; TCC) is effective against Gram-positive bacteria but shows little efficacy against Gram-negative strains, potentially altering the composition of indigenous microflora within and on the human body. To date, the consequence of continuous or previous nonprescription antimicrobial exposure from compounds in personal care products on commensal microflora is still elusive. Previous research has shown that TCC exposure during gestation and lactation induced dysbiosis of gut microbial communities among exposed dams and neonates. However, the impact of antimicrobial exposure specifically after discontinuation of the use of TCC on the gut microbiota has not been investigated. In this study, weaned Sprague Dawley rats (postnatal day, PND 22) were provided ad lib access to TCC-supplemented diet (0.2% w/w or 0.5% w/w) for 4 weeks (phase I) followed by a 4-week washout period (phase II) to determine gut microflora changes both during continuous exposure to TCC and to determine the potential rebound following TCC withdrawal. Fecal samples were collected at baseline (PND 22) prior to TCC exposure and throughout phase I and phase II. The V4 region of 16S rDNA was sequenced from extracted total fecal DNA with the MiSeq platform. Exposure to both 0.2% w/w and 0.5% w/w TCC was sufficient to alter diversity of microbiota during phase I of treatment. This effect was further prolonged into phase II, even when TCC exposure was discontinued. Collectively, these data highlight the impact of both continuous and prior TCC exposure on gut microbial ecology and shed light onto the potential long-term health risk of daily nonprescription antimicrobial personal care product use.
http://ift.tt/2pcUpsJ
Scholar : These new articles for Archives and Manuscripts are available online
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Prevalence of C-shaped canal system in mandibular first and second molars in a Saudi population assessed via cone beam computed tomography: a retrospective study
Abstract
Objectives
The purpose of this study was to determine the prevalence of the C-shaped root canal configuration, location of the longitudinal groove, sex differences, and unilateral/bilateral presence in mandibular first and second molars in a Saudi population using cone beam computed tomography (CBCT).
Materials and methods
CBCT images for the mandibular first and second molars of 487 patients (a total of 529 first molars and 681 s molars) were evaluated. The teeth were assessed for the presence of C-shaped root canals according to Fan criteria. Subdivisions were also made according to sex, direction of the longitudinal groove, and unilateral/bilateral presence.
Results
Only one C-shaped mandibular first molar was observed (0.19%), whereas 62 second molars (9.1%) exhibited C-shaped anatomy. Unilateral presence of the C-shaped root canal system was more common (53.85%). Female patients had a higher prevalence than males. Longitudinal grooves were most commonly found on the root lingual surface (58.1%).
Conclusions
The prevalence of the C-shaped canal configuration in a Saudi Arabian population was 0.19% in the mandibular first molar and 9.1% in the mandibular second molar. Longitudinal groove prevalence was highest on the lingual surface. Women had a significantly higher prevalence of the C-shaped canal configuration than men. Patients with unilateral presence of the C-shaped canal configuration were more common than those with bilateral presence.
Clinical relevance
Tooth type, patient sex, and ethnicity can help clinicians predict the prevalence of the C-shaped canal system in mandibular molars.
http://ift.tt/2Hx59tC
Scholar : These new articles for Activities, Adaptation & Aging are available online
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Scholar : These new articles for Critique: Studies in Contemporary Fiction are available online
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Quick synthesis of 2-propanol derived fluorescent carbon dots for bioimaging applications
Publication date: April 2018
Source:Optical Materials, Volume 78
Author(s): Raja Angamuthu, Priya Palanisamy, Vasanthakumar Vasudevan, Sedhu Nagarajan, Ramesh Rajendran, Raj Vairamuthu
Herein, for the first time, we present a one-pot ingenious preparative method for fluorescent carbon dots from 2-propanol (2P-CDs) without external treatments. Structure, morphology, chemical composition and fluorescence properties of the 2P-CDs were examined. These results confirm that the as-synthesized 2P-CDs are amorphous, monodispersed, spherical and the average particle size is 2.5 ± 0.7 nm. Most importantly, excitation-dependent emission properties were observed, which suggest that these 2P-CDs may be used in multicolor bioimaging applications. When incubated with HeLa cells, the 2P-CDs exhibit low cytotoxicity, and positive biocompatibility. Confocal microscopy image shows the uptake of 2P-CDs by HeLa cells and the application of probable biomarker is demonstrated.
