Understanding conflict and the role of community development: Is building a peaceful society within our reach?

Publication date: Available online 22 September 2017
Source:Aggression and Violent Behavior
Author(s): August John Hoffman
The nature of human conflict and causal factors that are associated with extreme violence, hate crimes and terrorism (both domestic and global) have remained perplexing problems given their increasing prevalence despite recent international efforts to address these crimes (Al Ramiah & Hewstone, 2013). The current article summarizes Staub's (2013) essay: Building Peaceful Society and provides a community-based preventative approach that examines the psychological, cultural and sociological factors that contribute to modern extremism and hate crimes. Preventative methods involving interdependent community participation, community-based and prevention oriented (P&EI), "green" sustainable community service activities and civic engagement programs are offered as viable methods to reduce ethnic conflict, hate crimes and to help build a more peaceful society. Suggestions for future research are offered.



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The role of values in forensic and correctional rehabilitation

Publication date: Available online 21 September 2017
Source:Aggression and Violent Behavior
Author(s): Tony Ward, Roxanne Heffernan
The principles of forensic and correctional rehabilitation inquiry, key forensic and correctional concepts, and their translation into practice are shot through with normative commitments of one type or another. The degree to which values pervade every level and aspect of research and practice is rarely, if ever, acknowledged. This is a problem, as it means that there may be a tendency to adopt research and practice positions that are ideological in nature and insufficiently unjustified. In this paper we examine how values of various types guide and shape action at the level of scientific inquiry, influence the construction of rehabilitation theories, and shape the concepts of dynamic risk and protective factors. For each class of normative issues, we propose ways in which researchers and practitioners can acknowledge these challenges while also respecting the factual basis of science.



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Lichen Planus triggered by infliximab biosimilar CT-P13 and recurred during secukinumab treatment

Abstract

we read with interest the manuscript published by Gonzales et al,¹ highlighting lichenoid reactions as an emerging side effect of biologics, with special regard to infliximab-biosimilar. We recently observed a 50-year-old male patient with a long-standing history of moderate-to-severe psoriasis, who developed oral lichen planus (LP) triggered by infliximab biosimilar CT-P13. Interestingly the same patient experienced cutaneous and oral LP when treated with IL-17A blocker, secukinumab. The patient suffered for hypertension, in treatment with valsartan, and anxiety. He previously failed to respond to phototherapy, methotrexate, etanercept and adalimumab.

This article is protected by copyright. All rights reserved.

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Irradiance, as well as body site and timing of readings, is important in determining ultraviolet A minimal erythemal dose

Abstract

Irradiance, as well as body site and timing of readings, is important in determining ultraviolet A minimal erythemal dose. (Response to Gambichler et al. July BJD)

Gambichler et al. demonstrated that, in their population, using a 25 mWcm⁻² ultraviolet A-1 (UVA-1) source the median 24-hour delayed minimal erythema dose (MED) on the inner forearm was > 130 Jcm⁻².¹ This differs from the 20 Jcm⁻² to 28 Jcm⁻² median MED reported from our centre.²

This article is protected by copyright. All rights reserved.

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Risk of malignancies associated with ustekinumab

Abstract

A recently published report by Florek et al.¹ associates malignancies with ustekinumab (STELARA^®) treatment. Janssen emphasizes patient safety and welcomes rigorous safety analyses from other parties. However, it is unclear how this report adds to the understanding of ustekinumab's safety profile.

This article is protected by copyright. All rights reserved.

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Murine typhus masquerading as retiform purpura-like rashes

http://ift.tt/2hnDi3N

Inherited palmoplantar keratodermas: the heart of the matter

http://ift.tt/2hl6Lig

Sex hormone status in premenopausal women with frontal fibrosing alopecia: a multicentre review of 43 patients

http://ift.tt/2hmvFdO

Improvement of wound healing by regulated oxygen-enriched negative pressure-assisted wound therapy in a rabbit model

Summary

Background

Development of drug therapies and other techniques for wound care have resulted in significant improvement of the cure rate and shortening of the healing time for wounds. A modified technique of regulated oxygen-enriched negative pressure-assisted wound therapy (RO-NPT) has been reported.

Aim

To evaluate the efficacy and impact of RO-NPT on wound recovery and inflammation.

Methods

Infected wounds were established on 40 adult female white rabbits, which were then randomized to one of four groups: O₂ group, regulated negative pressure-assisted wound therapy (RNPT) group, regulated oxygen-enriched negative pressure-assisted wound therapy (RO-NPT) group and healthy control (HC) group. Each day, the O₂ group was treated with a constant oxygen supply (1 L/min) to the wound, while the RNPT group was treated with continuous regulated negative pressure (70 ± 5 mmHg) and the RNPT + O₂ group was treated with both. The HC group was treated with gauze dressing alone, which was changed every day. Leucocyte count, colony count and wound-healing rate were calculated. Levels of tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-8 were evaluated by ELISA.

Results

RO-RNPT significantly decreased bacterial count and TNF-α level, and increased the wound-healing rate. IL-1β, IL-8 and leucocyte count had a tendency to increase in the early phase of inflammation and a tendency to decrease in the later phase of inflammation in the RO-RNPT group.

Conclusions

RO-NPT therapy assisted wound recovery and inflammation control compared with the RNPT and oxygen-enriched therapies. RO-NPT therapy also increased levels of IL-1β and IL-8 and attenuated expression of TNF-α in the early phase of inflammation.

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A case of severe drug reaction secondary to alemtuzumab with successful re-exposure

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Biochars derived from giant reed ( Arundo donax L.) with different treatment: characterization and ammonium adsorption potential

Abstract

The adsorption characteristics of Arundo donax L.(AD) biochars for ammonium(NH₄⁺-N) were investigated. Absorbents were characterized through scanning electron microscopy, X-ray diffraction, and Fourier transform infrared spectroscopy analyses. AD-500 and AD-800 were produced from raw AD and pyrolyzed from room temperature to 500 and 800 °C, respectively. PD-500 was prepared by impregnating AD with a mild alkali solution and pyrolyzing from room temperature to 500 °C. The feasibility of the use of AD-500, AD-800, and PD-500 removing NH₄⁺-N from an aqueous solution was examined. The adsorption system followed the pseudo-first-order model. Results showed that the adsorption capacities of AD-biochars for NH₄⁺-N were enhanced after the final pyrolysis; temperature was increased or the mild alkali pretreatment was administered. When the initial NH₄⁺-N concentration was changed from 4 to 8 mM, the NH₄⁺-N sorption capacity of the biochar increased from 23 to 51%, with the final pyrolysis temperature increasing from 500 to 800 °C. The improved ratios were 12 to 33% when the biochar was prepared at 500 °C after the mild alkali pretreatment, and NH₄⁺-N sorption was enhanced due to ion exchange in the PD biochar.

Graphical abstract

Biochars derived from giant reed (Arundo donax L.) with different treatment :characterization and ammonium adsorption potential.

http://ift.tt/2xlTVEr

Source apportionment of polycyclic aromatic carbons (PAHs) in sediment core from Honghu Lake, central China: comparison study of three receptor models

Abstract

The spatial distribution of polycyclic aromatic hydrocarbons (PAHs) and their source contributions employing receptor models has been widely reported. However, the temporal distribution of PAH source contributions is less studied. Thus, in this paper, three receptor models including principle component analysis-multiple linear regression (PCA-MLR), positive matrix factorization (PMF), and Unmix were used to PAH source apportionment study in a sediment core from Honghu Lake, China. Sixteen USEPA priority PAHs in 37 sliced sediment layers (1-cm interval) were measured, with the concentrations of ∑₁₆PAH (sum of 16 PAHs) ranging from 93.0 to 431 ng g⁻¹. The source apportionment results derived from three receptor models were similar, with three common sources: mixed sources of biomass burning and coal combustion (31.0–41.4% on average), petroleum combustion (31.8–45.5%), and oil leakage (13.1–21.3%). The PMF model segregated an additional source: domestic coal combustion (contributed 20.9% to the ∑₁₆PAHs). Four aspects including intra-comparison, inter-comparison, source numbers and compositions, and source contributions were considered in comparison study. The results indicated that the PMF model was most reasonable in PAH source apportionment research in this study.

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Protective role of liriodendrin in mice with dextran sulphate sodium-induced ulcerative colitis

Publication date: November 2017
Source:International Immunopharmacology, Volume 52
Author(s): Zhen Zhang, Lei Yang, Botao Wang, Lanqiu Zhang, Qi Zhang, Dihua Li, Shukun Zhang, Hongwei Gao, Ximo Wang
Sargentodoxa cuneata, containing syringaresinol and its glycoside liriodendrin as the main bioactive compounds, is a well-known traditional Chinese medicine for treating intestinal inflammation. In our preliminary study, liriodendrin inhibited NF-kB activation in sepsis-induced acute lung injury. The present study was designed to investigate its effect on dextran sulfate sodium (DSS)-induced colitis in a mouse model and to explore the possible related mechanisms. Experimental colitis was established by giving mice drinking water containing 3% (w/v) DSS for 7days. The mice were pretreated with liriodendrin (100mg/kg/day, intragastrically) 3days before DSS treatment. We determined the effects of liriodendrin on disease activity index (DAI), colon length, histopathological examination, antioxidants, and anti-inflammatory activities. Our results showed that liriodendrin greatly decreased MPO and MDA activities and significantly increased SOD and GPx activities in the colon. Moreover, liriodendrin improved DAI, colon length and histological damage in colon and reduced the levels of pro-inflammatory cytokines, such as TNF-a, IL-1β and IL-6. Meanwhile, assessments by western blot revealed that liriodendrin significantly suppressed the activation of Akt and NF-κB pathways and up-regulated the expression of ERβ in the colon. In vitro, liriodendrin down-regulated production of pro-inflammatory cytokines and suppressed NF-κB signalling pathways in LPS-induced RAW 264.7 macrophages in a concentration-dependent manner. In addition, syringaresinol, the hydrolysate of liriodendrin, more potently down-regulated production of pro-inflammatory cytokines and suppressed NF-κB and Akt signalling pathways in LPS-induced RAW 264.7 macrophages,which were abolished by using a pure ER antagonist, ICI182, 780. Taken together, liriodendrin-mediated suppression of inflammatory damage in the colon may be attributable to the in vivo transformation to syringaresinol and liriodendrin may be a promising therapeutic approach preventive agent for colitis treatment.



