bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antitrypanosomal Treatment with Benznidazole Is Superior to Posaconazole Regimens in Mouse Models of Chagas Disease
Authors: Khare Shilpi , Liu Xianzhong , Stinson Monique , Rivera Ianne , Groessl Todd , Tuntland Tove , Yeh Vince , Wen Ben , Molteni Valentina , Glynne Richard , Supek Frantisek 
Published: August 2015

ABSTRACT

Two CYP51 inhibitors, posaconazole and the ravuconazole prodrug E1224, were recently tested in clinical trials for efficacy in indeterminate Chagas disease. The results from these studies show that both drugs cleared parasites from the blood of infected patients at the end of the treatment but that parasitemia rebounded over the following months. In the current study, we sought to identify a dosing regimen of posaconazole that could permanently clear
Trypanosoma cruzi
from mice with experimental Chagas disease. Infected mice were treated with posaconazole or benznidazole, an established Chagas disease drug, and parasitological cure was defined as an absence of parasitemia recrudescence after immunosuppression. Twenty-day therapy with benznidazole (10 to 100 mg/kg of body weight/day) resulted in a dose-dependent increase in antiparasitic activity, and the 100-mg/kg regimen effected parasitological cure in all treated mice. In contrast, all mice remained infected after a 25-day treatment with posaconazole at all tested doses (10 to 100 mg/kg/day). Further extension of posaconazole therapy to 40 days resulted in only a marginal improvement of treatment outcome. We also observed similar differences in antiparasitic activity between benznidazole and posaconazole in acute
T. cruzi
heart infections. While benznidazole induced rapid, dose-dependent reductions in heart parasite burdens, the antiparasitic activity of posaconazole plateaued at low doses (3 to 10 mg/kg/day) despite increasing drug exposure in plasma. These observations are in good agreement with the outcomes of recent phase 2 trials with posaconazole and suggest that the efficacy models combined with the pharmacokinetic analysis employed here will be useful in predicting clinical outcomes of new drug candidates.
U.S.-Based National Sentinel Surveillance Study for the Epidemiology of Clostridium difficile-Associated Diarrheal Isolates and Their Susceptibility to Fidaxomicin
Authors: Snydman D. R. , McDermott L. A. , Jacobus N. V. , Thorpe C. , Stone S. , Jenkins S. G. , Goldstein E. J. C. , Patel R. , Forbes B. A. , Mirrett S. , Johnson S. , Gerding D. N. 
Published: August 2015

ABSTRACT

In 2011 a surveillance study for the susceptibility to fidaxomicin and epidemiology of
Clostridium difficile
isolates in the United States was undertaken in seven geographically dispersed medical centers. This report encompasses baseline surveillance in 2011 and 2012 on 925 isolates. A convenience sample of
C. difficile
isolates or toxin positive stools from patients were referred to a central laboratory. Antimicrobial susceptibility was determined by agar dilution (CLSI M11-A8). Clinical and Laboratory Standards Institute (CLSI), Food and Drug Administration, or European Union of Clinical Antimicrobial Susceptibility Testing (EUCAST) breakpoints were applied where applicable. Toxin gene profiles were characterized by multiplex PCR on each isolate. A random sample of 322 strains, stratified by institution, underwent restriction endonuclease analysis (REA). The fidaxomicin MIC
90
was 0.5 μg/ml for all isolates regardless of REA type or toxin gene profile, and all isolates were inhibited at ≤1.0 μg/ml. By REA typing, BI strains represented 25.5% of the isolates. The toxin gene profile of
tcdA
,
tcdB
, and
cdtA/B
positive with a
tcdC
18-bp deletion correlated with BI REA group. Moxifloxacin and clindamycin resistance was increased among either BI or binary toxin-positive isolates. Metronidazole and vancomycin showed reduced susceptibility (EUCAST criteria) in these isolates. Geographic variations in susceptibility, REA group and binary toxin gene presence were observed. Fidaxomicin activity against
C. difficile
isolated in a national surveillance study did not change more than 1 year after licensure. This analysis provides baseline results for future comparisons.
Antileishmanial Activity of Disulfiram and Thiuram Disulfide Analogs in anEx VivoModel System Is Selectively Enhanced by the Addition of Divalent Metal Ions
Authors: Peniche Alex G. , Renslo Adam R. , Melby Peter C. , Travi Bruno L. 
Published: August 2015