Graphical abstract
http://ift.tt/2HzcvNo
Impact of database quality in knowledge-based treatment planning for prostate cancer
Source:Practical Radiation Oncology
Author(s): Phillip D.H. Wall, Robert L. Carver, Jonas D. Fontenot
PurposeInvestigate dose-volume prediction improvements in a common knowledge-based planning (KBP) method using a Pareto plan database compared to using a conventional, clinical plan database.MethodsTwo plan databases were created using retrospective, anonymized data of 124 VMAT prostate cancer patients. The clinical plan database (CPD) contained planning data from each patient's clinically-treated VMAT plan, which were manually optimized by various planners. The multi-criteria optimization database (MCOD) contained Pareto-optimal plan data from VMAT plans created using a standardized multi-criteria optimization protocol. Overlap volume histograms, incorporating fractional OAR volumes only within the treatment fields, were computed for each patient and used to match new patient anatomy to similar database patients. For each database patient, CPD and MCOD KBP predictions were generated for D10, D30, D50, D65, and D80 of the bladder and rectum in a leave-one-out manner. Prediction achievability was evaluated through a re-planning study on a subset of 31 randomly selected database patients using the best KBP predictions, regardless of plan database origin, as planning goals.ResultsMCOD predictions were significantly lower than CPD predictions for all five bladder dose-volumes and rectum D50 (p=0.004) and D65 (p<0.001), while CPD predictions for rectum D10 (p=0.005) and D30 (p<0.001) were significantly less than MCOD predictions. KBP predictions were statistically achievable in the re-plans for all predicted dose-volumes, excluding D10 of bladder (p=0.03) and rectum (p=0.04). Compared to clinical plans, re-plans showed significant average reductions in Dmean for bladder (7.8Gy; p<0.001) and rectum (9.4Gy; p<0.001), while maintaining statistically similar PTV, femoral head, and penile bulb dose.ConclusionKBP dose-volume predictions derived from Pareto plans were more optimal overall than those resulting from manually optimized clinical plans, which significantly improved KBP-assisted plan quality.
http://ift.tt/2FOdYlA
Manipulation of VEGF-induced angiogenesis by 2-N, 6-O-sulfated chitosan
Publication date: Available online 12 March 2018
Source:Acta Biomaterialia
Author(s): Yuanman Yu, Rui Chen, Yi Sun, Yuanzhong Pan, Wei Tang, Shuang Zhang, Lingyan Cao, Yuan Yuan, Jing Wang, Changsheng Liu
Emerging evidence suggests that vascular endothelial growth facto (VEGF) is important in the treatment of various ischemic and cardiovascular diseases. However, it often suffers from high cost and easy deactivation with a short half-life. Here, we describe a synthetic 2-N, 6-O-sulfated chitosan (26SCS) with a high affinity to VEGF promoting the binding of the signaling protein to its VEGF receptor 2 (VEGFR2), activating receptor phosphorylation and pro-angiogenic related genes expression, and further stimulating downstream VEGF-dependent endothelial cell viability, migration, tube formation and rat aortic rings outgrowth. Interestingly, the obvious recruitment of mural cells were occurred to stabilize the sprouted microvessels. In addition, the pro-angiogenic potential of 26SCS composited VEGF was confirmed in vivo using the chick embryo chorioallantoic membrane (CAM) assay with an extensive perfusable vascular network. A longer monitoring was administered subcutaneously to mice in a biocompatible gelatin sponge and showed that VEGF with 26SCS had the capability to efficiently enhance neovascularization. These findings highlight that 26SCS, the semi-synthetic natural polymer, may be a promising coagent with VEGF for vascular therapy.Statement of significanceVascular endothelial growth factor (VEGF) is crucial for facilitating angiogenesis to supply oxygen and nutrient during wound healing and tissue regeneration. However, appropriate use of VEGF is an ongoing challenge due to its rapidly clearance and severe side effects at higher dosage. In this study, we described a synthetic 2-N, 6-O-sulfated chitosan (26SCS) with a high affinity to VEGF, which could significantly promote its binding capacity to VEGF receptor 2 and further stimulate the angiogenic behavior of endothelial cells. We further confirmed that 26SCS was spatially combined with VEGF in a "lying manner", and this spatial arrangement was more conducive to exposure of the receptor binding domain of VEGF. Additionally, it also promoted in vivo angiogenesis in a chicken chorioallantoic membrane assay and mouse subcutaneous implant model. This strategy may afford a new avenue to enhance pro-angiogenic capacity of VEGF.
