Studies of CDK 8/19 inhibitors: Discovery of novel and selective CDK8/19 dual inhibitors and elimination of their CYP3A4 time-dependent inhibition potential

Publication date: 15 June 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
Author(s): Jun Fujimoto, Takaharu Hirayama, Yasuhiro Hirata, Yukiko Hikichi, Saomi Murai, Maki Hasegawa, Yuka Hasegawa, Kazuko Yonemori, Akito Hata, Kazunobu Aoyama, Douglas R. Cary
In this article, synthetic studies around a pyridylacrylamide-based hit compound (1), utilizing structure-based drug design guided by CDK8 docking models, is discussed. Modification of the pendant 4-fluorophenyl group to various heteroaromatic rings was conducted aiming an interaction with the proximal amino acids, and then replacement of the morpholine ring was targeted for decreasing potential of time-dependent CYP3A4 inhibition. These efforts led to the compound 4k, with enhanced CDK8 inhibitory activity and no apparent potential for time-dependent CYP3A4 inhibition (CDK8 IC50: 2.5nM; CYP3A4 TDI: 99% compound remaining). Compound 4k was found to possess a highly selective kinase inhibition profile, and also showed favorable pharmacokinetic profile. Oral administration of 4k (15mg/kg, bid. for 2weeks) suppressed tumor growth (T/C 29%) in an RPMI8226 mouse xenograft model.

Graphical abstract

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Identification of selective inhibitors of sphingosine kinases 1 and 2 through a structure–activity relationship study of 4-epi-jaspine B

Publication date: 15 June 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
Author(s): Hiroaki Ohno, Maho Honda, Naoka Hamada, Jun Miyagaki, Akira Iwata, Kazuhiro Otsuki, Toru Maruyama, Shinya Nakamura, Isao Nakanishi, Shinsuke Inuki, Nobutaka Fujii, Shinya Oishi
We recently reported that 4-epi-jaspine B exhibits potent inhibitory activity towards sphingosine kinases (SphKs). In this study, we investigated the effects of modifying the 2-alkyl group, as well as the functional groups on the THF ring of 4-epi-jaspine B using a diversity-oriented synthesis approach based on a late-stage cross metathesis reaction. The introduction of a p-phenylene tether to the alkyl group was favored in most cases, whereas the replacement of a carbon atom with an oxygen atom led to a decrease in the inhibitory activity. Furthermore, the introduction of a bulky alkyl group at the terminus led to a slight increase in the inhibitory activity of this series towards SphKs compared with 4-epi-jaspine B (the Q values of compound 13 for SphK1 and SphK2 were 0.2 and 0.4, respectively). Based on this study, we identified two isoform selective inhibitors, including the m-phenylene derivative 4 [IC50 (SphK1) ≥30μM; IC50 (SphK2)=2.2μM] and the methyl ether derivative 22 [IC50 (SphK1)=4.0μM; IC50 (SphK2) ≥30μM].

Graphical abstract

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Stereospecific cholinesterase inhibition by O,S-diethylphenylphosphonothioate

Publication date: 15 June 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
Author(s): Ahmed Mohammed, Jennifer Sneathen, Sara Glazier Frojen, Louis Kuo, Cynthia M. Dupureur
The inhibition kinetics and stereospecificity of the chiral nerve agent derivative O,S-diethylphenylphosphonothioate (DEPP) were examined for two forms of acetylcholinesterase (human and eel) and equine butyrylcholinesterase. Both S- and R-DEPP are poor inhibitors of eel AChE (IC50 150μM), consistent with a large, nondiscriminatory binding interaction in the active site of this enzyme. However, S-DEPP is active against human and equine AChE with low μM IC50s. DEPP stereospecificities (S/R) toward these enzymes are moderate (20) relative to other cholinesterase-organophosphate (OP) systems. Pralidoxime, a common rescue agent, affects a modest recovery of both hAChE and eqBChE from treatment with S-DEPP. This result is consistent with expected chemical modification by DEPP and indicates that a measurable amount of the enzyme-phosphonate adduct does not undergo aging. Kinetic analysis of inhibition of both hAChE and eqBChE by S-DEPP yields KI values near 8μM and k2 values of about 0.10min⁻¹. In both cases, the reaction is practically irreversible. Second order rate constants calculated from these values are similar to those obtained previously using other thio-substituted OPs with bulky groups. Since BChE has a more accommodating acyl pocket than AChE, the similar behaviors of both enzymes toward S-DEPP is notable and is likely a reflection of the weakened potency of DEPP relative to chemical warfare agents.

Graphical abstract

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The synthesis and evaluation of new butadiene derivatives as tubulin polymerization inhibitors

Publication date: 15 June 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
Author(s): Yanqing Pang, Jun Yan, Baijiao An, Ling Huang, Xingshu Li
A series of new butadiene derivatives was synthesized and evaluated as tubulin polymerization inhibitors for the treatment of cancer. The optimal butadiene derivative, 9a, exhibited IC50 values of 0.056–0.089μM for five human cancer cell lines. This paper included a mechanistic study of the antiproliferative activity, including a tubulin polymerization assay, an examination of morphological alterations of cancer cells, an analysis of cell cycle arrest and an apoptosis assay.

Graphical abstract

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Structure of a Myeloid cell leukemia-1 (Mcl-1) inhibitor bound to drug site 3 of Human Serum Albumin

Publication date: 15 June 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
Author(s): Bin Zhao, John Sensintaffar, Zhiguo Bian, Johannes Belmar, Taekyu Lee, Edward T. Olejniczak, Stephen W. Fesik
Amplification of the gene encoding Myeloid cell leukemia-1 (Mcl-1) is one of the most common genetic aberrations in human cancer and is associated with high tumor grade and poor survival. Recently, we reported on the discovery of high affinity Mcl-1 inhibitors that elicit mechanism-based cell activity. These inhibitors are lipophilic and contain an acidic functionality which is a common chemical profile for compounds that bind to albumin in plasma. Indeed, these Mcl-1 inhibitors exhibited reduced in vitro cell activity in the presence of serum. Here we describe the structure of a lead Mcl-1 inhibitor when bound to Human Serum Albumin (HSA). Unlike many acidic lipophilic compounds that bind to drug site 1 or 2, we found that this Mcl-1 inhibitor binds predominantly to drug site 3. Site 3 of HSA may be able to accommodate larger, more rigid compounds that do not fit into the smaller drug site 1 or 2. Structural studies of molecules that bind to this third site may provide insight into how some higher molecular weight compounds bind to albumin and could be used to aid in the design of compounds with reduced albumin binding.

Graphical abstract

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Synthesis and biological evaluation of novel aromatic and heterocyclic bis-sulfonamide Schiff bases as carbonic anhydrase I, II, VII and IX inhibitors

Publication date: 15 June 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
Author(s): Suleyman Akocak, Nabih Lolak, Alessio Nocentini, Gulcin Karakoc, Anzel Tufan, Claudiu T. Supuran
A series of sixteen novel aromatic and heterocyclic bis-sulfonamide Schiff bases were prepared by conjugation of well known aromatic and heterocyclic aminosulfonamide carbonic anhydrase (CA, EC 4.2.1.1) inhibitor pharmacophores with aromatic and heterocyclic bis-aldehydes. The obtained bis-sulfonamide Schiff bases were investigated as inhibitors of four selected human (h) CA isoforms, hCA I, hCA II, hCA VII and hCA IX. Most of the newly synthesized compounds showed a good inhibitory profile against isoforms hCA II and hCA IX, also showing moderate selectivity against hCA I and VII. Several efficient lead compounds were identified among this bis-sulfonamide Schiff bases with low nanomolar to sub-nanomolar activity against hCA II (Kis ranging between 0.4 and 861.1nM) and IX (Kis between 0.5 and 933.6nM). Since hCA II and hCA IX are important drug targets (antiglaucoma and anti-tumor agents), these isoform-selective inhibitors may be considered of interest for various biomedical applications.

Graphical abstract

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Design, synthesis, and pharmacological evaluation of 4-azolyl-benzamide derivatives as novel GPR52 agonists

Publication date: 15 June 2017
Source:Bioorganic & Medicinal Chemistry, Volume 25, Issue 12
Author(s): Kazuyuki Tokumaru, Yoshiteru Ito, Izumi Nomura, Takashi Nakahata, Yuji Shimizu, Emi Kurimoto, Kazunobu Aoyama, Kazuyoshi Aso
G protein-coupled receptor 52 (GPR52) agonists are expected to improve the symptoms of psychiatric disorders. During exploration for a novel class of GPR52 agonists with good pharmacokinetic profiles, we synthesized 4-(3-(3-fluoro-5-(trifluoromethyl)benzyl)-5-methyl-1H-1,2,4-triazol-1-yl)-2-methylbenzamide (4u; half maximal effective concentration (EC50)=75nM, maximal response (Emax)=122%) starting from a high-throughput screening hit 3 (EC50=470nM, Emax=56%). The structural features of a reported GPR52 agonist were applied to 3, led to design 4-azolylbenzamides as novel GPR52 agonists. A structure–activity relationship study of 4-azolylbenzamide resulted in the design of the 1,2,4-triazole derivative 4u, which demonstrated excellent bioavailability in rats (F=53.8%). Oral administration of 4u (10mg/kg) significantly suppressed methamphetamine-induced hyperlocomotion in mice. Thus, 4u is a promising lead compound for drug discovery research of GPR52 agonists.

Graphical abstract

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Pyoderma Gangrenosum after Deep Inferior Epigastric Perforator Breast Reconstruction: Systematic Review and Case Report

Background: Pyoderma gangrenosum (PG) is a rare skin disorder of the neutrophilic dermatoses spectrum that can mimic wound infections in surgical patients. PG after breast surgery has been reported but in limited amounts in autologous breast reconstruction patients. We present the first case of PG after a delayed bilateral deep inferior epigastric perforator flap breast reconstruction in the setting of systemic disease along with a systematic review. Methods: PubMed, Ovid, and Web of Science were systematically searched to obtain cases of PG after autologous breast reconstruction. Sixty articles were identified but only 16 were relevant to this study. Results: Systemic disease was present in 2 patients (13%). Wound onset occurred typically 5 days after surgery. Fever and/or leukocytosis was observed in 10 patients (63%). Wound cultures were positive in 2 patients (13%). Donor-site wounds were present in 9 patients (56%). Bilateral breast wounds were present in 67% of bilateral cases. Debridement was performed in 10 cases (63%). Skin graft or substitute was performed in 6 cases (38%). Resection of autologous flap was performed in 3 cases (19%). All patients were treated with systemic steroids (81%) and/or immunosuppressive medications (50%). Complete wound healing occurred by 4 months on average. Conclusion: If early ulcerative wounds develop at multiple sites after autologous breast reconstruction with worsening after debridement and antibiotic therapy, then PG should be considered. It is imperative that an early diagnosis and subsequent treatment with steroids and/or immunosuppressive medications be initiated so further surgical procedures, flap loss, and scarring can be minimized.

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Contracted Nose Correction with Dermofat and Conchal Cartilage

No abstract available

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Stem cells: The different flavours of iPS cells

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Plant genetics: Spatial transcriptomics in plants

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Cancer genomics: Tracking cancer evolution

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Dynamic chromatin technologies: from individual molecules to epigenomic regulation in cells

A full understanding of chromatin in diverse cellular processes requires the consideration of its dynamics, but most standard chromatin assays provide only a static snapshot. This Review describes various emerging methods for probing chromatin dynamics across a wide range of temporal and spatial scales, and discusses the resulting biological insights.