ABSTRACTCurrent treatments for cutaneous and visceral leishmaniasis are toxic, expensive, difficult to administer, and limited in efficacy and availability. Disulfiram has primarily been used to treat alcoholism. More recently, it has shown some efficacy as therapy against protozoan pathogens and certain cancers, suggesting a wide range of biological activities. We used anex vivosystem to screen several thiuram disulfide compounds for antileishmanial activity. We found five compounds (compound identifier [CID] 7188, 5455, 95876, 12892, and 3117 [disulfiram]) with anti-Leishmaniaactivity at nanomolar concentrations. We further evaluated these compounds with the addition of divalent metal salts based on studies that indicated these salts could potentiate the action of disulfiram. In addition, clinical studies suggested that zinc has some efficacy in treating cutaneous leishmaniasis. Several divalent metal salts were evaluated at 1 μM, which is lower than the normal levels of copper and zinc in plasma of healthy individuals. The leishmanicidal activity of disulfiram and CID 7188 were enhanced by several divalent metal salts at 1 μM. Thein vitrotherapeutic index (IVTI) of disulfiram and CID 7188 increased 12- and 2.3-fold, respectively, againstL. majorwhen combined with ZnCl2. The combination of disulfiram with ZnSO4resulted in a 1.8-fold increase in IVTI againstL. donovani. This novel combination of thiuram disulfides and divalent metal ions salts could have application as topical and/or oral therapies for treatment of cutaneous and visceral leishmaniasis.
Permeable Reactive Barriers Designed To Mitigate Eutrophication Alter Bacterial Community Composition and Aquifer Redox Conditions
Authors: Hiller Kenly A. , Foreman Kenneth H. , Weisman David , Bowen Jennifer L. 
Published: August 2015

ABSTRACT
Permeable reactive barriers (PRBs) consist of a labile carbon source that is positioned to intercept nitrate-laden groundwater to prevent eutrophication. Decomposition of carbon in the PRB drives groundwater anoxic, fostering microbial denitrification. Such PRBs are an ideal habitat to examine microbial community structure under high-nitrate, carbon-replete conditions in coastal aquifers. We examined a PRB installed at the Waquoit Bay National Estuarine Research Reserve in Falmouth, MA. Groundwater within and below the PRB was depleted in oxygen compared to groundwater at sites upgradient and at adjacent reference sites. Nitrate concentrations declined from a high of 25 μM upgradient and adjacent to the barrier to <0.1 μM within the PRB. We analyzed the total and active bacterial communities filtered from groundwater flowing through the PRB using amplicons of 16S rRNA and of the 16S rRNA genes. Analysis of the 16S rRNA genes collected from the PRB showed that the total bacterial community had high relative abundances of bacteria thought to have alternative metabolisms, such as fermentation, including candidate phyla OD1, OP3, TM7, and GN02. In contrast, the active bacteria had lower abundances of many of these bacteria, suggesting that the bacterial taxa that differentiate the PRB groundwater community were not actively growing. Among the environmental variables analyzed, dissolved oxygen concentration explained the largest proportion of total community structure. There was, however, no significant correlation between measured environmental parameters and the active microbial community, suggesting that controls on the active portion may differ from the community as a whole.
Meat Processing Plant Microbiome and Contamination Patterns of Cold-Tolerant Bacteria Causing Food Safety and Spoilage Risks in the Manufacture of Vacuum-Packaged Cooked Sausages
Authors: Hultman Jenni , Rahkila Riitta , Ali Javeria , Rousu Juho , Björkroth K. Johanna 
Published: August 2015