Graphical abstract
http://ift.tt/2FA39nI
Targeting tumor hypoxia with stimulus-responsive nanocarriers in overcoming drug resistance and monitoring anticancer efficacy
Publication date: Available online 13 March 2018
Source:Acta Biomaterialia
Author(s): Zhiqi Xie, Wangwei Guo, Ningning Guo, Mingyi Huangfu, Huina Liu, Mengting Lin, WenHong Xu, Jiejian Chen, TianTian Wang, Qichun Wei, Min Han, Jianqing Gao
Although existing nanomedicines have focused on the tumor microenvironment with the goal of improving the effectiveness of conventional chemotherapy, the penetration of a tumor's core still represents a formidable barrier for existing drug delivery systems. Therefore, a novel multifunctional hypoxia-induced size-shrinkable nanoparticle has been designed to increase the penetration of drugs, nucleic acids, or probes into tumors. This cooperative strategy relies on three aspects: (i) the responsiveness of nanoparticles to hypoxia, which shrink when triggered by low oxygen concentrations; (ii) the core of a nanoparticle involves an internal cavity and strong positive charges on the surface to deliver both doxorubicin and siRNA; and (iii) a reactive oxygen species (ROS) probe is incorporated in the nanoparticle to monitor its preliminary therapeutic response in real time, which is expected to realize the enhanced efficacy together with the ability to self-monitor the anticancer activity. A more effective inhibition of tumor growth was observed in tumor-bearing zebrafish, demonstrating the feasibility of this cooperative strategy for in vivo applications. This research highlights a promising value in delivering drugs, nucleic acids, or probes to a tumor's core for cancer imaging and treatment.Statement of significanceHypoxia-induced chemoresistance of tumor cells still represents a formidable barrier, as it is difficult for existing drug delivery systems to penetrate the tumor hypoxia core. This study involves the hypoxia-responsive size-shrinkable nanoparticle co-delivery of DOX and siRNA to enhance the penetration of DOX deep within tumors and subsequently disturb crucial pathways of cancer development induced by hypoxia and to improve sensitization to DOX chemotherapy. Furthermore, the nanopreparation can combine the ROS probe as a self-reporting nanopreparation to realize the function of real-time feedback efficacy, which has a good application prospect in the diagnosis and treatment of cancer.
Graphical abstract
http://ift.tt/2tSrO1J
A Neutralizing Antibody Recognizing Primarily N-linked Glycan Targets the Silent Face of the HIV Envelope
Publication date: Available online 13 March 2018
Source:Immunity
Author(s): Tongqing Zhou, Anqi Zheng, Ulrich Baxa, Gwo-Yu Chuang, Ivelin S. Georgiev, Rui Kong, Sijy O'Dell, Syed Shahzad-ul-Hussan, Chen-Hsiang Shen, Yaroslav Tsybovsky, Robert T. Bailer, Syna K. Gift, Mark K. Louder, Krisha McKee, Reda Rawi, Catherine H. Stevenson, Guillaume B.E. Stewart-Jones, Justin D. Taft, Eric Waltari, Yongping Yang, Baoshan Zhang, Sachin S. Shivatare, Vidya S. Shivatare, Chang-Chun D. Lee, Chung-Yi Wu, James C. Mullikin, Carole A. Bewley, Dennis R. Burton, Victoria R. Polonis, Lawrence Shapiro, Chi-Huey Wong, John R. Mascola, Peter D. Kwong, Xueling Wu
Virtually the entire surface of the HIV-1-envelope trimer is recognized by neutralizing antibodies, except for a highly glycosylated region at the center of the "silent face" on the gp120 subunit. From an HIV-1-infected donor, #74, we identified antibody VRC-PG05, which neutralized 27% of HIV-1 strains. The crystal structure of the antigen-binding fragment of VRC-PG05 in complex with gp120 revealed an epitope comprised primarily of N-linked glycans from N262, N295, and N448 at the silent face center. Somatic hypermutation occurred preferentially at antibody residues that interacted with these glycans, suggesting somatic development of glycan recognition. Resistance to VRC-PG05 in donor #74 involved shifting of glycan-N448 to N446 or mutation of glycan-proximal residue E293. HIV-1 neutralization can thus be achieved at the silent face center by glycan-recognizing antibody; along with other known epitopes, the VRC-PG05 epitope completes coverage by neutralizing antibody of all major exposed regions of the prefusion closed trimer.