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Effects of sex steroids on the pattern of methylation and expression of the promoter region of estrogen and androgen receptors in people with gender dysphoria under cross-sex hormone treatment

Publication date: Available online 21 May 2017
Source:The Journal of Steroid Biochemistry and Molecular Biology
Author(s): Gloria Aranda, Eduardo Fernández-Rebollo, Marta Pradas-Juni, Felicia Alexandra Hanzu, Susana G. Kalko, Irene Halperin, Mireia Mora
Cross-sex hormone therapy (CHT) is critical for phenotypical and physiological transition in adults with gender dysphoria (GD). However, the impact of the CHT onto the molecular level/epigenetic regulation has not been comprehensively addressed. We postulate that CHT in GD could drive changes at the androgen receptor (AR), estrogen receptor alpha (ESR1) and estrogen receptor beta (ESR2), affecting their DNA methylation pattern and mRNA expression that may influence in the phenotypical changes associated to CHT.We carried out a prospective observational study on individuals with a diagnosis of GD. 18 subjects (no previous CHT): 12 female to male (FtoM) and 6 male to female (MtoF). An Epityper Mass array TM method was used to study the DNA methylation and Real-time PCR quantitative reverse transcription PCR (qRT-PCR) was used to quantify the gene expression. The analysis of AR, ESR1 and ESR2 receptor was performed at baseline, 6 and 12 months after CHT. No differences in DNA methylation of ESR were found in MtoF, while DNA methylation was increased in FtoM at 6 and 12 months of CHT. The AR showed a significant increase of methylation in MtoF group after 12 months of estrogenic treatment Regarding the expression analysis, AR expression was significantly decreased in FtoM upon CHT treatment. AR, ESR1 and ESR2 methylation were correlated with anthropometric, metabolic and hormonal parameters in FtoM and MtoF.Our results support that CHT is associated to epigenetic changes that might affect the response to treatment with sex steroids.



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Development of a quantitative assessment method of pigmentary skin disease using ultraviolet optical imaging

Background/Purpose

The visual scoring method has been used as a subjective evaluation of pigmentary skin disorders. Severity of pigmentary skin disease, especially melasma, is evaluated using a visual scoring method, the MASI (melasma area severity index). This study differentiates between epidermal and dermal pigmented disease. The study was undertaken to determine methods to quantitatively measure the severity of pigmentary skin disorders under ultraviolet illumination.

Methods

The optical imaging system consists of illumination (white LED, UV-A lamp) and image acquisition (DSLR camera, air cooling CMOS CCD camera). Each camera is equipped with a polarizing filter to remove glare. To analyze images of visible and UV light, images are divided into frontal, cheek, and chin regions of melasma patients. Each image must undergo image processing. To reduce the curvature error in facial contours, a gradient mask is used.

Results

The new method of segmentation of front and lateral facial images is more objective for face-area-measurement than the MASI score. Image analysis of darkness and homogeneity is adequate to quantify the conventional MASI score. Under visible light, active lesion margins appear in both epidermal and dermal melanin, whereas melanin is found in the epidermis under UV light.

Conclusion

This study objectively analyzes severity of melasma and attempts to develop new methods of image analysis with ultraviolet optical imaging equipment. Based on the results of this study, our optical imaging system could be used as a valuable tool to assess the severity of pigmentary skin disease.

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Reflectance confocal microscopy analysis of equivocal melanocytic lesions with severe regression

Background

The differential diagnosis between regressing nevi and melanoma might be challenging; regressing areas can represent a confounding factor for the diagnosis and the histology still remain mandatory to rule out melanoma. Reflectance confocal microscopy may add valuable information by revealing features suggestive of the nature of the melanocytic proliferation.

Objective

To assess the impact of confocal microscopy in the management of regressive melanocytic lesions.

Methods

The dermoscopic analysis of 92 melanocytic lesions showing that more than 30% of regressions have been retrospectively considered, among them, 32 melanocytic lesions with a 7 check point list ≥3 they were assessed at the rcm and subsequently excised. For each selected lesion, dermoscopic features of regression (white scar-like areas, blue areas, blue white areas), distribution of regressing areas (central, peripheral, or both) and the percentage of regression have been examined by an expert in dermoscopy, blinded to the histological and confocal diagnosis. Subsequently, two experts in confocal microscopy revaluated, blinded from histology, RCM images.

Results

Of the 32 lesions analyzed, 23 (71.5%) were diagnosed histologically as nevi, and 9 (28.5%) as melanomas. 26 of 32 lesions (81.5%) exhibited regression >50% of the overall. On RCM, 11 lesions have been interpreted as malignant and 21 as benign. On RCM the majority of nevi exhibited regular architecture without cytological atypia. Epidermal disarray, pagetoid infiltration, disarranged dermo-epidermal junction architecture and atypical nests were considered as suspicious for malignancy. Good concordance between confocal readers has been detected.

Conclusion

A combined dermoscopic/confocal approach can be used for the management of lesions exhibiting dermoscopic features of regression in order to provide a more conclusive pre-histological diagnosis avoiding a high number of unnecessary excisions. Limits of this study were represented by the relatively small number of lesions and the retrospective approach. Further, prospective studies on a larger number of cases, will be necessary in order to compare the efficacy of dermoscopy alone versus dermoscopy in combination with RCM for the evaluation of regression, suspected pigmented lesions.

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Racial differences in colorectal cancer survival at a safety net hospital

Publication date: August 2017
Source:Cancer Epidemiology, Volume 49
Author(s): Umit Tapan, Shin Yin Lee, Janice Weinberg, Vijaya B. Kolachalama, Jean Francis, Marjory Charlot, Kevan Hartshorn, Vipul Chitalia
BackgroundWhile racial disparity in colorectal cancer survival have previously been studied, whether this disparity exists in patients with metastatic colorectal cancer receiving care at safety net hospitals (and therefore of similar socioeconomic status) is poorly understood.MethodsWe examined racial differences in survival in a cohort of patients with stage IV colorectal cancer treated at the largest safety net hospital in the New England region, which serves a population with a majority (65%) of non-Caucasian patients. Data was extracted from the hospital's electronic medical record. Survival differences among different racial and ethnic groups were examined graphically using Kaplan-Meier analysis. A univariate cox proportional hazards model and a multivariable adjusted model were generated.ResultsBlack patients had significantly lower overall survival compared to White patients, with median overall survival of 1.9 years and 2.5 years respectively. In a multivariate analysis, Black race posed a significant hazard (HR 1.70, CI 1.01–2.90, p=0.0467) for death. Though response to therapy emerged as a strong predictor of survival (HR=0.4, CI=0.2-0.7, p=0.0021), it was comparable between Blacks and Whites.ConclusionsDespite presumed equal access to healthcare and socioeconomic status within a safety-net hospital system, our results reinforce findings from previous studies showing lower colorectal cancer survival in Black patients, and also point to the importance of investigating other factors such as genetic and pathologic differences.



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IFC (Ed. Board)

Publication date: May 2017
Source:Brain Research Bulletin, Volume 131





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EEG activity as an objective measure of cognitive load during effortful listening: A study on pediatric subjects with bilateral, asymmetric sensorineural hearing loss

Publication date: August 2017
Source:International Journal of Pediatric Otorhinolaryngology, Volume 99
Author(s): Pasquale Marsella, Alessandro Scorpecci, Giulia Cartocci, Sara Giannantonio, Anton Giulio Maglione, Isotta Venuti, Ambra Brizi, Fabio Babiloni
ObjectivesDeaf subjects with hearing aids or cochlear implants generally find it challenging to understand speech in noisy environments where a great deal of listening effort and cognitive load are invested. In prelingually deaf children, such difficulties may have detrimental consequences on the learning process and, later in life, on academic performance. Despite the importance of such a topic, currently, there is no validated test for the assessment of cognitive load during audiological tasks. Recently, alpha and theta EEG rhythm variations in the parietal and frontal areas, respectively, have been used as indicators of cognitive load in adult subjects.The aim of the present study was to investigate, by means of EEG, the cognitive load of pediatric subjects affected by asymmetric sensorineural hearing loss as they were engaged in a speech-in-noise identification task.MethodsSeven children (4F and 3M, age range = 8–16 years) affected by asymmetric sensorineural hearing loss (i.e. profound degree on one side, mild-to-severe degree on the other side) and using a hearing aid only in their better ear, were included in the study. All of them underwent EEG recording during a speech-in-noise identification task: the experimental conditions were quiet, binaural noise, noise to the better hearing ear and noise to the poorer hearing ear. The subjects' Speech Recognition Thresholds (SRT) were also measured in each test condition. The primary outcome measures were: frontal EEG Power Spectral Density (PSD) in the theta band and parietal EEG PSD in the alpha band, as assessed before stimulus (word) onset.ResultsNo statistically significant differences were noted among frontal theta power levels in the four test conditions. However, parietal alpha power levels were significantly higher in the "binaural noise" and in the "noise to worse hearing ear" conditions than in the "quiet" and "noise to better hearing ear" conditions (p < 0.001). SRT scores were consistent with task difficulty, but did not correlate with alpha and theta power level variations.ConclusionThis is the first time that EEG has been applied to children with sensorineural hearing loss with the purpose of studying the cognitive load during effortful listening. Significantly higher parietal alpha power levels in two of three noisy conditions, compared to the quiet condition, are consistent with increased cognitive load. Specifically, considering the time window of the analysis (pre-stimulus), parietal alpha power levels may be a measure of cognitive functions such as sustained attention and selective inhibition. In this respect, the significantly lower parietal alpha power levels in the most challenging listening condition (i.e. noise to the better ear) may be attributed to loss of attention and to the subsequent fatigue and "withdrawal" from the task at hand.



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Significance and Nature of Bystander Responses Induced by Various Agents

Publication date: Available online 21 May 2017
Source:Mutation Research/Reviews in Mutation Research
Author(s): Neha Verma, Ashu Bhan Tiku
Bystander effects in a biological system are the responses shown by non-targeted neighbouring cells/tissues/organisms. These responses are triggered by factors released from targeted cells when exposed to a stress inducing agent. The biological response to stress inducing agents is complex, owing to the diversity of mechanisms and pathways activated in directly targeted and bystander cells. These responses are highly variable and can be either beneficial or hazardous depending on the cell lines tested, dose of agent used, experimental end points and time course selected. Recently non-targeted cells have even been reported to rescue the directly exposed cells by releasing protective signals that might be induced by non-targeted bystander responses. The nature of bystander signal/s is not yet clear. However, there are evidences suggesting involvement of ROS, RNS, protein factors and even DNA molecules leading to the activation of a number of signaling pathways. These can act independently or in a cascade, to induce events leading to changes in gene expression patterns that could elicit detrimental or beneficial effects.Many review articles on radiation induced bystander responses have been published. However, to the best of our knowledge, a comprehensive review on bystander responses induced by other genotoxic chemicals and stress inducing agents has not been published so far. Therefore, the aim of the present review is to give an overview of the literature on different aspects of bystander responses: agents that induce these responses, factors that can modulate bystander responses and the mechanisms involved.