ABSTRACT

Refrigerated food processing facilities are specific man-made niches likely to harbor cold-tolerant bacteria. To characterize this type of microbiota and study the link between processing plant and product microbiomes, we followed and compared microbiota associated with the raw materials and processing stages of a vacuum-packaged, cooked sausage product affected by a prolonged quality fluctuation with occasional spoilage manifestations during shelf life. A total of 195 samples were subjected to culturing and amplicon sequence analyses. Abundant mesophilic psychrotrophs were detected within the microbiomes throughout the different compartments of the production plant environment. However, each of the main genera of food safety and quality interest, e.g.,
Leuconostoc
,
Brochothrix
, and
Yersinia
, had their own characteristic patterns of contamination. Bacteria from the genus
Leuconostoc
, commonly causing spoilage of cold-stored, modified-atmosphere-packaged foods, were detected in high abundance (up to >98%) in the sausages studied. The same operational taxonomic units (OTUs) were, however, detected in lower abundances in raw meat and emulsion (average relative abundance of 2% ± 5%), as well as on the processing plant surfaces (<4%). A completely different abundance profile was found for OTUs phylogenetically close to the species
Yersinia pseudotuberculosis
. These OTUs were detected in high abundance (up to 28%) on the processing plant surfaces but to a lesser extent (<1%) in raw meat, sausage emulsion, and sausages. The fact that
Yersinia
-like OTUs were found on the surfaces of a high-hygiene packaging compartment raises food safety concerns related to their resilient existence on surfaces.
Management of persistent postconcussion symptoms in youth: a randomised control trial protocol
Authors: Reed Nick , Greenspoon Dayna , Iverson Grant L , DeMatteo Carol , Fait Philippe , Gauvin-Lepage Jérôme , Hunt Anne , Gagnon Isabelle J 
Published: August 2015

IntroductionCurrent management of concussion consists of early education, rest until symptom free, with gradual return to school and physical activity protocols. Although this management strategy is effective for most youth who sustain a concussion, it is not an appropriate strategy for youth with persistent postconcussion symptoms. Prolonged rest and periods of restricted activity may place youth at risk for secondary issues and contribute to the chronicity of postconcussion symptoms. The purpose of this study is to evaluate the efficacy of an active rehabilitation protocol for youth who are slow to recover from concussion. It is hypothesised that an active rehabilitation intervention can reduce persistent postconcussion symptoms, improve function and facilitate return to activity. This article describes the research protocol.Methods and analysisThis is a randomised clinical trial with blinded outcome measurement. Participants will be recruited and randomly assigned to 1 of 2 treatment groups, an active rehabilitation intervention or a standard care education group. Both groups will receive standard care education. However, the active rehabilitation group will participate in an additional low-intensity exercise programme consisting of aerobic, coordination and visualisation exercises. Both the active rehabilitation and the standard care education interventions will be 6 weeks in duration. The primary outcome measure is postconcussion symptoms. Secondary outcome measures include functional recovery (cognitive, motor, psychosocial and emotional functioning) and return to activity. Outcome measures will be administered preintervention and postintervention. The primary outcome measure will also be repeated 2 weeks into the intervention period.Ethics and disseminationThis study has been approved by the Holland Bloorview Kids Rehabilitation Hospital research ethics board (REB # 13-459). The findings from this study will be shared with the general public, sport associations, relevant brain injury organisations and healthcare professionals.Trial registration numberNCT02257749.
Eating As Treatment (EAT) study protocol: a stepped-wedge, randomised controlled trial of a health behaviour change intervention provided by dietitians to improve nutrition in patients with head and neck cancer undergoing radiotherapy
Authors: Britton Ben , McCarter Kristen , Baker Amanda , Wolfenden Luke , Wratten Chris , Bauer Judith , Beck Alison , McElduff Patrick , Halpin Sean , Carter Gregory 
Published: August 2015