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The effect of Astragaloside IV on ethanol-induced gastric mucosal injury in rats: Involvement of inflammation

Publication date: November 2017
Source:International Immunopharmacology, Volume 52
Author(s): Shumin Qin, Keer Huang, Zhigang Fang, Jinjin Yin, Ruwei Dai
The present study aimed to investigate the potential protective effects of Astragaloside IV (AS-IV) against ethanol-induced gastric mucosal injury in rats. The animals were divided into 7 groups and pretreated with vehicle, various doses of AS-IV (1,2 and 4mg/kg, i.p.) or omeprazole (40mg/kg), 75min later, the gastric mucosal injury was induced by oral administration of ethanol. One hour after ethanol ingestion, the rats were euthanized and gastric tissues were collected to biochemical analyze. Myeloperoxidase (MPO), tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), interleukin 10 (IL-10), nuclear factor kappa B (NF-κB) p65 protein, TNF receptor-associated factor 2 (TRAF2) and nuclear NF-κB (nNF-κB) proteins were estimated by enzyme-linked immunosorbent assay or western blot analysis. The gastric mucosal lesions were assessed by macroscopic and histopathological examinations. The results showed pretreatment with AS-IV attenuated the severity of ethanol gastric mucosal damage as evidenced by lowering of injury scores, histopathologic aberrations and leukocyte invasion. These actions were analogous to the reference omeprazole. AS-IV suppressed gastric inflammation by curbing of MPO, TNF-α levels along with NF-κB p65 and TRAF2 expression. It also augmented the anti-inflammatory IL-10 levels. Meanwhile, AS-IV could inhibit NF-κB transcription by inhibiting the expression of NF-κB p65 and increasing the expression of nNF-κB. It seems that AS-IV as an anti-inflammatory agent may have a protective effect against ethanol-induced mucosal injury by inhibition of neutrophil infiltration and reducing the expression of NF-κB p65, TRAF2 and inflammatory cytokines via regulating TNF-α/NF-κB signal pathway in gastric tissue.



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Simultaneous determination of tert-butylhydroquinone, propyl gallate, and butylated hydroxyanisole by flow-injection analysis with multiple-pulse amperometric detection

Publication date: 1 February 2018
Source:Talanta, Volume 178
Author(s): Dmytro Bavol, Anastasios Economou, Jiri Zima, Jiri Barek, Hana Dejmkova
We report the first amperometric method for the simultaneous determination of tert-butylhydroquinone (tBHQ), propyl gallate (PG), and butylated hydroxyanisole (BHA) using flow injection analysis coupled to multiple-pulse amperometry. A sequence of potential pulses was selected in order to detect tBHQ, PG, and BHA separately in a single injection step at a glassy carbon electrode without the need of a preliminary separation. A mixture of methanol and 0.040M Britton-Robinson buffer was used both as a carrier solution and for dilution of analyzed solutions before injection. The method is precise (RSD < 5%, n = 10), fast (a frequency of 140 injections h⁻¹), provides sufficiently low quantification limits (2.51, 1.45, and 0.85μmolL^–1 for tBHQ, PG, and BHA, respectively) and can be easily applied without high demands on instrumentation. As a practical application, the determination of these antioxidants contained in commercial chewing gum samples was carried out by applying a simple extraction procedure.

Graphical abstract

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Treatment of oesophageal cancer – Stressing the patient perspective

Publication date: October 2017
Source:European Journal of Cancer, Volume 84
Author(s): Florian Lordick




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First-line treatment in metastatic colorectal cancer: Important or crucial?

Publication date: October 2017
Source:European Journal of Cancer, Volume 84
Author(s): David Malka, Federico Rotolo, Valérie Boige




http://ift.tt/2wDAWb9

CT and MR imaging findings of inflammatory pseudotumors in the abdomen and pelvis: Current concepts and pictorial review

Publication date: Available online 21 September 2017
Source:Seminars in Ultrasound, CT and MRI
Author(s): Ulysses S. Torres, Carlos Matsumoto, Dalila R. Maia, Luis Ronan M.F. de Souza, Giuseppe D'Ippolito
The group of inflammatory pseudotumors (IPTs) encompasses a variety of rare neoplastic and non-neoplastic entities described to occur in almost every location in the body and whose clinical features and aggressive imaging findings (varying from infiltrative to mass-forming lesions), frequently mimic those of malignant tumors. The radiologic features of IPTs are variable and nonspecific, the imaging findings depending on the body location and involved organ. Abdominopelvic IPTs are rare and the purposes of this review, therefore, are to familiarize the radiologist with the wide spectrum of CT and MR imaging findings of IPTs in various locations throughout the abdomen and pelvis, discussing the imaging features that allow consideration of IPTs in the differential diagnosis of soft-tissue masses within the pertinent clinical setting. Radiologists should be aware of this group of entities, as a preoperative histopathological diagnosis upon radiological suspicion may help to differentiate IPTs from malignancy and to allow the most appropriate clinical work-up for these patients.



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Thyroid High-Impact Articles

FREE ACCESS through October 5, 2017.
Read now:

Latest Impact Factor: 5.515
The Official Journal of: American Thyroid Association

Management of Recurrent/Persistent Nodal Disease in Patients with Differentiated Thyroid Cancer: A Critical Review of the Risks and Benefits of Surgical Intervention Versus Active Surveillance
Ralph P. Tufano, Gary Clayman, Keith S. Heller, William B. Inabnet, Electron Kebebew, Ashok Shaha, David L. Steward, R. Michael Tuttle, for the American Thyroid Association Surgical Affairs Committee Writing Task Force

Impact of the Multi-Gene ThyroSeq Next-Generation Sequencing Assay on Cancer Diagnosis in Thyroid Nodules with Atypia of Undetermined Significance/Follicular Lesion of Undetermined Significance Cytology
Yuri E. Nikiforov, Sally E. Carty, Simon I. Chiosea, Christopher Coyne, Umamaheswar Duvvuri, Robert L. Ferris, William E. Gooding, Shane O. LeBeau, N. Paul Ohori, Raja R. Seethala, Mitchell E. Tublin, Linwah Yip, Marina N. Nikiforova

Thyroid Ultrasound Features and Risk of Carcinoma: A Systematic Review and Meta-Analysis of Observational Studies
Luciana Reck Remonti, Caroline Kaercher Kramer, Cristiane Bauermann Leitão, Lana Catani F. Pinto, Jorge Luiz Gross

Incidences of Unfavorable Events in the Management of Low-Risk Papillary Microcarcinoma of the Thyroid by Active Surveillance Versus Immediate Surgery
Hitomi Oda, Akira Miyauchi, Yasuhiro Ito, Kana Yoshioka, Ayako Naka

Subclinical Hypothyroidism in Pregnancy: A Systematic Review and Meta-Analysis
Spyridoula Maraka, Naykky M. Singh Ospina, Derek T. O'Keeffe, Ana E. Espinosa De Ycaza, Michael R. Gionfriddo, Patricia J. Erwin, Charles C. Coddington III, Marius N. Stan, M. Hassan Murad, Victor M. Montori

 

The post Thyroid High-Impact Articles appeared first on American Thyroid Association.

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A Randomized, Double‐Blinded, Phase II Trial of Gemcitabine and Nab‐Paclitaxel Plus Apatorsen or Placebo in Patients with Metastatic Pancreatic Cancer: The RAINIER Trial

AbstractLessons Learned. The addition of the heat shock protein 27 (Hsp27)‐targeting antisense oligonucleotide, apatorsen, to a standard first‐line chemotherapy regimen did not result in improved survival in unselected patients with metastatic pancreatic cancer.Findings from this trial hint at the possible prognostic and predictive value of serum Hsp27 that may warrant further investigation.Background.This randomized, double‐blinded, phase II trial evaluated the efficacy of gemcitabine/nab‐paclitaxel plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 (Hsp27) mRNA, or placebo in patients with metastatic pancreatic cancer.Methods.Patients were randomized 1:1 to Arm A (gemcitabine/nab‐paclitaxel plus apatorsen) or Arm B (gemcitabine/nab‐paclitaxel plus placebo). Treatment was administered in 28‐day cycles, with restaging every 2 cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and on treatment. The primary endpoint was overall survival (OS).Results.One hundred thirty‐two patients were enrolled, 66 per arm. Cytopenias and fatigue were the most frequent grade 3/4 treatment‐related adverse events for both arms. Median progression‐free survival (PFS) and OS were 2.7 and 5.3 months, respectively, for arm A, and 3.8 and 6.9 months, respectively, for arm B. Objective response rate was 18% for both arms. Patients with high serum level of Hsp27 represented a poor‐prognosis subgroup who may have derived modest benefit from addition of apatorsen.Conclusion.Addition of apatorsen to chemotherapy does not improve outcomes in unselected patients with metastatic pancreatic cancer in the first‐line setting, although a trend toward prolonged PFS and OS in patients with high baseline serum Hsp27 suggests this therapy may warrant further evaluation in this subgroup.

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Sarcopenia Is Associated with Quality of Life and Depression in Patients with Advanced Cancer

AbstractBackground.Patients with advanced cancer often experience muscle wasting (sarcopenia), yet little is known about the characteristics associated with sarcopenia and the relationship between sarcopenia and patients' quality of life (QOL) and mood.Materials and Methods.As part of a randomized trial, we assessed baseline QOL (Functional Assessment of Cancer Therapy‐General [FACT‐G]) and mood (Hospital Anxiety and Depression Scale [HADS]) in patients within 8 weeks of diagnosis of incurable lung or gastrointestinal cancer, and prior to randomization. Using computed tomography scans collected as part of routine clinical care, we assessed sarcopenia at the level of the third lumbar vertebra with validated sex‐specific cutoffs. We used logistic regression to explore characteristics associated with presence of sarcopenia. To examine associations between sarcopenia, QOL and mood, we used linear regression, adjusted for patients' age, sex, marital status, education, and cancer type.Results.Of 237 participants (mean age = 64.41 ± 10.93 years), the majority were male (54.0%) and married (70.5%) and had lung cancer (56.5%). Over half had sarcopenia (55.3%). Older age (odds ratio [OR] = 1.05, p = .002) and education beyond high school (OR = 1.95, p = .047) were associated with greater likelihood of having sarcopenia, while female sex (OR = 0.25, p < .001) and higher body mass index (OR = 0.79, p < .001) correlated with lower likelihood of sarcopenia. Sarcopenia was associated with worse QOL (FACT‐G: B = −4.26, p = .048) and greater depression symptoms (HADS‐depression: B = −1.56, p = .005).Conclusion.Sarcopenia was highly prevalent among patients with newly diagnosed, incurable cancer. The associations of sarcopenia with worse QOL and depression symptoms highlight the need to address the issue of sarcopenia early in the course of illness.Implications for Practice.In this study, we found that sarcopenia, assessed using computed tomography scans acquired as part of routine clinical care, is highly prevalent in patients with newly diagnosed, incurable cancer. Notably, patients with sarcopenia reported worse quality of life and greater depression symptoms than those without sarcopenia. These findings highlight the importance of addressing muscle loss early in the course of illness among patients with incurable cancer. In the future, investigators should expand upon these findings to develop strategies for assessing and treating sarcopenia while striving to enhance the quality of life and mood outcomes of patients with advanced cancer.

http://ift.tt/2jOPONT

Immunotherapy: A New (and Old) Approach to Treatment of Soft Tissue and Bone Sarcomas

AbstractSoft tissue and bone sarcomas are a rare and heterogeneous form of cancer. With standard of care treatment options including surgery, radiation, and chemotherapy, the long‐term survival is still low for high‐risk soft tissue sarcoma patients. New treatment strategies are needed. Immunotherapy offers a new potential treatment paradigm with great promise. Immunotherapy of soft tissue sarcomas dates back to Dr. Coley's first use of toxins in the late 1800s. A variety of strategies of immunotherapy have been tried in soft tissue and bone sarcomas, including various vaccines and cytokines, with limited success. Results of these early clinical trials with vaccines and cytokines were disappointing, but there are reasons to be optimistic. Recent advances, particularly with the use of adoptive T‐cell therapy and immune checkpoint inhibitors, have led to a resurgence of this field for all cancer patients. Clinical trials utilizing adoptive T‐cell therapy and immune checkpoint inhibitors in soft tissue and bone sarcomas are under way. This paper reviews the current state of evidence for the use of immunotherapy, as well as current immunotherapy strategies (vaccines, adopative T‐cell therapy, and immune checkpoint blockade), in soft tissue and bone sarcomas. By understanding the tumor microenviroment of sarcomas and how it relates to their immunoresponsiveness, better immunotherapy clinical trials can be designed, hopefully with improved outcomes for soft tissue and bone sarcoma patients.Implications for Practice.Immunotherapy is a promising treatment paradigm that is gaining acceptance for the management of several cancers, including melanoma, renal cell carcinoma, prostate cancer, and lung cancer. There is a long history of immunotherapy in the treatment of soft tissue and bone sarcomas, although with little success. It is important to understand past failures to develop future immunotherapy treatment strategies with an improved possibility of success. This article reviews the history of and current state of immunotherapy research in the treatment of soft tissue and bone sarcomas, with particular regard to vaccine trials, adoptive T‐cell therapy, and immune checkpoint blockade.