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Coste-efectividad de la utilización de la tirotropina recombinante humana previa a la ablación con radioyodo en el tratamiento del cáncer de tiroides en hospitales españoles

Publication date: Available online 20 May 2017
Source:Revista Española de Medicina Nuclear e Imagen Molecular
Author(s): J.A. Vallejo, M.A. Muros
ObjetivosPrevio a la ablación con radioyodo en el tratamiento del cáncer de tiroides, se necesita aumentar los niveles de tirotropina (TSH) mediante estimulación exógena (con tirotropina humana recombinante [rhTSH]) o endógena, retirando la terapia con hormona tiroidea (THW). La utilización de rhTSH evita el hipotiroidismo y favorece la eliminación posterior de radioyodo pero supone un coste del producto. Por tanto, era necesario realizar un análisis de coste-efectividad que tuviera en cuenta todos los costes y los beneficios de la utilización de esta terapia.Material y métodosMediante un modelo de Markov con 2 brazos de análisis (rhTSH y THW), estratificado en dosis altas (100mCi/3.700 MBq) y bajas (30mCi/1.110 MBq) de radioyodo, y utilizando 17 ciclos semanales se determinó el coste incremental por años de vida ajustados por calidad (AVAC) asociados a la utilización de rhTSH. Los parámetros clínicos incluidos en el modelo se basan en estudios publicados y en una encuesta realizada en España.ResultadosLa preparación con rhTSH para la radioablación es superior a la THW, presentando beneficios adicionales (0,048AVAC) a la vez que un ahorro en costes (–614,16€), con un ratio de coste-efectividad incremental (ICER) de –12.795€/AVAC. Los análisis de sensibilidad univariantes y multivariantes demuestran que el resultado es consistente.ConclusionesLa utilización de rhTSH previa a la radioablación en España supone un ahorro de costes a la vez que una serie de beneficios de salud para el paciente, por lo que es altamente coste-efectiva.ObjectivesIn thyroid cancer treatment, the thyroid-stimulating hormone (TSH) must be elevated before radioiodine ablation, either by exogenous (with recombinant human thyrotropin [rhTSH]) or endogenous stimulation by thyroid hormone withdrawal (THW). The use of rhTSH avoids hypothyroidism and favours the subsequent elimination of radioiodine, but involves the cost of the product. For this reason, a cost-effectiveness analysis was performed, taking into account all costs involved and the benefits associated with the use of this therapy.Material and methodsUsing a Markov modelling with two analysis arms (rhTSH and THW), stratified into high (100mCi/3700 MBq) and low (30mCi/1110 MBq) radioiodine doses, and using 17 weekly cycles, the incremental cost per quality-adjusted life-year (QALY) related to the use of rhTSH was determined. The clinical inputs included in the model were based on published studies and in a treatment survey conducted in Spain.ResultsRadioablation preparation with rhTSH is superior to THW, showing additional benefits (0.048 AVAC), as well as cost savings (–€614.16), with an incremental cost-effectiveness rate (ICER) of –€12,795/QALY. The univariate and multivariate sensitivity analyses showed the result to be robust.ConclusionsThe use of rhTSH previous to radioablation in Spain has cost savings, as well as a series of health benefits for the patient, making it highly cost-effective.



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Dietary Approaches to Stop Hypertension Diet, Weight Status, and Blood Pressure among Children and Adolescents: National Health and Nutrition Examination Surveys 2003-2012

Publication date: Available online 20 May 2017
Source:Journal of the Academy of Nutrition and Dietetics
Author(s): Juliana F.W. Cohen, Megan E. Lehnerd, Robert F. Houser, Eric B. Rimm
BackgroundThe Dietary Approaches to Stop Hypertension (DASH) diet is associated with lower blood pressure and reduced risk of cardiovascular disease among adults, but little is known about accordance with this dietary pattern or health benefits among children and adolescents.ObjectiveThe objectives were to evaluate accordance with the DASH diet, differences over time, and the association with health attributes among a nationally representative sample of US children and adolescents.DesignCross-sectional data from the 2003-2012 National Health and Nutrition Examination Surveys (NHANES) were analyzed.Participants/settingData from 9,793 individuals aged 8 to 18 years were examined.Main outcome measuresDASH accordance was estimated based on nine nutrient targets: total fat, saturated fat, protein, cholesterol, fiber, calcium, magnesium, potassium, and sodium; possible score range is 0 to 9.Statistical analyses performedAccordance with the DASH diet across time was examined comparing the 2011-2012 to 2003-2004 NHANES surveys. The association between DASH score and weight status was examined using multinomial logistic regression, and the associations with waist circumference, systolic blood pressure, and diastolic blood pressure were examined using multivariable linear regression.ResultsAccordance with the DASH diet was low across the age groups, with a range of mean DASH scores from 1.48 to 2.14. There were no significant changes across time. DASH score was inversely associated with systolic blood pressure (mm Hg) among 14- to 18-year-olds (β=−.46; 95% CI −.83 to −.09) among the larger sample of participants who completed at least one dietary recall, but no significant differences were seen in other age categories. In the subsample of participants with both dietary recalls, a significant inverse association was seen between DASH score and systolic blood pressure for 11- to 13-year-olds (β=−.57; 95% CI −1.02 to −.12). There were no significant associations between this dietary pattern and weight status, waist circumference, or diastolic blood pressure.ConclusionsFew US children and adolescents have diets that are in alignment with the DASH diet. Future research should explore strategies to encourage fruit, vegetable, and whole-grain consumption, as well as sodium reductions to help meet DASH nutrient targets in children and adolescents, as well as examine the potential benefits of this eating pattern on health in this population group.



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Enhancing hair growth in male androgenetic alopecia by a combination of fractional CO 2 laser therapy and hair growth factors

Abstract

Laser therapy and growth factors have been used as alternative treatments for male androgenetic alopecia (MAA). The aim of this study is to determine the efficacy and safety of hair growth factors alone or combined with ablative carbon dioxide (CO₂) fractional laser therapy in MAA. Twenty-eight men were enrolled in this randomized half-split study based on a left-head to right-head pattern. Fractional CO₂ laser treatment was unilaterally performed; hair growth factors were bilaterally applied. Six sessions with 2-week intervals were performed. Global photographs and dermoscopy assessments were performed at the baseline and 4 months after first treatment. Global photographs underwent blinded review by three independent dermatologists. Scanning electron microscopy was used to compare changes in hair-follicle phase and hair-shaft diameter. Twenty-seven participants completed the 4-month treatment schedule. One patient was lost. Mean hair density increased from 114 ± 27 to 143 ± 25/cm² (P < 0.001) in the combined group and from 113 ± 24 to 134 ± 19/cm² in the growth factor group (P < 0.001). The mean change from baseline between two groups was also compared (P = 0.003). Global photographs showed improvement in 93% (25/27) patients in the combined group and 67% (18/27) patients in the growth factor group. Under scanning electron microscopy, hair follicles appeared to transition from telogen to anagen, and hair-shaft diameter increased in five randomly selected patients. Ablative fractional CO₂ laser combined with hair growth factors may serve as an alternative treatment for MAA in individuals unwilling/unable to undergo medical or surgical treatment.

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MET overexpression and gene amplification: prevalence, clinico-pathological characteristics and prognostic significance in a large cohort of patients with surgically resected NSCLC

Abstract

The prevalence of overexpression and amplification of the proto-oncogene mesenchymal epithelial transition (MET) in non-small cell lung cancer (NSCLC) varies greatly in the literature. Since MET is a potential treatment target, knowledge of its prevalence and prognostic importance is crucial. We investigated MET expression and gene status in 735 NSCLC cases using tissue microarrays. Prognostic significance as well as correlations with various clinico-pathological parameters were evaluated. The prevalence of MET overexpression was 17% and MET amplification was present in 2.4% of cases. MET overexpression was found more frequently in adenocarcinomas (and TTF1-positive tumors) and female patients and was also associated with expression of members of the epidermal growth factor receptor (EGFR) signaling cascade. MET amplified tumors tended to express MET more frequently and more intensively. MET expression or gene status did not prove to be relevant prognostic factors. MET may not be an unequivocal prognostic parameter; however, its expression is associated with certain clinico-pathological characteristics and with EGFR and downstream EGFR effectors. This could be an important point for future studies addressing targeted MET therapy and should be considered as a possible means of optimizing the benefit and minimizing undesirable effects.

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Sol–gel-derived bioactive glass nanoparticle-incorporated glass ionomer cement with or without chitosan for enhanced mechanical and biomineralization properties

Publication date: Available online 20 May 2017
Source:Dental Materials
Author(s): Dong-Ae Kim, Jung-Hwan Lee, Soo-Kyung Jun, Hae-Won Kim, Mohamed Eltohamy, Hae-Hyoung Lee
ObjectiveThis study investigated the mechanical and in vitro biological properties (in immortalized human dental pulp stem cells (ihDPSCs)) of bioactive glass nanoparticle (BGN)-incorporated glass ionomer cement (GIC) with or without chitosan as a binder.MethodsAfter the BGNs were synthesized and characterized, three experimental GICs and a control (conventional GIC) that differed in the additive incorporated into a commercial GIC liquid (Hy-bond, Shofu, Japan) were produced: BG5 (5wt% of BGNs), CL0.5 (0.5wt% of chitosan), and BG5+CL0.5 (5wt% of BGNs and 0.5wt% of chitosan). After the net setting time was determined, weight change and bioactivity were analyzed in simulated body fluid (SBF) at 37°C. Mechanical properties (compressive strength, diametral tensile strength, flexural strength and modulus) were measured according to the incubation time (up to 28 days) in SBF. Cytotoxicity (1day) and biomineralization (14 days), assessed by alizarin red staining, were investigated using an extract from GIC and ihDPSCs. Data were analyzed using one-way analysis of variance (ANOVA) followed by Tukey's post hoc test; p<0.05.ResultsBGNs were sol–gel synthesized to be approximately 42nm in diameter with a spherical morphology and amorphous structure. After the bioactivity and suspension ability of the BGNs were confirmed, all the experimental GIC groups had setting times of less than 6min and approximately 1% weight loss after 28days of incubation. In addition, BGNs incorporated into GIC (BG5 and BG5+CL0.5) exhibited surface bioactivity. The mechanical properties were increased in the BGN-incorporated GICs compared to those in the control (p<0.05). Without cytotoxicity, the biomineralization capacity was ranked in the order BG5, BG5+CL0.5, control, and CL0.5 (p<0.05).SignificanceBGN-incorporated GIC showed enhanced mechanical properties such as compressive, diametral tensile and flexural strength as well as in vitro biomineralization properties in ihDPSCs without cytotoxicity. Therefore, the developed BGN-incorporated GIC is a promising restorative dental material, although further in vivo investigation is needed before clinical application.