IntroductionMaintaining adequate nutrition for Head and Neck Cancer (HNC) patients is challenging due to both the malignancy and the rigours of radiation treatment. As yet, health behaviour interventions designed to maintain or improve nutrition in patients with HNC have not been evaluated. The proposed trial builds on promising pilot data, and evaluates the effectiveness of a dietitian-delivered health behaviour intervention to reduce malnutrition in patients with HNC undergoing radiotherapy: Eating As Treatment (EAT).Methods and analysisA stepped-wedge cluster randomised design will be used. All recruitment hospitals begin in the control condition providing treatment as usual. In a randomly generated order, oncology staff at each hospital will receive 2 days of training in EAT before switching to the intervention condition. Training will be supplemented by ongoing supervision, coaching and a 2-month booster training provided by the research team. EAT is based on established behaviour change counselling methods, including motivational interviewing, cognitive–behavioural therapy, and incorporates clinical practice change theory. It is designed to improve motivation to eat despite a range of barriers (pain, mucositis, nausea, reduced or no saliva, taste changes and appetite loss), and to provide patients with practical behaviour change strategies. EAT will be delivered by dietitians during their usual consultations. 400 patients with HNC (nasopharynx, hypopharynx, oropharynx, oral cavity or larynx), aged 18+, undergoing radiotherapy (>60 Gy) with curative intent, will be recruited from radiotherapy departments at 5 Australian sites. Assessments will be conducted at 4 time points (first and final week of radiotherapy, 4 and 12 weeks postradiotherapy). The primary outcome will be a nutritional status assessment.Ethics and disseminationEthics approval from all relevant bodies has been granted. Study findings will be disseminated widely through peer-reviewed publications and conference presentations.Trial registration numberACTRN12613000320752.
Evidence of Late Cretaceous oroclinal bending in north-central Anatolia: palaeomagnetic results from Mesozoic and Cenozoic rocks along the İzmir–Ankara–Erzincan Suture Zone
Authors: Cinku Mualla Cengiz , Hisarli Mumtaz , Hirt Ann M. , Heller Friedrich , Ustaömer Timur , Kaya Nurcan , Öksüm Erdinç , Orbay Naci 
Published: August 2015

Abstract

The Sakarya Zone and the Kırşehir Block of northern Turkey are separated by the İzmir–Ankara–Erzincan Suture (IAES) Zone which is the remnant of the northern branch of the Neotethys Ocean. During the closure of the IAES in the Late Cretaceous, northwards drift of the Kırşehir Block and its eventual indentation into the Sakarya Zone produced crustal deformation defined by thrusts and reverse faults, mainly between the indenting Kırşehir Block and the Sakarya Zone. Previous palaeomagnetic studies in the eastern part of the Pontides and the Sakarya Zone showed that palaeomagnetic declinations could record the deformation that resulted in the curvature of the IAES. In order to define the tectonic deformation of the northern part of the Kırşehir Block, we present new palaeomagnetic data from 57 different sites that include Mesozoic–Cenozoic sedimentary and volcanic rocks. The results from Late Cretaceous rocks (40 sites) indicate that large clockwise rotations of
c.
140–165° occurred in the eastern limb of the bend, while anticlockwise rotations progressively decreased from
c.
80° to 55° from SW to NW in the western limb of the bend. In contrast, small clockwise and anticlockwise rotations are observed in the flat-lying segment of the suture zone. These rotation patterns are consistent with the geometrical trends of the IAES in northern Turkey. Declinations of seven different Middle Eocene sites within the Kırşehir Block are rotated anticlockwise by
c.
30–10°. This indicates that the deformation in the Sakarya Zone and the Kırşehir Block continued in the Middle Eocene.
Structural setting and evolution of the Afghan orogenic segment – a review
Authors: Siehl Agemar 
Published: August 2015