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The European Medicines Agency Review of Carfilzomib for the Treatment of Adult Patients with Multiple Myeloma Who Have Received at Least One Prior Therapy

AbstractOn November 19, 2015, a marketing authorization valid through the European Union was issued for carfilzomib in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma (MM) who have received at least one prior therapy.In a phase III trial in patients with relapsed MM, median progression‐free survival (PFS) for patients treated with carfilzomib in combination with lenalidomide and dexamethasone (CRd) was 26.3 months versus 17.6 months for those receiving lenalidomide and dexamethasone alone (hazard ratio = 0.69; 95% confidence interval, 0.57–0.83; one‐sided log‐rank p value < .0001). The most frequently observed toxicity (grade ≥3, treatment arm vs. control arm) in the phase III trial included neutropenia (29.6% vs. 26.5%), anemia (17.9% vs. 17.7%), thrombocytopenia (16.8% vs. 12.3%), pneumonia (12.5% vs. 10.5%), fatigue (7.7% vs. 6.4%), hypertension (4.6% vs. 2.1%), diarrhea (3.8% vs. 4.1%), and respiratory tract infection (4.1% vs. 2.1%).The objective of this article is to summarize the scientific review of the application leading to regulatory approval in the European Union. The scientific review concluded that the gain in PFS of 8.7 months observed with the combination of CRd was considered clinically meaningful and was supported by a clear trend in overall survival benefit, although the data were not mature. The delay in disease progression appeared superior to available alternatives in the setting of relapsed MM at the time of the marketing authorization of carfilzomib. Therefore, given the overall accepted safety profile, which was considered manageable in the current context, the benefit risk for CRd was considered positive.Implications for Practice.Carfilzomib (Kyprolis) was approved in the European Union in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. The addition of carfilzomib to lenalidomide and dexamethasone resulted in a clinically meaningful and statistically significant improvement of progression‐free survival compared with lenalidomide and dexamethasone, which was supported by a clear trend in overall survival benefit, although the data were not mature. At the time of the marketing authorization of carfilzomib, the delay in disease progression appeared superior to available alternatives in the setting of relapsed multiple myeloma. In terms of safety, the overall accepted safety profile was considered manageable.

http://ift.tt/2jPfev5

Effects of grassland degradation and precipitation on carbon storage distributions in a semi-arid temperate grassland of Inner Mongolia, China

Publication date: November 2017
Source:Acta Oecologica, Volume 85
Author(s): Xiaobing Li, Yunxiao Bai, Wanyu Wen, Hong Wang, Ruihua Li, Guoqing Li, Han Wang
Environmental degradation influences carbon (C) cycling and storage in grassland ecosystems by altering vegetation productivity. However, the impacts of different degradation intensities on vegetation–soil C distributions in grasslands have not been well documented. We measured C storage in soil, roots, and plants under light, moderate, and severe degradation levels in a typical steppe region of Xilinhot, Inner Mongolia, China in 2011 and 2012. Grassland C storage was highest in soil, followed by roots, and then aboveground plant biomass. Grassland degradation and precipitation significantly influenced C storage distributions. During the dry year (2011), total C storage in vegetation and soil was highest under light degradation. Carbon storage in aboveground plant biomass and roots increased with degradation intensity. During the wet year (2012), C storage was highest in aboveground plant biomass and roots under light degradation. Root biomass tended to be concentrated in the soil surface during the wet year.



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Laughter catches attention!

Publication date: Available online 21 September 2017
Source:Biological Psychology
Author(s): Ana P. Pinheiro, Carla Barros, Marcelo Dias, Sonja A. Kotz
In social interactions, emotionally salient and sudden changes in vocal expressions attract attention. However, only a few studies examined how emotion and attention interact in voice processing. We investigated neutral, happy (laughs) and angry (growls) vocalizations in a modified oddball task.Participants silently counted the targets in each block and rated the valence and arousal of the vocalizations. A combined event-related potential and time-frequency analysis focused on the P3 and pre-stimulus alpha power to capture attention effects in response to unexpected events.Whereas an early differentiation between emotionally salient and neutral vocalizations was reflected in the P3a response, the P3b was selectively enhanced for happy voices. The P3b modulation was predicted by pre-stimulus frontal alpha desynchronization, and by the perceived pleasantness of the targets.These findings indicate that vocal emotions may be differently processed based on task relevance and valence. Increased anticipation and attention to positive vocal cues (laughter) may reflect their high social relevance.



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EEG Differences between Eyes-Closed and Eyes-Open Resting Remain in Healthy Ageing

Publication date: Available online 21 September 2017
Source:Biological Psychology
Author(s): Robert J. Barry, Frances M. De Blasio
In young adults and children, the eyes-closed (EC) resting state is one of low EEG arousal, with the change to eyes-open (EO) primarily involving an increase in arousal. We used this arousal perspective to interpret EC/EO differences in healthy young and older adults. EEG was recorded from 20 young (Mage=20.4years) and 20 gender-matched older (Mage=68.2years) right-handed adults during two 3min resting conditions; EC then EO. Older participants displayed less delta and theta, some reduction in alpha, and increased beta. Global activity in all bands reduced with opening the eyes, but did not differ with age, indicating that the energetics of EEG reactivity is maintained in healthy ageing. However, older adults had more focal changes than young adults, particularly in beta, suggesting the mobilisation of additional localised resources. This maintained reactivity, and heightened focal activity, may underlie preserved performance levels in healthy ageing.



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Reactive oxygen species and glutathione antioxidants in the testis of the soil biosentinel Podarcis sicula (Rafinesque 1810)

Abstract

Important toxicological achievements have been made during the last decades using reptiles. We focus our investigation on gonadal reproductive health of the soil biosentinel Podarcis sicula which is very sensitive to endocrine-disrupting chemicals. The aim of this study is to quantitatively detect, by sensitive microassays, reactive oxygen species and the glutathione antioxidants in the testis and investigate if they are differentially expressed before and after remediation of a site of the "Land of Fires" (Campania, Italy) subject to illicit dumping of unknown material. The oxidative stress level was evaluated by electron spin resonance spectroscopy applying a spin-trapping procedure able to detect products of lipid peroxidation, DNA damage and repair by relative mobility shift, and poly(ADP-ribose) polymerase enzymatic activity, respectively, the expression of glutathione peroxidase 4 transcript by real-time quantitative PCR analysis, the antioxidant glutathione S-transferase, a well-assessed pollution index, by enzymatic assay and the total soluble antioxidant capacity. Experimental evidences from the different techniques qualitatively agree, thus confirming the robustness of the combined experimental approach. Collected data, compared to those from a reference unpolluted site constitute evidence that the reproductive health of this lizard is impacted by pollution exposure. Remediation caused significant reduction of reactive oxygen species and downregulation of glutathione peroxidase 4 mRNAs in correspondence of reduced levels of glutathione S-transferase, increase of antioxidant capacity, and repair of DNA integrity. Taken together, our results indicate directions to define new screening approaches in remediation assessment.

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Segmenting Hippocampal Subfields from 3T MRI with Multi-modality Images

Publication date: Available online 21 September 2017
Source:Medical Image Analysis
Author(s): Zhengwang Wu, Yaozong Gao, Feng Shi, Guangkai Ma, Valerie Jewells, Dinggang Shen
Hippocampal subfields play important roles in many brain activities. However, due to the small structural size, low signal contrast, and insufficient image resolution of 3T MR, automatic hippocampal subfields segmentation is less explored. In this paper, we propose an automatic learning-based hippocampal subfields segmentation method using 3T multi-modality MR images, including structural MRI (T1, T2) and resting state fMRI (rs-fMRI). The appearance features and relationship features are both extracted to capture the appearance patterns in structural MR images and also the connectivity patterns in rs-fMRI, respectively. In the training stage, these extracted features are adopted to train a structured random forest classifier, which is further iteratively refined in an auto-context model by adopting the context features and the updated relationship features. In the testing stage, the extracted features are fed into the trained classifiers to predict the segmentation for each hippocampal subfield, and the predicted segmentation is iteratively refined by the trained auto-context model. To our best knowledge, this is the first work that addresses the challenging automatic hippocampal subfields segmentation using relationship features from rs-fMRI, which is designed to capture the connectivity patterns of different hippocampal subfields. The proposed method is validated on two datasets and the segmentation results are quantitatively compared with manual labels using the leave-one-out strategy, which shows the effectiveness of our method. From experiments, we find a) multi-modality features can significantly increase subfields segmentation performance compared to those only using one modality; b) automatic segmentation results using 3T multi-modality MR images could be partially comparable to those using 7T T1 MRI.



http://ift.tt/2w9ujJB

Integrating Geometric Configuration and Appearance Information into a Unified Framework for Anatomical Landmark Localization

Publication date: Available online 21 September 2017
Source:Medical Image Analysis
Author(s): Martin Urschler, Thomas Ebner, Darko Štern
In approaches for automatic localization of multiple anatomical landmarks, disambiguation of locally similar structures as obtained by locally accurate candidate generation is often performed by solely including high level knowledge about geometric landmark configuration. In our novel localization approach, we propose to combine both image appearance information and geometric landmark configuration into a unified random forest framework integrated into an optimization procedure that iteratively refines joint landmark predictions by using the coordinate descent algorithm. Depending on how strong multiple landmarks are correlated in a specific localization task, this integration has the benefit that it remains flexible in deciding whether appearance information or the geometric configuration of multiple landmarks is the stronger cue for solving a localization problem both accurately and robustly. Furthermore, no preliminary choice on how to encode a graphical model describing landmark configuration has to be made. In an extensive evaluation on five challenging datasets involving different 2D and 3D imaging modalities, we show that our proposed method is widely applicable and delivers state-of-the-art results when compared to various other related methods.