Graphical abstract

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The effects of different opacifiers on the translucency of experimental dental composite resins

Publication date: Available online 20 May 2017
Source:Dental Materials
Author(s): Karine Haas, Gulelala Azhar, Duncan J. Wood, Keyvan Moharamzadeh, Richard van Noort
ObjectiveThe aim of this study was to evaluate the effects of different opacifiers on the translucency of experimental dental composite-resins.MethodsThree metal oxides that are used as opacifiers were tested in this study: titanium oxide (TiO2), aluminium oxide (Al2O3) and zirconium oxide (ZrO2). Experimental composite-resins were fabricated containing 25wt.% urethane dimethacrylate (UDMA)-based resin matrix and 75% total filler including different concentrations of metal oxides (0, 0.25, 0.5, 0.75 and 1wt.%) blended into silane treated barium-silicate filler. The specimens (15.5mm diameter and 1mm thickness) were light-cured and tested in the transmittance mode using a UV/VIS spectrophotometer at wavelengths from 380 to 700nm under a standard illuminant D65. The color differences (ΔE* ab) between different concentrations of opacifiers were also measured in transmittance mode based on their Lab values.ResultsStatistical analysis by ANOVA and Tukey's test showed a significant decrease (p<0.05) in light transmittance with the addition of opacifiers to the experimental composite-resins. There was a linear correlation between different concentrations of TiO2 and Al2O3 and total transmittance. Total transmittance was also found to be wavelength dependent. The color differences for the concentrations of 0–1wt.% of the opacifiers were above 1 ΔE* unit, with Al2O3 showing the smallest color shift.SignificanceThe type and the amount of the opacifiers used in this study had a significant effect on the translucency of the experimental UDMA-based dental composite resins. The most effective opacifier was TiO2, followed by ZrO2 and Al2O3 in decreasing order, respectively.



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Utility of an electronic database and checklist system for Improvement in MRI acquisition

Publication date: Available online 20 May 2017
Source:Current Problems in Diagnostic Radiology
Author(s): Juan E. Small, Laura Semine, Jaclyn Therrien, Patricia Doyle, Lorraine Kelly, Robert Marquis, Curtis W. Bakal
PurposeTo determine whether implementation of an easily accessible electronic database promotes significant reporting of MRI acquisition errors. Additionally, we wanted to see if analysis of the error reports could be used to create a comprehensive checklist to avoid the most common errors.MethodsA new, simple and efficient electronic database reporting system was written in-house and implemented at our institution. Over the course of four months, use of this database enabled collection and analysis of sufficient data for trend analysis. A simple 4 point checklist for MRI technologist use was developed based on the most commonly reported errors. Reported MRI acquisition error rates were collected and analyzed thereafter.ResultsBy the first full month of implementation, MRI scan error reporting increased from a previous negligible baseline rate to 3.03%. The comprehensive checklist was based on the four most common issues reported. Verification of checklist use showed that adherence to this requirement averaged greater than 94%. Immediately following roll out of the checklist, the percentage of errors reported fell to 1.7% with a continued decline in error reports thereafter. An approximately 60% reduction in errors in the last month of the study was evident as compared to the first month of data collection.ConclusionsThe use of an efficient error reporting system and implementation of a checklist based on the most common MRI acquisition errors results in a substantial decrease in the baseline MRI acquisition error rates.



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Presence of new mutations in the TP53 gene in patients with low-risk myelodysplastic syndrome: two case reports

Myelodysplastic syndromes are heterogeneous disorders. Patients with myelodysplastic syndrome disease often have ineffective hematopoiesis, cytopenias, blood cell dysplasia in one or more cell types, and are a...

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Presence of new mutations in the TP53 gene in patients with low-risk myelodysplastic syndrome: two case reports

Myelodysplastic syndromes are heterogeneous disorders. Patients with myelodysplastic syndrome disease often have ineffective hematopoiesis, cytopenias, blood cell dysplasia in one or more cell types, and are a...

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Hashimoto’s Encephalopathy Presenting with Unusual Behavioural Disturbances in an Adolescent Girl

Hashimoto's encephalopathy (HE) is a rare autoimmune disorder with neurological and neuropsychiatric manifestations and elevated titres of anti-thyroid antibodies. Here we are reporting a case of HE in a 19-year-old girl who presented with seizure-like episodes, confusion, and behavioural disturbances with catatonic symptoms such as posturing, echopraxia, echolalia, and ambivalence. Patient did not respond to antipsychotics and anticonvulsants. On further investigation, patient was found to have high serum anti-TPO antibodies of about 1261 U/mL with euthyroid status, which supported a suspicion of HE. Our consultant neurologist confirmed the diagnosis and she was started on injection of methylprednisolone 750 mg OD. Since patient started showing clinical improvement, her antipsychotic medications were tapered off. On follow-up, patient has recovered and is functioning well. Since HE is a diagnosis of exclusion, very high anti-TPO antibodies and good response to steroids supported the diagnosis of HE in this patient after excluding other etiological possibilities. This case has been reported because the clinical presentation was predominantly neurobehavioural manifestations which is uncommon with HE.

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Communicative Access Measures for Stroke: Development and Evaluation of a Quality Improvement Tool

Publication date: Available online 20 May 2017
Source:Archives of Physical Medicine and Rehabilitation
Author(s): Aura Kagan, Nina Simmons-Mackie, J. Charles Victor, Melodie T.Y. Chan
Objective1) To develop a systems level quality improvement tool targeting communicative access to information and decision-making for stroke patients with language disorders and 2) to evaluate the resulting tool – Communicative Access Measures for Stroke (CAMS).DesignSurvey development and evaluation was in line with accepted guidelines, and included item generation and reduction, survey formatting and composition, pre-testing, pilot-testing, and reliability assessment.SettingDevelopment and evaluation were carried out in hospital and community agency settings.ParticipantsThe project utilized a convenience sample of 31 participants for the survey development, and 63 participants for the CAMS reliability study (broken down into 6 administrators/managers, 32 frontline staff, 25 participants with aphasia). The number of eligible participants invited to the reliability study included 45 community-based organizations in Ontario as well as 4400 individuals from communities of practice.InterventionsNot applicable.Main Outcome Measure(s)Data were analyzed using kappa statistics and intraclass correlations for each item score on all surveys.ResultsA tool, the Communicative Access Measures for Stroke (CAMS), comprising three surveys, was developed for health facilities from the perspectives of 1) administrators/policy makers, 2) staff/frontline health care providers, and 3) patients with aphasia (using a communicatively accessible version). Reliability for items on the CAMS Administrator and CAMS Staff surveys was moderate to high (Kappa/ICCs ranging from 0.54 to 1.00). As expected, reliability was lower for the CAMS Patient survey with most items having ICCs between 0.4 and 0.6.Conclusion(s): These findings suggest that CAMS may provide useful quality improvement information for health care facilities with an interest in improving care for patients with stroke and aphasia.



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Microarray data and gene expression statistics for Saccharomyces cerevisiae exposed to simulated asbestos mine drainage

Publication date: August 2017
Source:Data in Brief, Volume 13
Author(s): Heather E. Driscoll, Janet M. Murray, Erika L. English, Timothy C. Hunter, Kara Pivarski, Elizabeth D. Dolci
Here we describe microarray expression data (raw and normalized), experimental metadata, and gene-level data with expression statistics from Saccharomyces cerevisiae exposed to simulated asbestos mine drainage from the Vermont Asbestos Group (VAG) Mine on Belvidere Mountain in northern Vermont, USA. For nearly 100 years (between the late 1890s and 1993), chrysotile asbestos fibers were extracted from serpentinized ultramafic rock at the VAG Mine for use in construction and manufacturing industries. Studies have shown that water courses and streambeds nearby have become contaminated with asbestos mine tailings runoff, including elevated levels of magnesium, nickel, chromium, and arsenic, elevated pH, and chrysotile asbestos-laden mine tailings, due to leaching and gradual erosion of massive piles of mine waste covering approximately 9km². We exposed yeast to simulated VAG Mine tailings leachate to help gain insight on how eukaryotic cells exposed to VAG Mine drainage may respond in the mine environment. Affymetrix GeneChip® Yeast Genome 2.0 Arrays were utilized to assess gene expression after 24-h exposure to simulated VAG Mine tailings runoff. The chemistry of mine-tailings leachate, mine-tailings leachate plus yeast extract peptone dextrose media, and control yeast extract peptone dextrose media is also reported. To our knowledge this is the first dataset to assess global gene expression patterns in a eukaryotic model system simulating asbestos mine tailings runoff exposure. Raw and normalized gene expression data are accessible through the National Center for Biotechnology Information Gene Expression Omnibus (NCBI GEO) Database Series GSE89875 (http://ift.tt/2rF7prB).



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(S001) Regional Nodal Irradiation in Elderly Node Positive Women: A Patterns of Care Study on Changes in Utilization Over a Decade

International Journal of Radiation Oncology, Biology, Physics, Volume 98, Issue 2, Supplement, 2017 Jun 1 | Molitoris, Jason K., MD, PhD; Diwanji, Tejan, MD; Snider, James W., MD;...
To evaluate practice patterns for the treatment of elderly women with low volume node positive breast cancer (BC) and the factors associated with the use of regional nodal irradiation (RNIacrnm1) in the setting of breast conservation using a natio...

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(S009) In Silico Trial of MR-Guided Mid-Treatment Adaptive Planning for Hypofractionated Stereotactic Radiotherapy in Centrally Located Thoracic Tumors

International Journal of Radiation Oncology, Biology, Physics, Volume 98, Issue 2, Supplement, 2017 Jun 1 | Henke, Lauren E., MD; Kashani, Rojano, PhD; Przybysz, Daniel, MD;...
Background Hypofractionated (>5fx) stereotactic radiotherapy (HSRT) may allow for biologically equivalent dose to tumor with a lower risk of organ at risk (OARacrnm1) toxicity in centrally located thoracic tumors (CTTacrnm1). Adaptive planning ...

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(S002) Population-Based Analysis of the Effect of Margin Status on 10-Year Local Recurrence and Breast Cancer-Specific Survival in Women Treated With Breast-Conserving Therapy

International Journal of Radiation Oncology, Biology, Physics, Volume 98, Issue 2, Supplement, 2017 Jun 1 | Tyler, Susan A., MD, MSc, FRCPC; Truong, Pauline, MD, FRCPC; Lesperance, Mary, PhD;...
Purpose The 2014 SSO/ASTRO consensus advocates "no ink on tumor" as an adequate surgical margin for invasive breast cancer. This study evaluates outcomes relative to margin status in a population-based cohort of women treated with breast-conservin...

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(S004) Hypofractionated Radiation Therapy After Breast Conservation Surgery for Ductal Carcinoma in Situ

International Journal of Radiation Oncology, Biology, Physics, Volume 98, Issue 2, Supplement, 2017 Jun 1 | Chan, Dennis P., BA; Lee, John W., MD; Kumar, Rahul J., MD
Purpose/Objective(s) Adjuvant hypofractionated whole breast radiation therapy (WBRTacrnm1) for early stage breast cancer has become a standard treatment regimen because of its equivalent efficacy, attractive cost, and convenience. Randomized clini...

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(S013) Dosimetric Analysis of Treating Malignant Pleural Mesothelioma Using Volumetric Modulated ARC Therapy

International Journal of Radiation Oncology, Biology, Physics, Volume 98, Issue 2, Supplement, 2017 Jun 1 | Thompson, Marcher R., MD; Dumane, Vishruta A., PhD; Rosenzweig, Kenneth E., MD
Background In the treatment of malignant pleural mesothelioma (MPMacrnm1), there is evidence to support the use of pleurectomy/decortication (P/Dacrnm1) as the primary treatment. This presents a unique challenge to the radiation oncologist to trea...

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(S023) Colorectal Cancer Screening Among Men With Newly Diagnosed Prostate Cancer

International Journal of Radiation Oncology, Biology, Physics, Volume 98, Issue 2, Supplement, 2017 Jun 1 | Leachman, Brooke K., MD; Scharf, Lawrence J., MD; Sobczak, Mark L., MD
Introduction Prostate & colorectal cancers (CRCacrnm1) are the first and third most common cancers in men, both of which can be detected with routine screening methods. Nationally, about 60% of men have undergone * colorectal cancer * screenin...