Graphical abstract
Teaser
The center of the "silent face" on the HIV-1 envelope is shielded by glycans and has been devoid of antibody recognition. Zhou et al. identify the antibody VRC-PG05, which binds a glycan-dominated epitope at the silent face center and completes antibody recognition of all major exposed regions of the envelope trimer.http://ift.tt/2FDHqHK
Histone Deacetylases 1 and 2 Regulate Microglia Function during Development, Homeostasis, and Neurodegeneration in a Context-Dependent Manner
Publication date: Available online 13 March 2018
Source:Immunity
Author(s): Moumita Datta, Ori Staszewski, Elena Raschi, Maximilian Frosch, Nora Hagemeyer, Tuan Leng Tay, Thomas Blank, Mario Kreutzfeldt, Doron Merkler, Stephanie Ziegler-Waldkirch, Patrick Matthias, Melanie Meyer-Luehmann, Marco Prinz
Microglia as tissue macrophages contribute to the defense and maintenance of central nervous system (CNS) homeostasis. Little is known about the epigenetic signals controlling microglia function in vivo. We employed constitutive and inducible mutagenesis in microglia to delete two class I histone deacetylases, Hdac1 and Hdac2. Prenatal ablation of Hdac1 and Hdac2 impaired microglial development. Mechanistically, the promoters of pro-apoptotic and cell cycle genes were hyperacetylated in absence of Hdac1 and Hdac2, leading to increased apoptosis and reduced survival. In contrast, Hdac1 and Hdac2 were not required for adult microglia survival during homeostasis. In a mouse model of Alzheimer's disease, deletion of Hdac1 and Hdac2 in microglia, but not in neuroectodermal cells, resulted in a decrease in amyloid load and improved cognitive impairment by enhancing microglial amyloid phagocytosis. Collectively, we report a role for epigenetic factors that differentially affect microglia development, homeostasis, and disease that could potentially be utilized therapeutically.
Graphical abstract
Teaser
Little is known about the epigenetic signals that control microglia function in vivo. Datta et al. show that histone deacetylases Hdac1 and Hdac2 are essential for microglial survival and expansion during development but not during steady state. In Alzheimer's disease mouse model, deletion of microglial Hdac1 and Hdac2 reduces amyloid pathology and improves cognitive function.http://ift.tt/2FQScO4
Biomaterial scaffolds for non-invasive focal hyperthermia as a potential tool to ablate metastatic cancer cells
Publication date: June 2018
Source:Biomaterials, Volume 166
Author(s): Francisco Pelaez, Navid Manuchehrabadi, Priyatanu Roy, Harishankar Natesan, Yiru Wang, Emilian Racila, Heather Fong, Kevin Zeng, Abby M. Silbaugh, John C. Bischof, Samira M. Azarin
Currently, there are very few therapeutic options for treatment of metastatic disease, as it often remains undetected until the burden of disease is too high. Microporous poly(ε-caprolactone) biomaterials have been shown to attract metastasizing breast cancer cells in vivo early in tumor progression. In order to enhance the therapeutic potential of these scaffolds, they were modified such that infiltrating cells could be eliminated with non-invasive focal hyperthermia. Metal disks were incorporated into poly(ε-caprolactone) scaffolds to generate heat through electromagnetic induction by an oscillating magnetic field within a radiofrequency coil. Heat generation was modulated by varying the size of the metal disk, the strength of the magnetic field (at a fixed frequency), or the type of metal. When implanted subcutaneously in mice, the modified scaffolds were biocompatible and became properly integrated with the host tissue. Optimal parameters for in vivo heating were identified through a combination of computational modeling and ex vivo characterization to both predict and verify heat transfer dynamics and cell death kinetics during inductive heating. In vivo inductive heating of implanted, tissue-laden composite scaffolds led to tissue necrosis as seen by histological analysis. The ability to thermally ablate captured cells non-invasively using biomaterial scaffolds has the potential to extend the application of focal thermal therapies to disseminated cancers.