Graphical abstract

http://ift.tt/2feTDHe

High sensitivity cardiac troponin I detection in physiological environment using AlGaN/GaN High Electron Mobility Transistor (HEMT) Biosensors

Publication date: 15 February 2018
Source:Biosensors and Bioelectronics, Volume 100
Author(s): Indu Sarangadharan, Abiral Regmi, Yen-Wen Chen, Chen-Pin Hsu, Pei-chi Chen, Wen-Hsin Chang, Geng-Yen Lee, Jen-Inn Chyi, Shu-Chu Shiesh, Gwo-Bin Lee, Yu-Lin Wang
In this study, we report the development of a high sensitivity assay for the detection of cardiac troponin I using electrical double layer gated high field AlGaN/GaN HEMT biosensor. The unique gating mechanism overcomes the drawback of charge screening seen in traditional FET based biosensors, allowing detection of target proteins in physiological solutions without sample processing steps. Troponin I specific antibody and aptamer are used as receptors. The tests carried out using purified protein solution and clinical serum samples depict high sensitivity, specificity and wide dynamic range (0.006–148ng/mL). No additional wash or sample pre-treatment steps are required, which greatly simplifies the biosensor system. The miniaturized HEMT chip is packaged in a polymer substrate and easily integrated with a portable measurement unit, to carry out quantitative troponin I detection in serum samples with<2µl sample volume in 5min. The integrated prototype biosensor unit demonstrates the potential of the method as a rapid, inexpensive, high sensitivity CVD biomarker assay. The highly simplified protocols and enhanced sensor performance make our biosensor an ideal choice for point of care diagnostics and personal healthcare systems.



http://ift.tt/2yfFFwj

Peptide biosensors for anticancer drugs: Design in silico to work in denaturizing environment

Publication date: 15 February 2018
Source:Biosensors and Bioelectronics, Volume 100
Author(s): Filomena Guida, Anna Battisti, Ivan Gladich, Mauro Buzzo, Elena Marangon, Luciana Giodini, Giuseppe Toffoli, Alessandro Laio, Federico Berti
One of the main targets in current clinical oncology is the development of a cheap device capable of monitoring in real-time the concentration of a drug in the blood of a patient. This would allow fine-tuning the dosage according to the patient's metabolism, a key condition to reduce side effects. By using surface plasmon resonance and fluorescence spectroscopy we here show that short peptides designed in silico by a recently developed algorithm are capable of binding the anticancer drug irinotecan (CPT-11) with micromolar affinity. Importantly, the recognition takes place in the denaturating solution used in standard therapeutic drug monitoring to detach the drug from the proteins that are present in human plasma, and some of the peptides are capable of distinguishing CPT-11 from its metabolite SN-38. These results suggest that the in silico design of small artificial peptides is now a viable route for designing sensing units, opening a wide range of applications in diagnostic and clinical areas.



http://ift.tt/2xlmwtm

Functionalized polyacrylamide as an acetylcholinesterase-inspired biomimetic device for electrochemical sensing of organophosphorus pesticides

Publication date: 15 February 2018
Source:Biosensors and Bioelectronics, Volume 100
Author(s): Livia F. Sgobbi, Sergio A.S. Machado
A plethora of publications has continuously reported electrochemical biosensors for detection of pesticides. However, those devices rarely accomplish commercial application due to technical issues associated with the lack of stability and high cost of the biological recognition element (enzyme). Alternatively, the biomimetic catalysts have arisen as a candidate for application in electrochemical biosensors to overcome the enzymatic drawbacks, combining low cost scalable materials with superior stability. Herein, for the first time, we propose a biomimetic biosensor for organophosphorus pesticide detection employing a functionalized polyacrylamide, polyhydroxamicalkanoate (PHA), which mimics the performance of the acetylcholinesterase (AChE) enzyme. The PHA bears functional groups inserted along its backbone chain working as active sites. Thereby, PHA was immobilized on screen printed electrodes (SPE) through a blend formation with poly(ethylene glycol) methyl ether (mPEG) to prevent its leaching out from the surface. Under optimum conditions, the biomimetic sensor was employed for the amperometric detection of paraoxon-ethyl, fenitrothion and chlorpyrifos ranging from 1.0 and 10.0μmolL⁻¹ with a limit of detection of 0.36μmolL⁻¹, 0.61μmol L⁻¹, and 0.83μmolL⁻¹, respectively. Typical AChE-based interfering species did not affect the PHA performance, which endorsed its superior behavior. The proposed biomimetic biosensor, denoted as SPE/PHA/mPEG, represents a significant advance in the field, offering a new path for low cost devices by means of an artificial enzyme, simple configuration and superior stability. Moreover, the biosensor performance can be further improved by modifying the electrode surface to enhance electronic transfer rate.

Graphical abstract

http://ift.tt/2yh2ujf

Efficient label-free chemiluminescent immunosensor based on dual functional cupric oxide nanorods as peroxidase mimics

Publication date: 15 February 2018
Source:Biosensors and Bioelectronics, Volume 100
Author(s): Juan Li, Yue Cao, Samuel S. Hinman, Kristy S. McKeating, Yiwen Guan, Xiaoya Hu, Quan Cheng, Zhanjun Yang
Dual-functional cupric oxide nanorods (CuONRs) as peroxidase mimics are proposed for the development of a flow-through, label-free chemiluminescent (CL) immunosensor. Forming the basis of this cost-efficient, label-free immunoassay, CuONRs, synthesized using a simple hydrothermal method, were deposited onto epoxy-activated standard glass slides, followed by immobilization of biotinylated capture antibodies through a streptavidin bridge. The CuONRs possess excellent catalytic activity, along with high stability as a solid support. Antigens could then be introduced to the sensing system, forming large immunocomplexes that prevent CL substrate access to the surface, thereby reducing the CL signal in a concentration dependent fashion. Using carcinoembryonic antigen (CEA) as a model analyte, the proposed label-free immunosensor was able to rapidly determine CEA with a wide linear range of 0.1–60ngmL⁻¹ and a low detection limit of 0.05ngmL⁻¹. This nanozyme-based immunosensor is simple, sensitive, cost-efficient, and has the potential to be a very promising platform for fast and efficient biosensing applications.

Graphical abstract

http://ift.tt/2yhzWpG

Highly efficient electro-oxidation catalyst under ultra-low voltage for degradation of aspirin

Abstract

A novel cryptomelane-Ir (cry-Ir) electrode is prepared for Ir to enter into the cryptomelane (named as cry-Mn) structure and used for aspirin degradation. This catalyst can efficiently reduce the Ir usage from 85 to 34%. Also, the onset potential of cry-Ir is about 1.40 V and the over potential is about 0.34 V at 10 mA cm⁻², indicating that cry-Ir has an excellent oxygen evolution reaction (OER) activity to produce oxidizing species and can decrease electrolytic voltage during the electro-oxidation process. So, the electrical efficiency per log order (EE/O) for cry-Ir electrode is only 5% of PbO₂ electrode, which is the best electrode for organic degradation. Also, cry-Ir has large tunnel size which favors insertion of aspirin molecule into cry-Ir structure and enhances the contact between reactive intermediates and the contaminant. Using cry-Ir as anode, 100% aspirin removal and 55% chemical oxygen demand (COD) removal could be obtained at 4 V. We also compare cry-Ir electrode with IrO₂ and find that IrO₂ anode can only eliminate 20% aspirin under the same condition. As a result, cry-Ir is a promising anode material for organic pollutant degradation.

Graphical abstract

Aspirin removal after 4h under different voltages. Aspirin removal on IrO₂/Ti-f and cry-Ir/Ti-f after 4h.

http://ift.tt/2hmEp79

Nitrates and phosphates in cave waters of Kraków-Częstochowa Upland, southern Poland

Abstract

The paper presents the varied presence of nitrates and phosphates in water from caves located in Częstochowa and Kraków, in urban, strongly anthropogenic conditions, representing the vadose zone of the fissure-karstic-porous massif of Upper Jurassic limestones. Hydrochemical research was carried out by the authors in the Cave on the Stone in Częstochowa in 2012–2015, in caves of the Zakrzówek horst from 1996 to 2002, and in the Dragon's Cave by the research team of J. Motyka in 1995–1998. A number of NO₃ and PO₄ measurements were performed in waters sampled at these research sites: 20 measurements each of NO₃ and PO₄ at the Cave on the Stone, 228 of NO₃ and 422 of PO₄ at Zakrzówek, and 19 each of NO₃ and PO₄ at the Dragon's Cave. To assess the quality aspect of N and P compounds in waters from the Cave on the Stone, the results of geochemical modelling were processed using PHREEQC software. In cave waters, the oxidised form of nitrogen NO₃⁻ predominates; in surface waters in the vicinity, unoxidised forms prevail: NH₄₊, NH₃, and NH₄SO₄⁻. Among phosphorus speciations, dissolved forms are dominant: HPO₄²⁻, H₂PO₄⁻, and the insoluble form CaHPO₄; in surface waters, these forms are practically absent. Transformations of water chemistry in 'urban' caves, often centuries old, manifest themselves in, inter alia, the occurrence of multi-ionic waters, including seasonal variations and extremely diversified concentrations, with very high concentrations in subpopulations of NO₃ (0.2–485 mg dm⁻³) and P (0.02–6.87 mg dm⁻³). The common presence of NO₃ in waters of the phreatic zone of the Częstochowa Upland, an area developed in an agricultural direction, is documented by, inter alia, the exploitation of intakes supplying the city of Częstochowa (10–57 mg dm⁻³, 2011) and crenological studies from 2008 to 2015 (NO₃, 2–58 mg dm⁻³), at simultaneously low phosphate concentrations (PO₄, 0.02–0.24 mg dm⁻³).

http://ift.tt/2hkMmd8

Experimental variation of the level and the ratio of angiogenic and osteogenic signaling affects the spatiotemporal expression of bone-specific markers and organization of bone formation in ectopic sites

Abstract

Objectives

The aim of the present study was to test the hypothesis that the ratio of angiogenic and osteogenic signaling affects ectopic bone formation when delivered in different amounts.

Materials and methods

Porous composite PDLLA/CaCO₃ scaffolds were loaded with rhBMP2 and rhVEGF in different dosage combinations and implanted into the gluteal muscles of 120 adult male Wistar rats. Bone formation and expression of alkaline phosphatase and Runx2 were quantified by histomorphometry. Spatial distribution across the scaffolds was assessed by using a grid that discriminated between the periphery and center of the scaffolds.

Results

The evaluation showed that the combined delivery of bone morphogenetic protein BMP2 and VEGF in different dosage combinations did not enhance the overall quantity of ectopic bone formation compared to the delivery of BMP2 alone. The addition of VEGF generally upregulated Runx2 after 4 weeks, which may have retarded terminal osteogenic differentiation. However, slow combined delivery of 1.5–2.0 μg BMP2 combined with 50 ng VEGF165 over a period of 5 weeks supported a more even distribution of bone formation across the implanted scaffolds whereas higher amounts of VEGF did not elicit this effect.

Conclusions

The findings suggest that structural organization rather than the quantity of ectopic bone formation is affected by the dosage and the ratio of BMP2 and VEGF levels at the observed intervals.