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(S012) Circulating Tumor DNA Detects Residual Disease and Anticipates Tumor Progression Earlier Than CT Imaging

International Journal of Radiation Oncology, Biology, Physics, Volume 98, Issue 2, Supplement, 2017 Jun 1 | Chaudhuri, Aadel A., MD, PhD; Chabon, Jacob J., BS; Lovejoy, Alexander F., PhD;...
Objective Cancer Personalized Profiling by deep Sequencing (CAPP-Seq) is a novel blood-based assay for quantitating circulating tumor DNA (ctDNA). CT imaging is the standard-of-care modality for lung cancer post-treatment surveillance. We performe...

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(S010) Stereotactic Body Radiotherapy (SBRT) for Operable vs. Medically Inoperable Stage I Non-Small Cell Lung Cancer: Long-Term Five-Year Outcomes and an Assessment by Fractionation Regimen, Tumor Size, and Tumor Location

International Journal of Radiation Oncology, Biology, Physics, Volume 98, Issue 2, Supplement, 2017 Jun 1 | Schonewolf, Caitlin A.; Heskel, Marina; Doucette, Abigail;...
Background SBRT is standard of care for medically inoperable stage I NSCLC, but limited long-term data exist. We hypothesized long-term local control (LCacrnm1) and cancer specific survival (CSSacrnm1) would not differ by fractionation schedule, t...

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(S011) Does Insurance Status Impact Survival Outcomes in Patients With Stage III Non-Small Cell Lung Cancer (NSCLC) Treated With Curative Intent?

International Journal of Radiation Oncology, Biology, Physics, Volume 98, Issue 2, Supplement, 2017 Jun 1 | Rice, Stephanie R., MD; Vyfhuis, Melissa, MD, PhD; Neha, Bhooshan, MD, PhD;...
Background Financial burden of oncologic care incorporates health-care insurance coverage and patient resources to support daily needs while undergoing treatment. Dependence on government-funded insurances may be a surrogate for a patient's lack o...

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(S019) Lymphocyte-Sparing Effect of Proton Therapy in Patients With Esophageal Cancer

International Journal of Radiation Oncology, Biology, Physics, Volume 98, Issue 2, Supplement, 2017 Jun 1 | Fang, Penny, MD; Shiraishi, Yutaka; Jiang, Wen, MD, PhD;...
Purpose We assess whether radiation treatment modality with proton therapy or intensity-modulated radiation therapy (IMRTacrnm1) is associated with lymphopenia in patients with esophageal cancer. Methods and Materials Patients treated nonsurgicall...

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(S014) Long-Terms Results of a Trial of Concurrent Chemotherapy and Escalating Doses of Radiation for Unresectable Non-Small Cell Lung Cancer: NCCTG N0028 (Alliance)

International Journal of Radiation Oncology, Biology, Physics, Volume 98, Issue 2, Supplement, 2017 Jun 1 | Ross, Helen, MD; Schild, Steven, MD; Hillman, Shauna;...
Introduction This phase I/II trial was designed to determine the maximally tolerated dose (MTDacrnm1) of thoracic radiotherapy (TRTacrnm1) as part of a combined modality approach. This report includes the long-term outcome of patients treated on t...

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(S022) Can Imaging-Based Biomarkers of Pancreatic Cancer be Used to Select Patients for Dose-Escalated Radiotherapy?

International Journal of Radiation Oncology, Biology, Physics, Volume 98, Issue 2, Supplement, 2017 Jun 1 | Moningi, Shalini, MD; Amer, Ahmed; Colbert, Lauren;...
Purpose Some patients with locally advanced pancreatic ductal adenocarcinoma (LAPCacrnm1) achieve long-term survival with escalated-dose radiotherapy. We investigated two imaging-based biomarkers as a way to select patients for escalated-dose radi...

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(S026) Phase II Trial of Elective Nodal Dose 36 Gy for Advanced Head and Neck Cancer

International Journal of Radiation Oncology, Biology, Physics, Volume 98, Issue 2, Supplement, 2017 Jun 1 | Maguire, Patrick D., MD; Neal, Charles R., MD; Adams, Ashley, BS;...
Purpose To evaluate efficacy, toxicity, and quality of life of a chemoradiotherapy (CRTacrnm1) regimen incorporating low dose elective nodal * Radiotherapy, Intensity-Modulated * for patients with stage III and IVa squamous cell cancer of the head...

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(S050) WITHDRAWN

International Journal of Radiation Oncology, Biology, Physics, Volume 98, Issue 2, Supplement, 2017 Jun 1
(no summary available)

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(S042) Invasive Lobular Carcinoma Predicts for an Increased Likelihood of Surgical Upstaging Requiring Post-Mastectomy Radiation Therapy

International Journal of Radiation Oncology, Biology, Physics, Volume 98, Issue 2, Supplement, 2017 Jun 1 | Van Wyhe, Renae D., MBA; Shaitelman, Simona F., MD; Caudle, Abigail S., MD;...
Purpose Imaging and physical exam are considered less precise in determining the extent of disease in invasive lobular carcinoma (ILC) relative to non-lobular subtypes. Anecdotally, surgical axillary evaluation frequently reveals positive nodes in...

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(S045) Loss of H3K27 Trimethylation Is Prognostic for Worse Outcomes From Meningioma

International Journal of Radiation Oncology, Biology, Physics, Volume 98, Issue 2, Supplement, 2017 Jun 1 | Raleigh, David R., MD, PhD; Cuevas-Ocampo, Areli K.; Wu, Ashley;...
Background Epigenetic gene regulation through Histone3 trimethylation at lysine 27 (H3K27me3) has prognostic significance in cancer, but the relevance of H3K27me3 for meningioma is unknown. Here we compare outcomes of local recurrence-free surviva...

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(S046) Long-Term Outcome and Toxicity of Stereotactic Ablative Body Radiotherapy (SABR) for Liver Metastases From Solid Tumors

International Journal of Radiation Oncology, Biology, Physics, Volume 98, Issue 2, Supplement, 2017 Jun 1 | Lu, Yi, MD, PhD; Tang, Chad, MD, MS; Liao, Zhongxing, MD;...
Purpose To report toxicity and outcome after stereotactic ablative body radiotherapy (SABRacrnm1) for patients with liver metastases. Methods and Materials From 2005 to 2016, 127 patients with liver metastases from different primaries had been irr...

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(S037) An Overview of Disparities Research in Access to Radiation Oncology Care

International Journal of Radiation Oncology, Biology, Physics, Volume 98, Issue 2, Supplement, 2017 Jun 1 | McClelland, Shearwood, MD; Deville, Curtiland, MD; Thomas, Charles R., MD;...
Introduction In the 21st century, the field of Radiation Oncology has markedly increased its role in patient care as advances in the precision of radiotherapy/radiosurgery/brachytherapy have enabled these techniques to become viable/superior alter...

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(P008) Impact of Radiotherapy on Lymphotropic Invasive Micropapillary Carcinoma of the Breast: An Analysis From the National Cancer Data Base

International Journal of Radiation Oncology, Biology, Physics, Volume 98, Issue 2, Supplement, 2017 Jun 1 | Lewis, Gary D.; Xing, Yan; Patel, Tejal;...
Purpose/Objectives Invasive micropapillary carcinoma (IMPCacrnm1) is an uncommon variant of breast cancer, accounting for <2% of all cases. Previous studies of this subtype demonstrated a higher propensity for lymph node metastases compared wit...

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(S038) Do Race or Income Influence Quality of Life (QOL) or Survival (OS) After Lung Stereotactic Body Radiotherapy (SBRT) in Stage I Non-Small Cell Lung Cancer? A Prospective Study

International Journal of Radiation Oncology, Biology, Physics, Volume 98, Issue 2, Supplement, 2017 Jun 1 | Movsas, Avielle, BA; Vance, Sean, MD; Al-Feghali, Karine, MD;...
Objective This prospective clinical study focused on the hypothesis that there would be no difference in survival or QOL based on race or income when patients with stage I NSCLC are treated with lung SBRT in a center with a multidisciplinary appro...

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Workflow sensitivity of post-processing methods in renal DCE-MRI

Publication date: Available online 20 May 2017
Source:Magnetic Resonance Imaging
Author(s): Erik Hanson, Eli Eikefjord, Jarle Rørvik, Erling Andersen, Arvid Lundervold, Erlend Hodneland
Objective: Estimation of renal filtration using dynamic contrast-enhanced imaging (DCE-MRI) requires a series of analysis steps. The possible number of distinct post-processing chains is large and grows rapidly with increasing number of processing steps or options. In this study we introduce a framework for systematic evaluation of the post-processing chains. The framework is later used to highlight the workflow processing chain sensitivity towards accuracy in estimation of glomerular filtration rate (GFR).Methods: Twenty healthy volunteers underwent DCE-MRI examinations as well as iohexol clearance for reference GFR measurements. In total, 692 different combinations of post-processing steps were explored for analysis, including options for kidney segmentation, B1 inhomogeneity correction, placement of arterial input function, gadolinium concentration estimation as well as handling of motion-corrupted volumes and breathing motion. The evaluation of various processing chains is presented using a classification tree framework and random forest ensemble learning.Results: Among the processing steps subject to testing, methods for calculating the gadolinium concentration as well as B1 inhomogeneity correction had the largest impact on accuracy of GFR estimations. Different segmentation methods did not play an important role in the post-processing of the MR data except from one processing chain where the automated segmentation outperformed the manual segmentation.Conclusion: The proposed classification trees were efficiently used as a statistical tool for visualization and communication of results to distinguish between important and less influential processing steps in renal DCE-MRI. We also identified several crucial factors in the processing chain.



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Staying Connected: Latest Innovations in Medical Technology for Seniors

Technology has been developing at a breakneck speed in recent years, and fortunately, it hasn't left seniors behind. In fact, it's been coming up with some amazing new gadgets designed to help seniors live more ...

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A Constellation of Rare Findings in a Case of Goldenhar Syndrome

An 18-month-old child presented with right macrostomia, bilateral preauricular skin tags, bilateral CTEV, squint in bilateral eyes, thoracic vertebral anomalies, right sided aortic arch, and associated left pulmonary agenesis. The patient did not have any associated respiratory symptoms. Ipsilateral pulmonary agenesis is considered as a rare association with Goldenhar syndrome and a case of contralateral pulmonary aplasia has been described as an even rarer association.

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The Current Value Of Determining The Mismatch Repair Status Of Colorectal Cancer: A Rationale For Routine Testing

Publication date: Available online 20 May 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): E. Ryan, K. Sheahan, B. Creavin, H.M. Mohan, D.C. Winter
Colorectal Cancer (CRC) is the third most prevalent cancer in men and women. Up to 15% of CRCs display microsatellite instability (MSI). MSI is reflective of a deficient mismatch repair (MMR) system and is most commonly caused by hypermethylation of the MLH1 promoter. However, it may also be due to autosomal dominant constitutional mutations in DNA MMR, termed Lynch Syndrome. MSI may be diagnosed via polymerase chain reaction (PCR) or alternatively, immunohistochemistry (IHC) can identify MMR deficiency (dMMR). Many institutions now advocate universal tumour screening of CRC via either PCR for MSI or IHC for dMMR to guide Lynch Syndrome testing. The association of sporadic MSI with methylation of the MLH1 promoter and an activating BRAF mutation may offer further exclusion criteria for genetic testing. Aside from screening for Lynch syndrome, MMR testing is important because of its prognostic and therapeutic implications. Several studies have shown MSI CRCs exhibit different clinicopathological features and prognosis compared to microsatellite-stable (MSS) CRCs. For example, response to conventional chemotherapy has been reported to be less in MSI tumours. More recently, MSI tumors have been shown to be responsive to immune-checkpoint inhibition providing a novel therapeutic strategy. This provides a rationale for routine testing for MSI or dMMR in CRC.