Graphical abstract
http://ift.tt/2txIP0G
Systemic study of solvent-assisted active loading of gambogic acid into liposomes and its formulation optimization for improved delivery
Publication date: June 2018
Source:Biomaterials, Volume 166
Author(s): Wei-Lun Tang, Wei-Hsin Tang, Andras Szeitz, Jayesh Kulkarni, Pieter Cullis, Shyh-Dar Li
The solvent-assisted active loading technology (SALT) was developed for encapsulating a water insoluble weak base into the liposomal core in the presence of 5% DMSO. In this study, we further examined the effect of various water miscible solvents in promoting active loading of other types of drugs into liposomes. To achieve complete drug loading, the amount of solvent required must result in complete drug solubilization and membrane permeability enhancement, but must be below the threshold that induces liposomal aggregation or causes bilayer disruption. We then used the SALT to load gambogic acid (GA, an insoluble model drug that shows promising anticancer effect) into liposomes, and optimized the loading gradient and lipid composition to prepare a stable formulation (Lipo-GA) that displayed >95% drug retention after incubation with serum for 3 days. Lipo-GA contained a high drug-to-lipid ratio of 1/5 (w/w) with a mean particle size of ∼75 nm. It also displayed a prolonged circulation half-life (1.5 h vs. 18.6 h) and enhanced antitumor activity in two syngeneic mice models compared to free GA. Particularly, complete tumor regression was observed in the EMT6 tumor model for 14 d with significant inhibition of multiple oncogenes including HIF-1α, VEGF-A, STAT3, BCL-2, and NF-κB.
Graphical abstract
http://ift.tt/2twhAno
“Stepwise Extraction” strategy-based injectable bioresponsive composite implant for cancer theranostics
Publication date: June 2018
Source:Biomaterials, Volume 166
Author(s): Bowen Yang, Han Lin, Chen Dai, Yu Chen, Jianlin Shi
"Smart" bioresponsive materials, which are sensitive to biological signals or pathological abnormalities, are appealing therapeutic platforms for the development of next-generation cancer theranostics. In this work, a novel "stepwise extraction" strategy has been proposed and demonstrated in constructing injectable bioresponsive composite implant, which features unique theranostic responsivenesses to exogenous and external triggers. The as-designed implant exhibits theranostic functions and biodegradability for cancer treatment based on the change of intratumoral microenvironment and the needs of therapeutic process. This "stepwise extraction" process, that is, "solvent extraction", "manganese extraction" and "phosphorus extraction", significantly promoted the biodegradation and disintegration of the bioresponsive implant step by step, accompanied by the corresponding component releases from the PLGA framework and furthermore, accomplished different specific theranostic functions needed at different treatment stages. This is the first demonstration of bioresponsive organic-inorganic hybrid implant with marked theranostic functions and excellent biodegradability by a "stepwise extraction" approach, paving the way to the solutions of unsatisfactory therapeutic efficacy and strong side effects in current cancer therapeutic modalities.
Graphical abstract
http://ift.tt/2FGD2uE
Competition of charge-mediated and specific binding by peptide-tagged cationic liposome–DNA nanoparticles in vitro and in vivo
Publication date: June 2018
Source:Biomaterials, Volume 166
Author(s): Emily Wonder, Lorena Simón-Gracia, Pablo Scodeller, Ramsey N. Majzoub, Venkata Ramana Kotamraju, Kai K. Ewert, Tambet Teesalu, Cyrus R. Safinya
Cationic liposome–nucleic acid (CL–NA) complexes, which form spontaneously, are a highly modular gene delivery system. These complexes can be sterically stabilized via PEGylation [PEG: poly (ethylene glycol)] into nanoparticles (NPs) and targeted to specific tissues and cell types via the conjugation of an affinity ligand. However, there are currently no guidelines on how to effectively navigate the large space of compositional parameters that modulate the specific and nonspecific binding interactions of peptide-targeted NPs with cells. Such guidelines are desirable to accelerate the optimization of formulations with novel peptides. Using PEG-lipids functionalized with a library of prototypical tumor-homing peptides, we varied the peptide density and other parameters (binding motif, peptide charge, CL/DNA charge ratio) to study their effect on the binding and uptake of the corresponding NPs. We used flow cytometry to quantitatively assess binding as well as internalization of NPs by cultured cancer cells. Surprisingly, full peptide coverage resulted in less binding and internalization than intermediate coverage, with the optimum coverage varying between cell lines. In, addition, our data revealed that great care must be taken to prevent nonspecific electrostatic interactions from interfering with the desired specific binding and internalization. Importantly, such considerations must take into account the charge of the peptide ligand as well as the membrane charge density and the CL/DNA charge ratio. To test our guidelines, we evaluated the in vivo tumor selectivity of selected NP formulations in a mouse model of peritoneally disseminated human gastric cancer. Intraperitoneally administered peptide-tagged CL–DNA NPs showed tumor binding, minimal accumulation in healthy control tissues, and preferential penetration of smaller tumor nodules, a highly clinically relevant target known to drive recurrence of the peritoneal cancer.