Clinical relevance

The development of carriers for dual growth factor delivery has to take into account the necessity to carefully balance the ratio of growth release.

http://ift.tt/2jMuJDX

Amino acid or peptide conjugates of acridine/acridone and quinoline/quinolone-containing drugs. A critical examination of their clinical effectiveness within a twenty-year timeframe in antitumor chemotherapy and treatment of infectious diseases

Publication date: 15 November 2017
Source:European Journal of Pharmaceutical Sciences, Volume 109
Author(s): Monika Kukowska
Acridines/acridones, quinolines/quinolones (chromophores) and their derivatives constitute extremely important family of compounds in current medicine. Great significance of the compounds is connected with antimicrobial and antitumor activities. Combining these features together in one drug seems to be long-term benefit, especially in oncology therapy. The attractiveness of the chromophore drugs is still enhanced by elimination their toxicity and improvement not only selectivity, specificity but also bioavailability. The best results are reached by conjugation to natural peptides. This paper highlights significant advance in the study of amino acid or peptide chromophore conjugates that provide highly encouraging data for novel drug development. The structures and clinical significance of amino acid or peptide chromophore conjugates are widely discussed.

Graphical abstract

http://ift.tt/2wKEAeD

Vaginal semisolid products: Technological performance considering physiologic parameters

Publication date: 15 November 2017
Source:European Journal of Pharmaceutical Sciences, Volume 109
Author(s): Rita Monteiro Machado, Ana Palmeira-de-Oliveira, José Martinez-de-Oliveira, Rita Palmeira-de-Oliveira
Vaginal semisolid products are frequently used to treat vaginal infections and atrophy-related symptoms of menopause. Formulations composition and the methods for their characterization, especially those developed concerning the target epithelia, are key tools to predict in vivo results at early stages of product development. However, recent studies on this subject have been almost exclusively focused on anti-HIV preparations. The aim of this work consists on improving traditional characterization methods by using physiological parameters in order to construct predictive tools to characterize a new ideal vaginal semisolid formulation whatever target it may have. Ten vaginal antimicrobial and hormonal products already available in the market were studied (Gino-Canesten®, Sertopic®, Dermofix®, Gyno-pevaryl®, Lomexin®, Gino Travogen®, Dalacin V®, Ovestin®, Blissel®, Colpotrophine®). Furthermore, Universal Placebo gel and Replens® were used for comparison. Products were characterized in terms of: pH and buffering capacity in a vaginal fluid simulant (VFS); osmolality - directly and upon dilution in VFS; textural parameters (firmness, adhesiveness and bioadhesion) using vaginal ex vivo porcine epithelium; and viscosity (including VFS dilution at 37°C and after administration on an ex vivo model). Interestingly, the majority of the tested commercial vaginal formulations did not present technological characteristics close to the ideal ones when tested under target biological conditions. The inclusion of such methodologic adaptations is expected to optimize cost-efficiency of new formulations development by predicting efficacy and safety profiles at early stages of product development.

Graphical abstract

http://ift.tt/2wKsySs

Phenazopyridine-phthalimide nano-cocrystal: Release rate and oral bioavailability enhancement

Publication date: 15 November 2017
Source:European Journal of Pharmaceutical Sciences, Volume 109
Author(s): Yu Huang, Jin-Mei Li, Zhi-Hui Lai, Jun Wu, Tong-Bu Lu, Jia-Mei Chen
Both cocrystal and nanocrystal technologies have been widely used in the pharmaceutical development for poorly soluble drugs. However, the synergistic effects due to the integration of these two technologies have not been well investigated. The aim of this study is to develop a nano-sized cocrystal of phenazopyridine (PAP) with phthalimide (PI) to enhance the release rate and oral bioavailability of PAP. A PAP–PI nano-cocrystal with particle diameter of 21.4±0.1nm was successfully prepared via a sonochemical approach and characterized by powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), scanning electron microscopy (SEM) and dynamic light scattering (DLS) analysis. An in vitro release study revealed a significant release rate enhancement for PAP–PI nano-cocrystal as compared to PAP–PI cocrystal and PAP hydrochloride salt. Further, a comparative oral bioavailability study in rats indicated significant improvement in Cmax and oral bioavailability (AUC0−∞) by 1.39- and 2.44-fold, respectively. This study demonstrated that this novel nano-cocrystal technology can be a new promising option to improve release rate and absorption of poorly soluble compounds in the pharmaceutical industry.

Graphical abstract

http://ift.tt/2wK0f6Q

Myricetin solid lipid nanoparticles: Stability assurance from system preparation to site of action

Publication date: 15 November 2017
Source:European Journal of Pharmaceutical Sciences, Volume 109
Author(s): Dina M. Gaber, Noha Nafee, Osama Y. Abdallah
Myricetin - a natural flavonoid - has attracted a great interest due to its antioxidant and free-radical scavenging potential. However, its physicochemical instability critically impairs its dosage form design, evaluation and administration. In an attempt to protect from degradation, MYR was encapsulated into Gelucire-based solid lipid nanoparticles (SLNs). The impact of medium pH, processing temperature and different additives on the drug degradation either in free or nanoencapsulated form was assessed. MYR stability was further monitored in essential biorelevant fluids.Investigations have led to the recommendation that the presence of fat-soluble antioxidant is necessary during SLN preparation to protect the drug at high temperature. Meanwhile, physiological buffers as well as simulated fluids should be supplemented with stabilizers as tween 80 and Poloxamer 407, in addition to water-soluble antioxidant such as sodium sulfite. Interestingly, mucin-containing fluids are suggested to provide better protection to MYR, in contrast, cell culture media do not guarantee MYR stability. The degradation kinetics changed from 1st to 2nd order mechanism after MYR nanoencapsulation. In presence of the aforementioned additives, MYR-SLNs significantly reduced the drug degradation rate constant up to 300-folds and prolonged the half-life time up to 4500-folds compared to free MYR in physiological buffers (One-way ANOVA, p<0.05). As a proof of concept, in vitro release experiment in presence of phosphate buffer (pH7.4) supplemented with these additives ensured sustained release of MYR over >8h with no signs of degradation.The study emphasizes virtuous guidance regarding appropriate nanoencapsulation conditions and evaluation attributes ensuing MYR physicochemical stability.

Graphical abstract

http://ift.tt/2wKswtO

Disposition of treosulfan and its active monoepoxide in a bone marrow, liver, lungs, brain, and muscle: Studies in a rat model with clinical relevance

Publication date: 15 November 2017
Source:European Journal of Pharmaceutical Sciences, Volume 109
Author(s): Michał Romański, Anna Kasprzyk, Mateusz Walczak, Agnieszka Ziółkowska, Franciszek Główka
For the recent years, the application of treosulfan (TREO)-based conditioning prior to hematopoietic stem cell transplantation (HSCT) has been increasing as an alternative to busulfan-based therapy, especially for patients presenting high risk of developing hepato-, pulmo-, and neurotoxicity. So far, the penetration of TREO and its epoxy-derivatives into central nervous system and aqueous humor of the eye has been investigated. However, lacking knowledge on the compounds distribution into the other key tissues precludes comprehensive understanding and assessment of TREO clinical efficacy and toxicity. In this paper, the disposition of TREO and its active monoepoxide (S,S-EBDM) in a bone marrow, liver, lungs, brain, and quadriceps femoris was studied in an animal model. Male and female adult Wistar rats (n=48/48) received an intraperitoneal injection of TREO at the dose of 500mg/kg b.w. Concentrations of TREO and S,S-EBDM in tissues were determined with a validated HPLC-MS/MS method. Pharmacokinetic calculations were performed in WinNonlin using a noncompartmental analysis. Mean values of the maximal concentrations of TREO and S,S-EBDM in the organs were sex-independent and ranged from 61 to 1650μM and 25–105μM, respectively. No quantifiable levels of S,S-EBDM were found in the liver. Average tissue/plasma area under the curve (AUC) ratio for unbound TREO increased in the sequence: brain (0.10)<muscle (0.77)<bone marrow=lungs (0.82)<liver (0.96). The tissue/plasma AUC ratio for unbound S,S-EBDM changed as follows: brain (0.35)<lungs (0.50)<bone marrow (0.75)<muscle (1.14). Elimination half-lives of the compounds in plasma and the organs ranged from 0.7h to 2.1h. Scaling of the obtained AUCs of TREO and S,S-EBDM and the literature AUCs of busulfan to concentrations of the drugs in HSCT patients' plasma show that TREO reaches much higher levels in the organs than busulfan. Nonetheless, low S,S-EBDM exposure in a liver, lungs, and brain, even compared with busulfan, may contribute to relatively low organ toxicity of TREO-based conditioning regimens. Similarity of the scaled bone marrow AUCs of S,S-EBDM and busulfan corresponds to comparable myeloablative potency of TREO- and busulfan-based conditioning. The biological half-lives of TREO and S,S-EBDM in plasma and the studied organs indicate that 48h lag time following administration of the last dose of TREO to HSCT patients is sufficient to protect the transplanted stem cells from the compounds' exposure.

Graphical abstract

http://ift.tt/2wK5HXc

Coupled effects of mulching and nitrogen fertilization on crop yield, residual soil nitrate, and water use efficiency of summer maize in the Chinese Loess Plateau

Abstract

Appropriate water-saving and nitrogen management strategies are critical for achieving sustainable agricultural development in dry sub-humid areas of the Chinese Loess Plateau. The present study was conducted in 2004, 2005, 2008, and 2012 based on a long-term field experiment and aimed to investigate the coupled impacts of mulching and N fertilization on maize yield, water use efficiency (WUE), and residual soil nitrate (RSN) accumulated in the soil profile (0–200 cm). The results demonstrated that mulch is conducive to increasing summer maize yield. The plastic film-mulched ridge and straw-mulched furrow (RF) treatment significantly increased maize yield across the studied period, while the straw mulch (SM) treatment did not significantly increase maize yield until the third experimental year. Compared with SM, the RF treatment showed more significant and positive effects on maize yield, WUE, and RSN accumulated in the 0–200 cm soil depth. N fertilization significantly increased maize yield and WUE, but no significant differences were observed when 120 and 240 kg N ha⁻¹ were applied. The N240 treatment was characterized by relatively high NO₃⁻-N accumulation in 0–200 cm soil depth and low ratios of soil nitrate in the upper to the lower soil layers, indicating a considerable potential for NO₃⁻-N leaching. Averaged across years, economic optimum N fertilizer rates (Nops) were 154, 148, and 150 kg N ha⁻¹ for the no mulch, RF, and SM treatments, respectively. This suggested that 25.8–51.2% of N rate can be reduced while maintaining an acceptably high maize yield. Additionally, understanding NO₃⁻-N depth distribution in 0–100 cm soil profile can adequately predict and represent the characteristics of NO₃⁻-N accumulated in the 100–200 cm and 0–200 cm soil layers because of their significant correlations, thus saving time and money. In conclusion, the practice of RF combined with properly reduced farmers' N rate (~ 150 kg N ha⁻¹) is the preferred option for maize production in the Chinese Loess Plateau, and further research is required to investigate the effects of mulching on summer maize under Nop conditions.

http://ift.tt/2wK6kQt

Biosynthesis of silver nanoparticles by leaf extract of Albizia saman (Jacq.) Merr. and their cytotoxic effect on mitotic chromosomes of Drimia indica (Roxb.) Jessop