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Brain metastases from Non-Small Cell Lung Carcinoma: changing concepts for improving patients’ outcome

Publication date: Available online 20 May 2017
Source:Critical Reviews in Oncology/Hematology
Author(s): Chloé Rancoule, Alexis Vallard, Jean-Baptiste Guy, Sophie Espenel, Peng Diao, Cyrus Chargari, Nicolas Magné
The management of Non Small Cell Lung Cancer (NSCLC) brain metastases is challenging, as this frequent complication negatively impacts patients' quality of life, and can be a life-threatening event.Through a review of the literature, we discuss the main therapeutic options and the recent developments that improved (and complicated) the management of NSCLC brain metastases patients. Most current validated approaches are local with exclusive or combined surgery, whole brain radiotherapy (WBRT) and stereotactic radiotherapy (SRT). At the same time, there is a growing role for systemic treatments that might significantly postpone WBRT. Targeted therapies efficacy/toxicity profile remains to be defined but predictive and prognostic molecular factors integration could help to select treatments fully adapted to life expectancy and progression risk.



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Nutritional composition of mungbean and soybean sprouts compared to their adult growth stage

Publication date: 15 December 2017
Source:Food Chemistry, Volume 237
Author(s): Andreas W. Ebert, Ching-Huan Chang, Miao-Rong Yan, Ray-Yu Yang
This study determined the level of phytonutrients in mungbean and soybean sprouts compared to mature mungbean grain and vegetable soybean. The comparison included landraces and improved mungbean and soybean varieties to assess the effect of breeding on the phytonutrient content of both crops. Sprouting mungbean enhanced vitamin C content 2.7-fold compared to mature mungbean grain. Relatively old mungbean accessions were superior in protein, calcium (Ca), iron (Fe), zinc (Zn), carotenoid and vitamin C content compared to improved mungbean lines at the fully mature stage. With regard to nutritional value, the vegetable soybean stage was superior to soybean sprouts in terms of content of protein (14% increase), Zn (45%), Ca (72%), and Fe (151%). Isoflavones, reported to have beneficial effects on human health, are found at high concentrations in soybean sprouts and could easily provide the recommended anticarcinogenic dose range from 1.5 to 2.0mg/kg of body weight per day.



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Predictors and Delays Associated with the Need for Advanced Techniques for Intravenous Access

Publication date: Available online 20 May 2017
Source:The Journal of Emergency Medicine
Author(s): Michael D. Witting, Siamak Moayedi, Latoya A. Brown, Ammar Ismail
BackgroundThe need for advanced techniques for intravenous access (ATIVA) can lead to delays in care and contribute to emergency department (ED) crowding.ObjectiveIn this article, we estimate the delay and predictors associated with the need for ATIVA.MethodsIn this case-control study, we collected data from ED cases requiring ATIVA and control patients in whom i.v. access was gained by traditional inspection and palpation. We included two control groups—a random retrospective sample and a prospective limited convenience sample. We collected time and acuity data from all groups and data on predictor variables from cases and prospective controls. We analyzed time data using quartile regression and predictor variable data using contingency table analysis and logistic regression.ResultsWe collected data from 116 cases (91 of which had time interval data), 98 retrospective controls, and 144 prospective controls. The median time from triage to i.v. line establishment was 199 min for cases vs. 64 min for prospective controls and 81 min for retrospective controls. The need for ATIVA was associated with a 1.1-greater quartile time interval (95% confidence interval [CI] 0.8–1.3). Two variables—i.v. drug use (IVDU; odds ratio 3.7; 95% CI 1.8–7.3) and prior need for ATIVA (odds ratio 5.2; 95% CI 2.7–9.8)—were associated with a need for ATIVA; obesity, renal failure, and diabetes were not.ConclusionsThe need for ATIVA increases median time to i.v. line placement by 118 to 135 min compared with traditional inspection and palpation. IVDU and prior need for an advanced technique are associated with a need for ATIVA.



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Outcomes of external septorhinoplasty in a Turkish male population

Publication date: Available online 20 May 2017
Source:Brazilian Journal of Otorhinolaryngology
Author(s): Mustafa Çelik, Gamze Didem Kilci, Engin Başer, Ayşegül Verim, Ömer Faruk Çalim, Bayram Veyseller, Orhan Özturan, Ahmet Altintaş
IntroductionThe first and one of the most important steps in facial plastic surgery is accurate preoperative facial analysis and recording of data that may help the surgeon to check the outcomes of his/her techniques, promoting a surgeon's professional development.ObjectiveTo evaluate the esthetic outcomes of external septorhinoplasty (SRP) relevant to ethnic facial harmony and to investigate the relationship of the columellar incision scar with the type of skin and columellar incision type in a Turkish population.MethodsIn total, 28 consecutive adult male patients with a mean age of 32.14±10.66 years (range: 18–61 years) were included the study. Primary outcomes were preoperative and postoperative photogrammetric facial analyses of the patients including measurement of nasofrontal angle, nasolabial angle and nasal projection ratios (Gode) assessed according to the data derived from the Rhinobase program. Results were compared to facial proportions of the Turkish population. Columellar incision scar scores related to the Fitzpatrick skin type classification of the patients and columellar incision types used for the external approach were secondary outcomes of the study.ResultsMean preoperative and postoperative nasofrontal angles were 148.04°±8.18° and 144.50°±7.15°, respectively, while mean preoperative and postoperative nasolabial angles were 87.59°±14.01° and 98.50°±9.71°, respectively. Mean preoperative and postoperative nasal tip projection ratios were 0.56±0.05 and 0.60±0.06, respectively. The differences between pre- and postoperative measurements were all significantly different and were in accordance with Turkish nasal harmony. Columellar inverted "V" incisions were performed in 15 (53.6%) patients while "V" incisions were used in 13 (46.4%) patients. Fitzpatrick skin Type 4 was seen in 46.42% of the patients, Fitzpatrick Type 3 in 46.42% and Fitzpatrick Type 2 in 7.14% of the patients. No significant difference was seen between columellar scar scores according to skin type and columellar incision type used for external septorhinoplasty.ConclusionsThis study demonstrated that outcomes for nasofrontal angle, nasolabial angle and nasal tip projection ratios analyzed using the Rhinobase program in patients who underwent external septorhinoplasty were similar to reference values for the Turkish population.



http://ift.tt/2rEWLBa

mTOR signaling in the differentiation and function of regulatory and effector T cells

Publication date: June 2017
Source:Current Opinion in Immunology, Volume 46
Author(s): Hu Zeng, Hongbo Chi
The mechanistic target of rapamycin (mTOR) signaling pathway integrates environmental signals and cellular metabolism to regulate T cell development, activation and differentiation. Recent studies reveal the importance of exquisite control of mTOR activity for proper T cell function, and detailed molecular mechanisms that regulate mTOR signaling in different T cell subsets. Here, we review the latest advances in our understanding of the mTOR pathway and its regulation in the differentiation and function of regulatory T cells and effector T cells.



http://ift.tt/2qE3UDe

Metabolic signatures of T-cells and macrophages in rheumatoid arthritis

Publication date: June 2017
Source:Current Opinion in Immunology, Volume 46
Author(s): Cornelia M Weyand, Markus Zeisbrich, Jörg J Goronzy
In most autoimmune diseases, a decade-long defect in self-tolerance eventually leads to clinically relevant, tissue-destructive inflammatory disease. The pathogenic potential of chronic persistent immune responses during the pre-clinical and clinical phase is ultimately linked to the bioenergetic fitness of innate and adaptive immune cells. Chronic immune cell stimulation, high cellular turn-over, structural damage to the host tissue and maladaptive wound healing, all require a reliable supply of nutrients, oxygen, and biosynthetic precursors. Here, we use the model system of rheumatoid arthritis (RA) to discuss immunometabolism from the vantage point of T-cells and macrophages that encounter fundamentally different metabolic stress scenarios in the RA host. We outline the general principle that both insufficient nutrient supply, as well as nutrient excess generate cellular stress responses and guide immune function. ATP^low, NADPH^high, ROS^low T-cells hyperproliferate and are forced into premature senescence. ATP^high, ROS^high macrophages dimerize the glycolytic enzyme pyruvate kinase to amplify STAT3-dependent inflammatory effector functions. A corollary of this model is that simple nutraceutical interventions will be insufficient to re-educate the immune system in RA. Instead, interference with cell-type-exclusive and differentiation-stage-dependent metabolic setpoints will be needed to reprogram arthritogenic pathways.



http://ift.tt/2q8Tat5

The Simpson grading in meningioma surgery: does the tumor location influence the prognostic value?

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The Simpson grading in meningioma surgery: does the tumor location influence the prognostic value?

J Neurooncol. 2017 May 19;:

Authors: Voß KM, Spille DC, Sauerland C, Molina ES, Brokinkel C, Paulus W, Stummer W, Holling M, Jeibmann A, Brokinkel B

Abstract
In meningiomas, location-specific differences of the prognostic value of the Simpson classification are sparsely investigated but can influence strategy of surgery. We therefore compared the prognostic value of the Simpson classification in different tumor locations. Progression was compared with Simpson grade in 826 meningioma patients (median age 58 years, female:male ratio 2.4) in location-specific uni- and multivariate analyses. Simpson grade strongly correlated with tumor location (p < .001). Within a median follow-up of 50 months, recurrence was observed in 107 of 803 patients (13%). In general, increasing Simpson grade (p = .002) and subtotal resection (STR, ≥grade III) were correlated with tumor recurrence [hazard ratio (HR): 1.87; p = .004]. In 268 convexity meningiomas, frequency of tumor recurrence correlated with Simpson grade (p = .034). Risk of recurrence was similar after grade I and II resections, tended to increase after grade III (HR: 2.35; p = .087) but was higher after grade IV resections (HR: 7.35; p = .003). Risk of recurrence was higher after STR (HR: 4.21; p = .001) than after gross total resection (GTR, ≤grade II). Contrarily, increasing Simpson grade and STR were not correlated with progression in 102 falx, 38 posterior fossa and nine intraventricular meningiomas. In 325 skull base lesions, risk of recurrence was similar after GTR and STR (p = .198) and was only increased after grade IV resections (HR: 3.26; p = .017). Simpson grading and extent of resection were not equally prognostic in all locations. Lower impact of extent of resection should be considered during surgery for skull base, posterior fossa and falx meningiomas.

PMID: 28527009 [PubMed - as supplied by publisher]

http://ift.tt/2rEDiR0

The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease.

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The bidirectional gut-brain-microbiota axis as a potential nexus between traumatic brain injury, inflammation, and disease.