Graphical abstract
http://ift.tt/2tGo1Eu
Cargo-free particles of ammonio methacrylate copolymers: From pharmaceutical inactive ingredients to effective anticancer immunotherapeutics
Publication date: June 2018
Source:Biomaterials, Volume 166
Author(s): Maryam Alsadat Shetab Boushehri, Valentin Stein, Alf Lamprecht
Nanoparticles create exciting platforms for anticancer immunotherapy and vaccination, though their inherent immunomodulatory properties have remained underexploited. Ammonio methacrylate copolymers (AMC) are well-established excipients in pharmaceutical industry and components of controlled-release oral formulations. Here, we demonstrate that nanoscaling of type A and B AMC (Eudragit® RL and RS) endows these inactive ingredients immunostimulatory properties exploitable for cancer therapy. The particles induce the secretion of various pro-inflammatory cytokines and chemokines from the cells of innate immunity. Though the underlying mechanisms are not fully uncovered, the current work established the partial involvement of Toll-like Receptor 4 (TLR4) and Nuclear factor κB (NF-κB). The size and charge-dependency of the particles' pro-inflammatory properties and cytokine/chemokine induction profile was also demonstrated. Within the context of cancer immunotherapy, biweekly peritumoral nanoparticle injection led to a complete regression of the syngeneic colorectal tumor, or a significant growth retardation thereof, considerably extending the survival of tumor-bearing animals. Additionally, presence of the immunological memory in treated animals was established. Given their better economical and relatively safer profile compared to well-established chemo- and immunotheraputics, and their ability to serve as carriers for drug targeting, vaccination and combination therapy, AMC nanoparticles (AMCNP) are fascinating subjects for further research in the field of cancer therapy.
Graphical abstract
http://ift.tt/2oY0GZZ
Harnessing biochemical and structural cues for tenogenic differentiation of adipose derived stem cells (ADSCs) and development of an in vitro tissue interface mimicking tendon-bone insertion graft
Source:Biomaterials, Volume 165
Author(s): Sajeesh Kumar Madhurakkat Perikamana, Jinkyu Lee, Taufiq Ahmad, Eun Mi Kim, Hayeon Byun, Sangmin Lee, Heungsoo Shin
Tendon-bone interface tissue is extremely challenging to engineer because it exhibits complex gradients of structure, composition, biologics, and cellular phenotypes. As a step toward engineering these transitional zones, we initially analyzed how different (topographical or biological) cues affect tenogenic differentiation of adipose-derived stem cells (ADSCs). We immobilized platelet-derived growth factor - BB (PDGF-BB) using polydopamine (PD) chemistry on random and aligned nanofibers and investigated ADSC proliferation and tenogenic differentiation. Immobilized PDGF greatly enhanced the proliferation and tenogenic differentiation of ADSCs; however, nanofiber alignment had no effect. Interestingly, the PDGF immobilized aligned nanofiber group showed a synergistic effect with maximum expression of tenogenic markers for 14 days. We also generated a nanofiber surface with spatially controlled presentation of immobilized PDGF on an aligned architecture, mimicking native tendon tissue. A gradient of immobilized PDGF was able to control the phenotypic differentiation of ADSCs into tenocytes in a spatially controlled manner, as confirmed by analysis of the expression of tenogenic markers and immunofluorescence staining. We further explored the gradient formation strategy by generation of a symmetrical gradient on the nanofiber surface for the generation of a structure mimicking bone-patellar-tendon-bone with provision for gradient immobilization of PDGF and controlled mineralization. Our study reveals that, together with biochemical cues, favorable topographical cues are important for tenogenic differentiation of ADSCs, and gradient presentation of PDGF can be used as a tool for engineering stem cell–based bone-tendon interface tissues.
http://ift.tt/2oUp2Dm
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