Abstract

Silver nanoparticles synthesized using the leaf extract of Albizia saman (Jacq.) Merr. were tested for induction of cytogenetic abnormality in root tip cells of Drimia indica (Roxb.) Jessop (family Asperagaceae). The leaves are known to be rich in various phytochemicals like flavonoids, glycosides, saponins, steroids, tannins, and terpenoids, which may be responsible for bioreduction, biocapping, and stabilization of nanoparticles. The various instruments used for characterization include UV-VIS spectrophotometer, fourier transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), X-Ray diffractometer (XRD), and high resolution transmission electron microscope (HR-TEM). The present study aims to evaluate the cytotoxic effect of biogenic silver nanoparticles on mitotic chromosomes by using root tip cells of D. indica. The root tips of D. indica was treated with suspensions of silver nanoparticles mixed in distilled water at different concentrations viz., 25, 50, 75, and 100% (w/v) for 6, 12, 18, and 24 h and then fixed in 1:3 ethanol: acetic acid following pre-treatment with 0.05% colchicine for cytological analysis. Silver nanoparticles induced a dose dependent decrease of mitotic index in root meristems. Furthermore, the treated meristem cells showed various types of chromosomal and mitotic aberrations such as anaphase bridge, sticky metaphase, lagging, or forward chromosome indicating genotoxic damage.

http://ift.tt/2xs8yrv

Use of honeybees ( Apis mellifera L.) as bioindicators for assessment and source appointment of metal pollution

Abstract

The ability of honeybees to collect particulate matter (PM) on their bodies makes them outstanding bioindicators. In this study, two cities, Pančevo (PA) and Vršac (VS), South Banat district, Vojvodina, Serbia, were covered with two sampling sites each. The aims of this study were to determine concentrations of Al, Ba, Cd, Co, Cr, Cu, Fe, Mn, Na, Ni, Sr, and Zn in the bodies of honeybees during July and September of 2013, 2014, and 2015 and to analyze their spatial and temporal variations and sources of analyzed elements, as well as to assess pollution levels in the two cities. Significant temporal differences were found for Al, Ba, Cd, Co, Cr, Cu, Fe, Mn, Na, Ni, and Zn. Trend of reduction in metal concentrations in bodies of honeybees during the years was observed. Statistically significant spatial variations were observed for Al, Ba, and Sr, with higher concentrations in VS. PCA and CA analyses were used for the first time to assess sources of metals found in honeybees. These analyses showed two sources of metals. Co, Cd, Na, Fe, Mn, Zn, and partly Cu were contributed to anthropogenic sources, while Ca, Al, Mg, Cr, Ba, Sr, and Ni were contributed to natural sources.

http://ift.tt/2wJW2QA

Comparison of control strategies for single-stage partial nitrification-anammox granular sludge reactor for mainstream sewage treatment—a model-based evaluation

Abstract

The low ammonium concentration, low temperature, presence of organic matter, and large variation of influent ammonium load pose serious challenges for the application of PN/AMX (partial nitrification-anammox) reactor in the mainstream wastewater treatment. Previous mathematical simulation studies of PN/AMX granule reactor mainly concentrated on the steady-state modeling. The steady-state simulation cannot be used for developing control strategies under dynamic condition. In this study, four control strategies were evaluated on their abilities to minimize the impact of feed disturbances on autotrophic nitrogen removal in mainstream wastewater. The four control strategies included are the following: (A) direct airflow adjustment to maintain the fixed NH₄⁺ set point, (B) fixed NH₄⁺ set point control manipulated by DO concentration with DO limit, (C) constant DO control strategy, and (D) adaptive change of NH₄⁺ set point control based on the feed disturbance (NH₄⁺ set point value achieved by DO concentration manipulation with DO limit). The results indicated that the control strategy A successfully implemented for high NH₄⁺ strength wastewater treatment cannot be directly transferred into the mainstream wastewater treatment, in which high NO₂⁻ accumulation was resulted during the NH₄⁺ peaks at the low-temperature period. Satisfactory TN removal could be achieved by maintaining either fixed or variable bulk NH₄⁺ set point values calculated based on the feed disturbances (control strategies B and D). The DO limit imposed on the DO concentration manipulation to derive the desired NH₄⁺ set point values was essential for the successful implementation of control strategies B and D. The control strategy C with constant DO concentration was not feasible for the PN/AMX process under dynamic feed disturbances. The control simulation results and the control variable sensitivity analysis indicated that the NH₄⁺ concentration was a better control variable than the DO concentration.

http://ift.tt/2xryvHs

Vaccine development for emerging virulent infectious diseases

Publication date: 4 October 2017
Source:Vaccine, Volume 35, Issue 41
Author(s): Joel N. Maslow
The recent outbreak of Zaire Ebola virus in West Africa altered the classical paradigm of vaccine development and that for emerging infectious diseases (EIDs) in general. In this paper, the precepts of vaccine discovery and advancement through pre-clinical and clinical assessment are discussed in the context of the recent Ebola virus, Middle East Respiratory Syndrome coronavirus (MERS-CoV), and Zika virus outbreaks. Clinical trial design for diseases with high mortality rates and/or high morbidity in the face of a global perception of immediate need and the factors that drive design in the face of a changing epidemiology are presented. Vaccines for EIDs thus present a unique paradigm to standard development precepts.



http://ift.tt/2wJXbaS

Immunoglobulin GM and KM genes and measles vaccine-induced humoral immunity

Publication date: 4 October 2017
Source:Vaccine, Volume 35, Issue 41
Author(s): Inna G. Ovsyannikova, Beth R. Larrabee, Daniel J. Schaid, Gregory A. Poland
Identifying genetic polymorphisms that explain variations in humoral immunity to live measles virus vaccine is of great interest. Immunoglobulin GM (heavy chain) and KM (light chain) allotypes are genetic markers known to be associated with susceptibility to several infectious diseases. We assessed associations between GM and KM genotypes and measles vaccine humoral immunity (neutralizing antibody titers) in a combined cohort (n=1796) of racially diverse healthy individuals (age 18–41years). We did not discover any significant associations between GM and/or KM genotypes and measles vaccine-induced neutralizing antibody titers. African-American subjects had higher neutralizing antibody titers than Caucasians (1260mIU/mL vs. 740mIU/mL, p=7.10×10⁻¹³), and those titers remained statistically significant (p=1.68×10⁻⁰⁹) after adjusting for age at enrollment and time since last vaccination. There were no statistically significant sex-specific differences in measles-induced neutralizing antibody titers in our study (p=0.375). Our data indicate a surprising lack of evidence for an association between GM and KM genotypes and measles-specific neutralizing antibody titers, despite the importance of these immune response genes.



http://ift.tt/2xrwMBY

Safety and efficacy of a Mycoplasma gallisepticum oppD knockout mutant as a vaccine candidate

Publication date: Available online 21 September 2017
Source:Vaccine
Author(s): Chi-Wen Tseng, Chien-Ju Chiu, Anna Kanci, Amir H. Noormohammadi, Glenn F. Browning, Philip F. Markham
Control of the important poultry pathogen Mycoplasma gallisepticum is highly dependent on safe and efficacious attenuated vaccines. In order to assess a novel vaccine candidate we evaluated the safety and efficacy of the M. gallisepticum mutant 26-1. The oppD1 gene in this mutant has been interrupted by a signature-tagged transposon and previous studies have shown that it can colonise the respiratory tract of chickens without inducing significant disease. The capacity of the oppD1 mutant to induce protective immunity in the respiratory tract after vaccination by eye-drop was assessed by challenging vaccinated birds with an aerosol of the virulent M. gallisepticum strain Ap3AS. Vaccination with the oppD1 mutant was shown to fully protect against the lesions caused by pathogenic M. gallisepticum in the air sacs and tracheas. It also protected against the effect of infection on weight gain, and partially protected against colonisation of the trachea by virulent M. gallisepticum. These results indicate that a M. gallisepticum mutant with the oppD1 gene knocked out could be used as a live attenuated vaccine as it is both safe and efficacious when administered by eyedrop to chickens.



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Development of a self-assembling protein nanoparticle vaccine targeting Plasmodium falciparum Circumsporozoite Protein delivered in three Army Liposome Formulation adjuvants

Publication date: 4 October 2017
Source:Vaccine, Volume 35, Issue 41
Author(s): Labdhi Seth, Karen M. Bingham Ferlez, Stephen A. Kaba, Derek M. Musser, Sharareh Emadi, Gary R. Matyas, Zoltan Beck, Carl R. Alving, Peter Burkhard, David E. Lanar
We have developed FMP014, a vaccine candidate against Plasmodium falciparum malaria, which is comprised of 60 identical monomer protein chains that form an icosahedral shaped self-assembling protein nanoparticle (SAPN). Each monomer contains selected P. falciparum Circumsporozoite Protein (PfCSP) CD4+ and CD8+ epitopes, universal TH epitopes, portions of the α-TSR domain, and 6 repeats of the NANP motifs of the PfCSP. Here we describe the conditions that are required for successful scale-up and cGMP manufacturing of FMP014 with a yield of ≈1.5g of drug substance per 100g of wet bacterial paste. When adjuvanted with an Army Liposomal Formulation (ALF) based adjuvant, the nanoparticle vaccine is highly immunogenic and prevents infection of mice by an otherwise lethal dose of transgenic P. berghei sporozoites expressing the full-length PfCSP.



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Editorial Board/Aims and Scope

Publication date: 4 October 2017
Source:Vaccine, Volume 35, Issue 41





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Stability and pre-formulation development of a plant-produced anthrax vaccine candidate

Publication date: 4 October 2017
Source:Vaccine, Volume 35, Issue 41
Author(s): R. Mark Jones, Michael Burke, Devon Dubose, Jessica A. Chichester, Slobodanka Manceva, April Horsey, Stephen J. Streatfield, Jeff Breit, Vidadi Yusibov
Second generation anthrax vaccines focus on the use of recombinant protective antigen (rPA) to elicit a strong, toxin neutralizing antibody responses in immunized subjects. The main difference between the rPA vaccines compared to the current licensed vaccine, anthrax vaccine absorbed (AVA), is the rPA vaccines are highly purified preparations of only rPA. These second generation rPA vaccines strive to elicit strong immune responses with substantially fewer doses than AVA while provoking less side effects. Many of the rPA candidates have shown to be effective in pre-clinical studies, but most of the second generation molecules have stability issues which reduce their efficacy over time. These stability issues are evident even under refrigerated conditions and thus emphasis has been directed to stabilizing the rPA molecule and determining an optimized final formulation. Stabilization of vaccines for long-term storage is a major challenge in the product development life cycle. The effort required to identify suitable formulations can be slow and expensive. The ideal storage for stockpiled vaccines would allow the candidate to withstand years of storage at ambient temperatures. The Fraunhofer Center for Molecular Biotechnology is developing a plant-produced rPA vaccine candidate that shows instability when stored under refrigerated conditions in a solution, as is typical for rPA vaccines. Increased stability of our plant-produced rPA vaccine candidate was achieved in a spray dried powder formulation that could eliminate the need for conventional cold chain allowing greater confidence to stockpile vaccine for civilian and military biodefense.