Brain Behav Immun. 2017 May 16;:

Authors: Sundman MH, Chen NK, Subbian V, Chou YH

Abstract
As head injuries and their sequelae have become an increasingly salient matter of public health, experts in the field have made great progress elucidating the biological processes occurring within the brain at the moment of injury and throughout the recovery thereafter. Given the extraordinary rate at which our collective knowledge of neurotrauma has grown, new insights may be revealed by examining the existing literature across disciplines with a new perspective. This article will aim to expand the scope of this rapidly evolving field of research beyond the confines of the central nervous system (CNS). Specifically, we will examine the extent to which the bidirectional influence of the gut-brain axis modulates the complex biological processes occurring at the time of traumatic brain injury (TBI) and over the days, months, and years that follow. In addition to local enteric signals originating in the gut, it is well accepted that gastrointestinal (GI) physiology is highly regulated by innervation from the CNS. Conversely, emerging data suggests that the function and health of the CNS is modulated by the interaction between 1) neurotransmitters, immune signaling, hormones, and neuropeptides produced in the gut, 2) the composition of the gut microbiota, and 3) integrity of the intestinal wall serving as a barrier to the external environment. Specific to TBI, existing pre-clinical data indicates that head injuries can cause structural and functional damage to the GI tract, but research directly investigating the neuronal consequences of this intestinal damage is lacking. Despite this void, the proposed mechanisms emanating from a damaged gut are closely implicated in the inflammatory processes known to promote neuropathology in the brain following TBI, which suggests the gut-brain axis may be a therapeutic target to reduce the risk of Chronic Traumatic Encephalopathy and other neurodegenerative diseases following TBI. To better appreciate how various peripheral influences are implicated in the health of the CNS following TBI, this paper will also review the secondary biological injury mechanisms and the dynamic pathophysiological response to neurotrauma. Together, this review article will attempt to connect the dots to reveal novel insights into the bidirectional influence of the gut-brain axis and propose a conceptual model relevant to the recovery from TBI and subsequent risk for future neurological conditions.

PMID: 28526435 [PubMed - as supplied by publisher]

http://ift.tt/2rExSpj

The Simpson grading in meningioma surgery: does the tumor location influence the prognostic value?

Related Articles

The Simpson grading in meningioma surgery: does the tumor location influence the prognostic value?

J Neurooncol. 2017 May 19;:

Authors: Voß KM, Spille DC, Sauerland C, Molina ES, Brokinkel C, Paulus W, Stummer W, Holling M, Jeibmann A, Brokinkel B

Abstract
In meningiomas, location-specific differences of the prognostic value of the Simpson classification are sparsely investigated but can influence strategy of surgery. We therefore compared the prognostic value of the Simpson classification in different tumor locations. Progression was compared with Simpson grade in 826 meningioma patients (median age 58 years, female:male ratio 2.4) in location-specific uni- and multivariate analyses. Simpson grade strongly correlated with tumor location (p < .001). Within a median follow-up of 50 months, recurrence was observed in 107 of 803 patients (13%). In general, increasing Simpson grade (p = .002) and subtotal resection (STR, ≥grade III) were correlated with tumor recurrence [hazard ratio (HR): 1.87; p = .004]. In 268 convexity meningiomas, frequency of tumor recurrence correlated with Simpson grade (p = .034). Risk of recurrence was similar after grade I and II resections, tended to increase after grade III (HR: 2.35; p = .087) but was higher after grade IV resections (HR: 7.35; p = .003). Risk of recurrence was higher after STR (HR: 4.21; p = .001) than after gross total resection (GTR, ≤grade II). Contrarily, increasing Simpson grade and STR were not correlated with progression in 102 falx, 38 posterior fossa and nine intraventricular meningiomas. In 325 skull base lesions, risk of recurrence was similar after GTR and STR (p = .198) and was only increased after grade IV resections (HR: 3.26; p = .017). Simpson grading and extent of resection were not equally prognostic in all locations. Lower impact of extent of resection should be considered during surgery for skull base, posterior fossa and falx meningiomas.

PMID: 28527009 [PubMed - as supplied by publisher]

http://ift.tt/2rEDiR0

Carotid-falciform optic neuropathy: microsurgical treatment.

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Carotid-falciform optic neuropathy: microsurgical treatment.

World Neurosurg. 2017 May 16;:

Authors: Woodall MN, Alleyne CH

Abstract
BACKGROUND: Several recent reports have implicated vascular ectasia and vessel contact with dysfunction of the visual apparatus. A subset of patients with pre-chiasmatic visual deterioration have an ectatic internal carotid artery (ICA) that displaces and flattens the optic nerve (ON) rostrally as the ON exits the skull base. We will offer a proposed pathophysiological mechanism and describe a straightforward surgical technique for dealing with this interesting problem.
METHODS: Via an ipsilateral pterional craniotomy, the bony roof of the optic canal is removed. The falciform ligament is opened in parallel to the ON. Adhesions between the ICA and ON are then dissected, and a Teflon pledget is placed between the ICA and ON to complete the decompression.
RESULTS: Patients both in the literature and in this series experienced an improvement in their vision post-operatively.
CONCLUSION: We propose that three mechanisms contribute to this carotico-faliciform optic neuropathy: 1) mass effect from ICA ectasia, 2) ON irritation from vessel pulsatility, and 3) indirect compression by the falciform ligament from above. This fascinating disease process can be treated safely using standard microsurgical techniques with excellent outcomes.

PMID: 28526645 [PubMed - as supplied by publisher]

http://ift.tt/2r5dII6

Unravelling respiratory syncytial virus outbreaks in Buenos Aires, Argentina: Molecular basis of the spatio-temporal transmission.

Unravelling respiratory syncytial virus outbreaks in Buenos Aires, Argentina: Molecular basis of the spatio-temporal transmission.

Virology. 2017 May 17;508:118-126

Authors: Rojo GL, Goya S, Orellana M, Sancilio A, Rodriguez Perez A, Montali C, García C, Sosa L, Musto A, Alvarez D, Castello A, Viegas M

Abstract
Respiratory syncytial virus (RSV) is the main viral cause of hospitalization due to acute lower respiratory tract infections in infants worldwide. Several vaccines against RSV are under research and development, which are about to be approved. We evaluated transmission patterns in different settings to determine age-specific vaccination targets from a viral perspective. We sequenced the G glycoprotein's ectodomain of a constant clinical sampling between two epidemic outbreaks in a limited geographical region and performed phylogeographic analyses. We described a spatio-temporal transmission between local strains, which were originated in the center of the analyzed area and then spread to others. Interestingly, that central area reported the highest population density of the region and also showed overcrowding. This information should be considered by public health systems to evaluate vaccination at all ages in those areas to decrease viral transmission and in lower density populations only susceptible children should be vaccinated.

PMID: 28527341 [PubMed - as supplied by publisher]

http://ift.tt/2q5CBiu

Characterisation of antibiotic prescriptions for acute respiratory tract infections in Danish general practice: a retrospective registry based cohort study.

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Characterisation of antibiotic prescriptions for acute respiratory tract infections in Danish general practice: a retrospective registry based cohort study.

NPJ Prim Care Respir Med. 2017 May 19;27(1):37

Authors: Aabenhus R, Hansen MP, Saust LT, Bjerrum L

Abstract
Inappropriate use of antibiotics is contributing to the increasing rates of antimicrobial resistance. Several Danish guidelines on antibiotic prescribing for acute respiratory tract infections in general practice have been issued to promote rational prescribing of antibiotics, however it is unclear if these recommendations are followed. We aimed to characterise the pattern of antibiotic prescriptions for patients diagnosed with acute respiratory tract infections, by means of electronic prescriptions, labeled with clinical indications, from Danish general practice. Acute respiratory tract infections accounted for 456,532 antibiotic prescriptions issued between July 2012 and June 2013. Pneumonia was the most common indication with 178,354 prescriptions (39%), followed by acute tonsillitis (21%) and acute otitis media (19%). In total, penicillin V accounted for 58% of all prescriptions, followed by macrolides (18%) and amoxicillin (15%). The use of second-line agents increased with age for all indications, and comprised more than 40% of the prescriptions in patients aged >75 years. Women were more often prescribed antibiotics regardless of clinical indication. This is the first Danish study to characterise antibiotic prescription patterns for acute respiratory tract infections by data linkage of clinical indications. The findings confirm that penicillin V is the most commonly prescribed antibiotic agent for treatment of patients with an acute respiratory tract infection in Danish general practice. However, second-line agents like macrolides and amoxicillin with or without clavulanic acid are overused. Strategies to improve the quality of antibiotic prescribing especially for pneumonia, acute otitis media and acute rhinosinusitis are warranted.
RESPIRATORY TRACT INFECTIONS: TRACKING THE OVERUSE OF ANTIBIOTICS: Better adherence to guidelines for prescribing antibiotics for different respiratory tract infections are warranted in Danish general practice. The over-use of antibiotics, particularly so-called 'second-line' agents such as amoxicillin, increases resistance and may lead to a potentially catastrophic scenario where antibiotics are no longer effective. Exactly how widespread the over-use of antibiotics is for different infections, however, is not clear. Rune Aabenhus at the University of Copenhagen and co-workers analyzed primary care data regarding antibiotic prescriptions for acute respiratory tract infections including pneumonia and ear infections in Denmark. They found that penicillin V-the current recommended first-line drug in Scandinavian countries-accounted for 58 per cent of prescriptions, a figure which should be improved. Amoxicillin and macrolides were over-prescribed, particularly in elderly patients. The team also call for further analysis of prescriptions given by out-of-hours clinics.

PMID: 28526836 [PubMed - in process]

http://ift.tt/2qHubBa

Antimicrobial stewardship for hospitalized patients with viral respiratory tract infections.

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Antimicrobial stewardship for hospitalized patients with viral respiratory tract infections.

Am J Infect Control. 2017 May 16;:

Authors: Lowe CF, Payne M, Puddicombe D, Mah A, Wong D, Kirkwood A, Hull MW, Leung V

Abstract
BACKGROUND: The purpose of this study was to implement a targeted antimicrobial stewardship intervention for patients with a viral respiratory tract infection.
METHODS: This was a quasi-experimental before and after audit and feedback intervention of adult inpatients with a positive polymerase chain reaction for a respiratory virus in 2 acute care hospitals in Vancouver, Canada. Audit and feedback was implemented based on 2 criteria: microbiology (no positive bacterial cultures) and chest imaging (absence of pneumonia or consolidation on radiology dictation). A chart review was conducted to assess for days of antibiotics postviral diagnosis. Outcomes including length of stay, intensive care unit admission within 14 days, mechanical ventilation within 14 days, antibiotics prescribed within 14 days, Clostridium difficile infection diagnosed within 30 days, and readmission within 30 days were also reviewed in comparison with the previous year.
RESULTS: Antimicrobial stewardship recommendations for hospitalized patients with viral respiratory tract infections were accepted for 77% of cases. This targeted approach based on easily assessed parameters translated into a 1.3-day (95% confidence interval, 0.3-2.3; P < .01) decrease in mean days of antibiotics postviral diagnosis compared with the previous year without systematic interventions. Compared with the previous year, no differences were identified for adverse outcomes associated with the intervention.
CONCLUSIONS: A targeted antimicrobial stewardship intervention integrating virology testing with the treating physician facilitated a reduction in duration of antibiotic treatment for viral respiratory tract infections.