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Development of a candidate stabilizing formulation for bulk storage of a double mutant heat labile toxin (dmLT) protein based adjuvant

Publication date: 4 October 2017
Source:Vaccine, Volume 35, Issue 41
Author(s): Vishal M. Toprani, Neha Sahni, John M. Hickey, George A. Robertson, C. Russell Middaugh, Sangeeta B. Joshi, David B. Volkin
This work describes the formulation design and development of a novel protein based adjuvant, a double mutant of heat labile toxin (dmLT), based on knowledge of the protein's structural integrity and physicochemical degradation pathways. Various classes of pharmaceutical excipients were screened for their stabilizing effect on dmLT during exposure to thermal and agitation stresses as monitored by high throughput analytical assays for dmLT degradation. Sucrose, phosphate, sodium chloride, methionine and polysorbate-80 were identified as potential stabilizers that protected dmLT against either conformational destabilization, aggregation/particle formation or chemical degradation (e.g., Met oxidation and Lys glycation). Different combinations and concentrations of the selected stabilizers were then evaluated to further optimize dmLT stability while maintaining pharmaceutically acceptable ranges of solution pH and osmolality. The effect of multiple freeze-thaw (FT) cycles on the physical stability of candidate bulk formulations was also examined. Increasing the polysorbate-80 concentration to 0.1% in the lead candidate bulk formulation mitigated the loss of protein mass during FT. This formulation development study enabled the design of a new bulk formulation of the dmLT adjuvant and provides flexibility for future use in combination with a variety of different vaccine dosage forms with different antigens.



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Development of a micro-neutralization assay for ebolaviruses using a replication-competent vesicular stomatitis hybrid virus and a quantitative PCR readout

Publication date: 4 October 2017
Source:Vaccine, Volume 35, Issue 41
Author(s): Stella S. Lee, Kathryn Phy, Keith Peden, Li Sheng-Fowler
Development of vaccines against highly pathogenic viruses that could also be used as agents of bioterrorism is both a public health issue and a national security priority. Methods that can quantify neutralizing antibodies will likely be crucial in demonstrating vaccine effectiveness, as most licensed viral vaccines are effective due to their capacity to elicit neutralizing antibodies. Assays to determine whether antibodies are neutralizing traditionally involve infectious virus, and the assay most commonly used is the plaque-reduction neutralization test (PRNT). However, when the virus is highly pathogenic, this assay must be done under the appropriate level of containment; for tier one select agents, such as Ebola virus (EBOV), it is performed under Biological Safety Level 4 (BSL-4) conditions. Developing high-throughput neutralization assays for these viruses that can be done in standard BSL-2 laboratories should facilitate vaccine development. Our approach is to use a replication-competent hybrid virus whose genome carries the envelope gene from the pathogenic virus on the genetic backbone of a non-pathogenic virus, such as vesicular stomatitis virus (VSV). We have generated hybrid VSVs carrying the envelope genes for several species of ebolavirus. The readout for infectivity is a one-step reverse transcriptase quantitative PCR (RT-qPCR), an approach that we have used for other viruses that allows robustness and adaptability to automation. Using this method, we have shown that neutralization can be assessed within 6–16h after infection. Importantly, the titers obtained in our assay with two characterized antibodies were in agreement with titers obtained in other assays. Finally, although in this paper we describe the VSV platform to quantify neutralizing antibodies to ebolaviruses, the platform should be directly applicable to any virus whose envelope is compatible with VSV biology.



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The in vitro MIMIC® platform reflects age-associated changes in immunological responses after influenza vaccination

Publication date: 4 October 2017
Source:Vaccine, Volume 35, Issue 41
Author(s): Allison Dauner, Pankaj Agrawal, Jose Salvatico, Tenekua Tapia, Vipra Dhir, S. Farzana Shaik, Donald R. Drake, Anthony M. Byers
Increasing research and development costs coupled with growing concerns over healthcare expenditures necessitate the generation of pre-clinical testing models better able to predict the efficacy of vaccines, drugs and biologics. An ideal system for evaluating vaccine immunogenicity will not only be reliable but also physiologically relevant, able to be influenced by immunomodulatory characteristics such as age or previous exposure to pathogens. We have previously described a fully autologous human cell-based MIMIC® (Modular IMmune In vitro Construct) platform which enables the evaluation of innate and adaptive immunity in vitro, including naïve and recall responses. Here, we establish the ability of this module to display reduced antibody production and T cell activation upon in vitro influenza vaccination of cells from elderly adults. In the MIMIC® system, we observe a 2.7–4.2-fold reduction in strain-specific IgG production to seasonal trivalent influenza vaccine (TIV) in the elderly when compared to adults, as well as an age-dependent decline in the generation of functional antibodies. A parallel decline in IgG production with increasing age was detected via short-term ex vivo stimulation of B cells after in vivo TIV vaccination in the same cohort. Using MIMIC®, we also detect a reduction in the number but not proportion of TIV-specific multifunctional CD154⁺IFNγ⁺IL-2⁺TNFα⁺ CD4⁺ T cells in elderly adults. Inefficient induction of multifunctional helper T cells with TIV stimulation in MIMIC® despite a normalized number of initial CD4⁺ T cells suggests a possible mechanism for an impaired anti-TIV IgG response in elderly adults. The ability of the MIMIC® system to recapitulate differential age-associated responses in vitro provides a dynamic platform for the testing of vaccine candidates and vaccine enhancement strategies in a fully human model including the ability to interrogate specific populations, such as elderly adults.



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An ensemble approach to predicting the impact of vaccination on rotavirus disease in Niger

Publication date: Available online 20 September 2017
Source:Vaccine
Author(s): Jaewoo Park, Joshua Goldstein, Murali Haran, Matthew Ferrari
Recently developed vaccines provide a new way of controlling rotavirus in sub-Saharan Africa. Models for the transmission dynamics of rotavirus are critical both for estimating current burden from imperfect surveillance and for assessing potential effects of vaccine intervention strategies. We examine rotavirus infection in the Maradi area in southern Niger using hospital surveillance data provided by Epicentre collected over two years. Additionally, a cluster survey of households in the region allows us to estimate the proportion of children with diarrhea who consulted at a health structure. Model fit and future projections are necessarily particular to a given model; thus, where there are competing models for the underlying epidemiology an ensemble approach can account for that uncertainty. We compare our results across several variants of Susceptible-Infectious-Recovered (SIR) compartmental models to quantify the impact of modeling assumptions on our estimates. Model-specific parameters are estimated by Bayesian inference using Markov chain Monte Carlo. We then use Bayesian model averaging to generate ensemble estimates of the current dynamics, including estimates of R0, the burden of infection in the region, as well as the impact of vaccination on both the short-term dynamics and the long-term reduction of rotavirus incidence under varying levels of coverage. The ensemble of models predicts that the current burden of severe rotavirus disease is 2.6–3.7% of the population each year and that a 2-dose vaccine schedule achieving 70% coverage could reduce burden by 39–42%.



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Replacing antibodies with modified DNA aptamers in vaccine potency assays

Publication date: 4 October 2017
Source:Vaccine, Volume 35, Issue 41
Author(s): Jeremiah J. Trausch, Mary Shank-Retzlaff, Thorsten Verch
Vaccine in vitro potency assays are vital regulatory tests that are used to confirm the presence and concentration of an antigen of interest in a form that directly or indirectly relates to protective activity in patients. Current assays come in many forms, but they almost exclusively use antibody reagents for selective detection of the target antigen. Antibodies provide specific recognition of vaccine antigens but also exhibit drawbacks such as stability limitations, cost, and lot-to-lot variation, which can make it challenging to maintain the reagent throughout the lifetime of the vaccine.We explored replacing antibodies with aptamers. Aptamers are macromolecules, such as nucleic acids, which can bind to their targets with high specificity and affinity, similar to that of antibodies. Some of the advantages of using aptamers over antibodies is that aptamers can be more stable, smaller, less expensive to produce, synthesized in vitro, and logistically easier to supply throughout the multi-decade lifespan of a commercial vaccine. We created modified DNA aptamers against the common vaccine carrier protein, CRM197. Several aptamers were discovered and one was chosen for further characterization. The binding kinetics of the aptamer revealed an off-rate 16-fold slower than anti-CRM197 antibodies used for comparison. The aptamers were more sensitive than available antibodies in some assay formats and comparable in others. The aptamer epitope was mapped to the receptor-binding domain of CRM197, a site adjacent to a known antibody binding site. These data address some key aspects for a path forward in replacing antibodies with aptamers for use as critical reagents in vaccine assays. We further highlight the possibility of using nucleic acid reagents to develop next generation potency assays.



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Safety and immunogenicity of heterologous prime-boost immunization with viral-vectored malaria vaccines adjuvanted with Matrix-M™

Publication date: Available online 21 September 2017
Source:Vaccine
Author(s): Navin Venkatraman, Nicholas Anagnostou, Carly Bliss, Georgina Bowyer, Danny Wright, Karin Lövgren-Bengtsson, Rachel Roberts, Ian Poulton, Alison Lawrie, Katie Ewer, Adrian V. S. Hill
The use of viral vectors in heterologous prime-boost regimens to induce potent T cell responses in addition to humoral immunity is a promising vaccination strategy in the fight against malaria. We conducted an open-label, first-in-human, controlled Phase I study evaluating the safety and immunogenicity of Matrix-M adjuvanted vaccination with a chimpanzee adenovirus serotype 63 (ChAd63) prime followed by a modified vaccinia Ankara (MVA) boost eight weeks later, both encoding the malaria ME-TRAP antigenic sequence (a multiple epitope string fused to thrombospondin-related adhesion protein). Twenty-two healthy adults were vaccinated intramuscularly with either ChAd63-MVA ME-TRAP alone (n=6) or adjuvanted with 25μg (n=8) or 50μg (n=8) Matrix-M. Vaccinations appeared to be safe and generally well tolerated, with the majority of local and systemic adverse events being mild in nature. The addition of Matrix-M to the vaccine did not increase local reactogenicity; however, systemic adverse events were reported more frequently by volunteers who received adjuvanted vaccine in comparison to the control group. T cell ELISpot responses peaked at 7-days post boost vaccination with MVA ME-TRAP in all three groups. TRAP-specific IgG responses were highest at 28-days post boost with MVA ME-TRAP in all three groups. There were no differences in cellular and humoral immunogenicity at any of the time points between the control group and the adjuvanted groups. We demonstrate that Matrix-M can be safely used in combination with ChAd63-MVA ME-TRAP heterologous prime-boost immunization without any reduction in cellular or humoral immunogenicity.Clinical Trials Registration NCT01669512.



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Post-licensure safety surveillance study of routine use of quadrivalent meningococcal diphtheria toxoid conjugate vaccine

Publication date: Available online 21 September 2017
Source:Vaccine
Author(s): J. Hansen, L. Zhang, N.P. Klein, C.A. Robertson, M.D. Decker, D.P. Greenberg, E. Bassily, R. Baxter
BackgroundMenactra® vaccine (MenACWY-D) was licensed in the United States in 2005 for persons 11–55years of age. The aim of this study was to assess the safety of MenACWY-D administered as part of routine clinical care to patients at Kaiser Permanente Northern California (KPNC).MethodsThis was an observational, retrospective study that included all KPNC members who received MenACWY-D during the study period. We monitored all vaccine recipients for non-elective hospitalizations, emergency department visits, and selected outcomes captured in the clinic setting (Bell's palsy, seizures, neuritis, Guillain-Barré syndrome, encephalopathy, encephalitis, epilepsy, transverse myelitis, multiple sclerosis, hypersensitivity reactions, idiopathic thrombocytopenic purpura, diabetes, arthritis, hemolytic anemia, collagen-vascular disease) through 6months after vaccination. Using vaccine recipients as their own controls, we calculated incidence rate ratios (IRRs) of outcomes during the post-vaccination risk interval and compared these with rates during a comparison interval more remote from vaccination. We also compared rates of outcomes in MenACWY-D recipients with those in matched controls who received selected vaccines in the prior year. We reviewed medical records for selected outcomes.ResultsFrom April 2005 through April 2006, 31,561 KPNC patients (>99% of whom were 11–55years of age) received MenACWY-D. Overall, there were 21 outcomes with significantly elevated IRRs and 44 outcomes with significantly reduced IRRs. Medical record review of outcomes with significantly elevated IRRs did not suggest any relationship with MenACWY-D. Two serious adverse events were considered possibly related to vaccination by the study investigator.ConclusionsThis study did not detect any safety concerns following MenACWY-D and provides reassurance that MenACWY-D administered as part of routine care was not associated with unexpected safety risks.ClinicalTrials.gov Identifier is NCT00254995.