PMID: 28526309 [PubMed - as supplied by publisher]

http://ift.tt/2q5Wru7

Passive and active immunization against respiratory syncytial virus for the young and old.

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Passive and active immunization against respiratory syncytial virus for the young and old.

Expert Rev Vaccines. 2017 May 19;:

Authors: Villafana T, Falloon J, Griffin MP, Zhu Q, Esser MT

Abstract
INTRODUCTION: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in infants worldwide and also causes significant disease in the elderly. Despite 60 years of RSV research and vaccine development, there is only one approved medicine to prevent RSV infections. Palivizumab, a monoclonal antibody (mAb) against the RSV fusion (F) protein, is indicated for preterm infants and children at high-risk for RSV infections. It is an active time in RSV vaccine and mAb development with 14 vaccines and 2 mAbs currently being tested in clinical trials as of 13 February 2017. Active vaccination of women in the third trimester or passive immunization of infants with a mAb are particularly attractive approaches as the most severe disease occurs within the first 6 months of life. Areas covered: Here, we review current approaches for preventing RSV in the young and old, describe proposed clinical endpoints for studies in pediatric and adult clinical trials and highlight results from recent and ongoing clinical studies. Expert commentary. With 16 candidates in clinical development, approval of the first RSV vaccine or mAb for the prevention of RSV in all infants or the elderly is likely to occur in the next five years.

PMID: 28525961 [PubMed - as supplied by publisher]

http://ift.tt/2rq9b2l

Preparation and nanoformulation of new quinolone scaffold-based anticancer agents: Enhancing solubility for better cellular delivery.

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Preparation and nanoformulation of new quinolone scaffold-based anticancer agents: Enhancing solubility for better cellular delivery.

Eur J Pharm Sci. 2017 May 16;:

Authors: Elghazawy NH, Hefnawy A, Sedky NK, El-Sherbiny IM, Arafa RK

Abstract
A new series of 5,7-dibromoquinoline scaffold-based derivatives with varied flexibility substituents at position 8 of the ring system has been synthesized as potential anticancer agents. The new compounds were evaluated for their in vitro antiproliferative activity versus the human breast cancer cell lines MCF-7 and MDA-MB231. Generally, both cell lines were responsive to the cytotoxic effect of the synthesized analogues. Compounds 4a, 5c and 7b were chosen for nanoformulation studies to assess the effect of enhancing their solubility profile on their cytotoxic ability. Indeed, the pluronic nanomicelles of the three formulated derivatives showed an observable significant increase in their cytotoxic efficacy demonstrating a positive impact of the used nanoformulations on the delivery of the active compounds to their cellular biological targets.

PMID: 28526600 [PubMed - as supplied by publisher]

http://ift.tt/2q8POX1

Metabolic Alterations at the Crossroad of Aging and Oncogenesis.

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Metabolic Alterations at the Crossroad of Aging and Oncogenesis.

Int Rev Cell Mol Biol. 2017;332:1-42

Authors: Raffaghello L, Longo V

Abstract
Aging represents the major risk factor for cancer. Cancer and aging are characterized by a similar dysregulated metabolism consisting in upregulation of glycolysis and downmodulation of oxidative phosphorylation. In this respect, metabolic interventions can be viewed as promising strategies to promote longevity and to prevent or delay age-related disorders including cancer. In this review, we discuss the most promising metabolic approaches including chronic calorie restriction, periodic fasting/fasting-mimicking diets, and pharmacological interventions mimicking calorie restriction. Metabolic interventions can also be viewed as adjuvant anticancer strategies to be combined to standard cancer therapy (chemotherapeutic agents, ionizing radiation, and drugs with specific molecular target), whose major limiting factors are represented by toxicity against healthy cells but also limited efficacy easily circumvented by tumor cells. In fact, conventional cancer therapy is unable to distinguish normal and cancerous cells and thus causes toxic side effects including secondary malignancies, cardiovascular and respiratory complications, endocrinopathies, and other chronic conditions, that resemble and, in some cases, accelerate the age-related disorders and profoundly affect the quality of life. In this scenario, geroscience contributes to the understanding of the mechanisms of protection of normal cells against a cytotoxic agent and finding strategies focused on the preserving healthy cells while enhancing the efficacy of the treatment against malignant cells.

PMID: 28526131 [PubMed - in process]

http://ift.tt/2q8ZXmx

Venous thromboembolism in hospitalized patients receiving chemotherapy for malignancies at Japanese community hospital: prospective observational study.

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Venous thromboembolism in hospitalized patients receiving chemotherapy for malignancies at Japanese community hospital: prospective observational study.

BMC Cancer. 2017 May 19;17(1):351

Authors: Kitayama H, Kondo T, Sugiyama J, Kurimoto K, Nishino Y, Hirayama M, Tsuji Y

Abstract
BACKGROUND: Although Asian population was recognized to have a lower risk of venous thromboembolism (VTE), its increasing prevalence and incidence remain unclear in patients with malignancies. We attempted to predict VTE development using activation markers of coagulation and fibrinolysis.
METHODS: We enrolled patients with malignancy admitted to Tonan Hospital between April and December 2014 to receive a new-for-them chemotherapy regimen. All patients were examined for VTE by computed tomography and whole-leg compression ultrasonography before chemotherapy and three months later. We also examined plasma levels of thrombin-antithrombin complex (TAT) and plasmin α2-plasmin inhibitor complex (PIC) before chemotherapy. The cut off values of TAT and PIC were set at 2.1 ng/mL and 1.8 μg/mL, respectively.
RESULTS: Of 97 patients, the majority (67%) had distant metastases. The most common malignancies were colorectal (26%), breast (23%), and stomach (19%) cancer. VTE was detected in 29 patients (31%); all were asymptomatic. VTE was newly developed in 12 patients in the three-month observation period, which means the incidence was 49 per 1000 person-years. Non-increased PIC with increased TAT was the only significant risk factor for both VTE prevalence and incidence in multivariate analysis, and the odds ratios were 3.0 (95% confidence interval, 1.1-8.2; P = 0.034) and 9.4 (95% confidence interval, 1.7-51.9; P = 0.011), respectively.
CONCLUSIONS: The prevalence and incidence of VTE were high in hospitalized Japanese patients receiving chemotherapy for malignancies. Non-increased PIC with increased levels of TAT may be an independent risk factor for VTE development.

PMID: 28525975 [PubMed - in process]

http://ift.tt/2q8Wjct

Dianhydrogalactitol, a potential multitarget agent, inhibits glioblastoma migration, invasion, and angiogenesis.

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Dianhydrogalactitol, a potential multitarget agent, inhibits glioblastoma migration, invasion, and angiogenesis.

Biomed Pharmacother. 2017 May 15;91:1065-1074

Authors: Jiang X, Huang Y, Wang X, Liang Q, Li Y, Li F, Fu X, Huang C, Liu H

Abstract
The complexity of cancer has led to single-target agents exhibiting lower-than-desired clinical efficacy. Drugs with multiple targets provide a feasible option for the treatment of complex tumors. Multitarget anti-angiogenesis agents are among the new generation of anticancer drugs and have shown favorable clinical efficacy. Dianhydrogalactitol (DAG) is a chemotherapeutic agent for chronic myeloid leukemia and lung cancer. Recently, it has been tested in phase II trials of glioblastoma treatment; however, mechanisms of DAG in glioblastoma have not been elucidated. Here we show that DAG could inhibit the migration and invasion of U251 cell line by inhibiting matrix metalloproteinase-2 (MMP2) expression. Furthermore, DAG could also inhibit tumor angiogenesis in vitro as well as in the zebrafish model. Mechanistic studies reveal that DAG inhibited both VEGFR2 and FGFR1 pathways. Our results suggest that DAG may be a potential multitarget agent that can inhibit tumor migration, invasion, and angiogenesis, and the anti-angiogenic effects may be involved in dual-suppression VEGF/VEGFR2 and FGF2/FGFR1 signal pathways.

PMID: 28525947 [PubMed - as supplied by publisher]

http://ift.tt/2q9249V

Mining for osteogenic surface topographies: In silico design to in vivo osseo-integration

Publication date: August 2017
Source:Biomaterials, Volume 137
Author(s): Frits F.B. Hulshof, Bernke Papenburg, Aliaksei Vasilevich, Marc Hulsman, Yiping Zhao, Marloes Levers, Natalie Fekete, Meint de Boer, Huipin Yuan, Shantanu Singh, Nick Beijer, Mark-Anthony Bray, David J. Logan, Marcel Reinders, Anne E. Carpenter, Clemens van Blitterswijk, Dimitrios Stamatialis, Jan de Boer
Stem cells respond to the physicochemical parameters of the substrate on which they grow. Quantitative material activity relationships – the relationships between substrate parameters and the phenotypes they induce – have so far poorly predicted the success of bioactive implant surfaces. In this report, we screened a library of randomly selected designed surface topographies for those inducing osteogenic differentiation of bone marrow-derived mesenchymal stem cells. Cell shape features, surface design parameters, and osteogenic marker expression were strongly correlated in vitro. Furthermore, the surfaces with the highest osteogenic potential in vitro also demonstrated their osteogenic effect in vivo: these indeed strongly enhanced bone bonding in a rabbit femur model. Our work shows that by giving stem cells specific physicochemical parameters through designed surface topographies, differentiation of these cells can be dictated.



http://ift.tt/2rD4e3G

Mechanisms of resistance to systemic therapy in metastatic castration-resistant prostate cancer.

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Mechanisms of resistance to systemic therapy in metastatic castration-resistant prostate cancer.

Cancer Treat Rev. 2017 May 08;57:16-27

Authors: Galletti G, Leach BI, Lam L, Tagawa ST

Abstract
Patients with metastatic castration-resistant prostate cancer (mCPRC) now have an unprecedented number of approved treatment options, including chemotherapies (docetaxel, cabazitaxel), androgen receptor (AR)-targeted therapies (enzalutamide, abiraterone), a radioisotope (radium-223) and a cancer vaccine (sipuleucel-T). However, the optimal treatment sequencing pathway is unknown, and this problem is exacerbated by the issues of primary and acquired resistance. This review focuses on mechanisms of resistance to AR-targeted therapies and taxane-based chemotherapy. Patients treated with abiraterone, enzalutamide, docetaxel or cabazitaxel may present with primary resistance, or eventually acquire resistance when on treatment. Multiple resistance mechanisms to AR-targeted agents have been proposed, including: intratumoral androgen production, amplification, mutation, or expression of AR splice variants, increased steroidogenesis, upregulation of signals downstream of the AR, and development of androgen-independent tumor cells. Known mechanisms of resistance to chemotherapy are distinct, and include: tubulin alterations, increased expression of multidrug resistance genes, TMPRSS2-ERG fusion genes, kinesins, cytokines, and components of other signaling pathways, and epithelial-mesenchymal transition. Utilizing this information, biomarkers of resistance/response have the potential to direct treatment decisions. Expression of the AR splice variant AR-V7 may predict resistance to AR-targeted agents, but available biomarker assays are yet to be prospectively validated in the clinic. Ongoing prospective trials are evaluating the sequential use of different drugs, or combination regimens, and the results of these studies, combined with a deeper understanding of mechanisms of primary and acquired resistance to treatment, have the potential to drive future treatment decisions in mCRPC.

PMID: 28527407 [PubMed - as supplied by publisher]

http://ift.tt/2r5cHzq