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Waning protection of influenza vaccination during four influenza seasons, 2011/2012 to 2014/2015

Publication date: Available online 20 September 2017
Source:Vaccine
Author(s): J. Puig-Barberà, A. Mira-Iglesias, M. Tortajada-Girbés, F.X. López-Labrador, J. Librero-López, J. Díez-Domingo, M. Carballido-Fernández, C. Carratalá-Munuera, P Correcher-Medina, V. Gil-Guillén, R. Limón-Ramírez, J. Mollar-Maseres, M.C. Otero-Reigada, H. Schwarz
BackgroundConcerns have been raised about intraseasonal waning of the protection conferred by influenza vaccination.MethodsDuring four influenza seasons, we consecutively recruited individuals aged 18years or older who had received seasonal influenza vaccine and were subsequently admitted to the hospital for influenza infection, asassessed by reverse transcription polymerase chain reaction. We estimated the adjusted odds ratio (aOR) of influenza infection by date of vaccination, defined by tertiles, as early, intermediate or late vaccination. We used a test-negative approach with early vaccination as reference to estimate the aOR of hospital admission with influenza among late vaccinees. We conducted sensitivity analyses by means of conditional logistic regression, Cox proportional hazards regression, and using days between vaccination and hospital admission rather than vaccination date.ResultsAmong 3615 admitted vaccinees, 822 (23%) were positive for influenza. We observed a lower risk of influenza among late vaccinees during the 2011/2012 and 2014/2015A(H3N2)-dominant seasons: aOR=0.68 (95% CI: 0.47–1.00) and 0.69 (95% CI: 0.50–0.95). We found no differences in the risk of admission with influenza among late versus early vaccinees in the 2012/2013A(H1N1)pdm09-dominant or 2013/2014B/Yamagata lineage-dominant seasons: aOR=1.18 (95% CI: 0.58–2.41) and 0.98 (95% CI: 0.56–1.72). When we restricted our analysis to individuals aged 65years or older, we found a statistically significant lower risk of admission with influenza among late vaccinees during the 2011/2012 and 2014/2015A(H3N2)-dominant seasons: aOR=0.61 (95% CI: 0.41–0.91) and 0.69 (95% CI: 0.49–0.96). We observed 39% (95% CI: 9–59%) and 31% (95% CI: 5–50%) waning of vaccine effectiveness among participants aged 65years or older during the two A(H3N2)-dominant seasons. Similar results were obtained in the sensitivity analyses.ConclusionWaning of vaccine protection was observed among individuals aged 65years old or over in two A(H3N2)-dominant influenza seasons.



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Epidemiology of childhood intussusception in Bangladesh: Findings from an active national hospital based surveillance system, 2012–2016

Publication date: Available online 20 September 2017
Source:Vaccine
Author(s): Syed M. Satter, Negar Aliabadi, Catherine Yen, Paul A. Gastañaduy, Makhdum Ahmed, Abdullah Mamun, Khaleda Islam, Meerjady S. Flora, Mahmudur Rahman, K. Zaman, Mustafizur Rahman, James D. Heffelfinger, Stephen P. Luby, Emily S. Gurley, Umesh D. Parashar
IntroductionRotavirus vaccines have significantly decreased the burden of diarrheal diseases in countries that have introduced them into their immunization programs. In some studies, there has been a small association between rotavirus vaccines and intussusception in post-marketing surveillance, highlighting the importance of tracking incidence before and after vaccine introduction. The objective of this study was to describe the epidemiology of intussusception among Bangladeshi children pre-vaccine introduction.MethodsWe conducted active, hospital-based surveillance for intussusception at 7 tertiary care hospitals with pediatric surgical facilities during July 2012 to September 2016. Hospitalized children under 2years of age were identified according to Brighton Collaboration level 1 criteria for intussusception. The frequency and proportion of intussusception among overall surgical admissions, as well as the demographic and clinical information of the cases is described.ResultsOverall 153 cases of intussusception among children <2years-old were identified at participating sites over the enrolment period, confirmed by Level 1 Brighton criteria. These cases represented 2% of all surgical admissions under 2years of age. One hundred twelve cases (73%) were male; the median age was 7months; and the median duration of hospitalization was 7days. One hundred forty-six (95%) children with intussusception required surgery, and 11 (7%) died.ConclusionsConfirmed cases of intussusception represented nearly 2% of pediatric surgical admissions at tertiary referral centers in Bangladesh during the study period and 7% of children with intussusception died. Given the high burden of rotavirus disease in Bangladesh, vaccine introduction is warranted, however, further studies after introduction of rotavirus vaccine are necessary to determine any association between vaccine and intussusception in this setting.



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Control of Cell Shape, Neurite Outgrowth, and Migration by a Nogo-A/HSPG Interaction

Publication date: Available online 21 September 2017
Source:Developmental Cell
Author(s): Anissa Kempf, Enrica Boda, Jessica C.F. Kwok, Rafael Fritz, Valentina Grande, Andrea M. Kaelin, Zorica Ristic, Andre Schmandke, Antonio Schmandke, Bjoern Tews, James W. Fawcett, Olivier Pertz, Annalisa Buffo, Martin E. Schwab
Heparan sulfate proteoglycans (HSPGs) critically modulate adhesion-, growth-, and migration-related processes. Here, we show that the transmembrane protein, Nogo-A, inhibits neurite outgrowth and cell spreading in neurons and Nogo-A-responsive cell lines via HSPGs. The extracellular, active 180 amino acid Nogo-A region, named Nogo-A-Δ20, binds to heparin and brain-derived heparan sulfate glycosaminoglycans (GAGs) but not to the closely related chondroitin sulfate GAGs. HSPGs are required for Nogo-A-Δ20-induced inhibition of adhesion, cell spreading, and neurite outgrowth, as well as for RhoA activation. Surprisingly, we show that Nogo-A-Δ20 can act via HSPGs independently of its receptor, Sphingosine-1-Phosphate receptor 2 (S1PR2). We thereby identify the HSPG family members syndecan-3 and syndecan-4 as functional receptors for Nogo-A-Δ20. Finally, we show in explant cultures ex vivo that Nogo-A-Δ20 promotes the migration of neuroblasts via HSPGs but not S1PR2.

Graphical abstract

Teaser

The extracellular Δ20 domain of Nogo-A is a potent inhibitor of cell adhesion and neurite outgrowth in the adult CNS. Kempf et al. identify HSPGs as functional receptors for Nogo-A-Δ20. Nogo-A-Δ20 binds to HSPGs and regulates RhoA activation, cell spreading, neurite outgrowth, and neuroblast migration via HSPGs.


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YAP/TAZ and Hedgehog Coordinate Growth and Patterning in Gastrointestinal Mesenchyme

Publication date: Available online 21 September 2017
Source:Developmental Cell
Author(s): Jennifer L. Cotton, Qi Li, Lifang Ma, Joo-Seop Park, Jiayi Wang, Jianhong Ou, Lihua J. Zhu, Y. Tony Ip, Randy L. Johnson, Junhao Mao
YAP/TAZ are the major mediators of mammalian Hippo signaling; however, their precise function in the gastrointestinal tract remains poorly understood. Here we dissect the distinct roles of YAP/TAZ in endodermal epithelium and mesenchyme and find that, although dispensable for gastrointestinal epithelial development and homeostasis, YAP/TAZ function as the critical molecular switch to coordinate growth and patterning in gut mesenchyme. Our genetic analyses reveal that Lats1/2 kinases suppress expansion of the primitive mesenchymal progenitors, where YAP activation also prevents induction of the smooth muscle lineage through transcriptional repression of Myocardin. During later development, zone-restricted downregulation of YAP/TAZ provides the positional cue and allows smooth muscle cell differentiation induced by Hedgehog signaling. Taken together, our studies identify the mesenchymal requirement of YAP/TAZ in the gastrointestinal tract and highlight the functional interplays between Hippo and Hedgehog signaling underlying temporal and spatial control of tissue growth and specification in developing gut.

Graphical abstract

Teaser

The precise function of the Hippo effectors, YAP/TAZ, in the gastrointestinal tract remains elusive. Cotton et al. identify a key role of YAP/TAZ in coordination of growth and patterning in gut mesenchyme and highlight the functional interplay between Hippo and Hedgehog signaling underlying the spatial-temporal control of smooth muscle specification.


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CSNK1a1 Regulates PRMT1 to Maintain the Progenitor State in Self-Renewing Somatic Tissue

Publication date: Available online 21 September 2017
Source:Developmental Cell
Author(s): Xiaomin Bao, Zurab Siprashvili, Brian J. Zarnegar, Rajani M. Shenoy, Eon J. Rios, Natalie Nady, Kun Qu, Angela Mah, Daniel E. Webster, Adam J. Rubin, Glenn G. Wozniak, Shiying Tao, Joanna Wysocka, Paul A. Khavari
Somatic progenitors sustain tissue self-renewal while suppressing premature differentiation. Protein arginine methyltransferases (PRMTs) affect many processes; however, their role in progenitor function is incompletely understood. PRMT1 was found to be the most highly expressed PRMT in epidermal progenitors and the most downregulated PRMT during differentiation. In targeted mouse knockouts and in long-term regenerated human mosaic epidermis in vivo, epidermal PRMT1 loss abolished progenitor self-renewal and led to premature differentiation. Mass spectrometry of the PRMT1 protein interactome identified the CSNK1a1 kinase, which also proved essential for progenitor maintenance. CSNK1a1 directly bound and phosphorylated PRMT1 to control its genomic targeting to PRMT1-sustained proliferation genes as well as PRMT1-suppressed differentiation genes. Among the latter were GRHL3, whose derepression was required for the premature differentiation seen with PRMT1 and CSNK1a1 loss. Maintenance of the progenitors thus requires cooperation by PRMT1 and CSNK1a1 to sustain proliferation gene expression and suppress premature differentiation driven by GRHL3.

Graphical abstract

Teaser

Bao et al. demonstrate an essential role for the arginine methyltransferase PRMT1 in epidermal progenitor maintenance. They further identify the kinase CSNK1a1 as a key PRMT1-interacting protein. CSNK1a1 phosphorylates PRMT1 and cooperates with PRMT1 to suppress GRHL3-mediated terminal differentiation.


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