Abstract
The actual state of knowledge concerning the tectonic evolution of the Afghan orogenic segment is summarized in the context of the neighbouring regions. The segment can be divided into: (1) the Late Palaeozoic North Afghan Variscan domain, which forms the southern margin of the Turan Plate; (2) the Early Cimmerian (Late Triassic–Early Jurassic) Palaeotethys suture zone of Middle Afghanistan, with the associated magmatic arc and back-arc rift extending from the Parapamisos and western Hindu Kush to the northern Pamir Mountains; (3) the Late Cimmerian (Late Jurassic–Early Cretaceous) domain of the Central Afghan Block mosaic with Gondwana-derived terranes; and (4) the Cenozoic-age Himalayan domain, which fringes the Cimmerian domain along the transpressive boundary of the Indian Plate in the east and the accretionary complex of the Makran subduction zone in the south. This current review of the scattered literature of a country where geological fieldwork effectively ceased 35 years ago is intended to bridge the gap between the better-known regions to the west in eastern Iran, and to the east in the Pamir–Punjab syntaxis.
Energy-Efficient All-Spin Cache Hierarchy Using Shift-Based Writes and Multilevel Storage
Authors: Venkatesan Rangharajan , Sharad Mrigank , Roy Kaushik , Raghunathan Anand 
Published: August 2015

Spintronic memories are considered to be promising candidates for future on-chip memories due to their high density, nonvolatility, and near-zero leakage. However, they also face challenges such as high write energy and latency and limited read speed due to single-ended sensing. Further, the conflicting requirements of read and write operations lead to stringent design constraints that severely compromises their benefits.
Recently, domain wall memory was proposed as a spintronic memory that has a potential for very high density by storing multiple bits in the domains of a ferromagnetic nanowire. While reliable operation of DWM memory with multiple domains faces many challenges, single-bit cells that utilize domain wall motion for writes have been experimentally demonstrated [Fukami et al. 2009]. This bit-cell, which we refer to as Domain Wall Memory with Shift-based Write (DWM-SW), achieves improved write efficiency and features decoupled read-write paths, enabling independent optimizations of read and write operations. However, these benefits are achieved at the cost of sacrificing the original goal of improved density. In this work, we explore multilevel storage as a new direction to enhance the density benefits of DWM-SW. At the device level, we propose a new device--multilevel DWM with shift-based write (ML-DWM-SW)--that is capable of storing 2 bits in a single device. At the circuit level, we propose a ML-DWM-SW based bit-cell design and layout. The ML-DWM-SW bit-cell incurs no additional area overhead compared to the DWM-SW bit-cell despite storing an additional bit, thereby achieving roughly twice the density. However, it requires a two-step write operation and has data-dependent read and write energies, which pose unique challenges. To address these issues, we propose suitable architectural optimizations: (i) intra-word interleaving and (ii) bit encoding. We design “all-spin” cache architectures using the proposed ML-DWM-SW bit-cell for both general purpose processors as well as general purpose graphics processing units (GPGPUs). We perform an iso-capacity replacement of SRAM with spintronic memories and study the energy and area benefits at iso-performance conditions. For general purpose processors, the ML-DWM-SW cache achieves 10X reduction in energy and 4.4X reduction in cache area compared to an SRAM cache and 2X and 1.7X reduction in energy and area, respectively, compared to an STT-MRAM cache. For GPGPUs, the ML-DWM-SW cache achieves 5.3X reduction in energy and 3.6X area reduction compared to SRAM and 3.5X energy reduction and 1.9X area reduction compared to STT-MRAM.
The Evolution of T-cell Therapies for Solid Malignancies
Authors: Fousek Kristen , Ahmed Nabil 
Published: August 2015

AbstractPrimary resistant, recurrent, and relapsed solid tumors are often nonresponsive to conventional antineoplastic therapies. Moreover, in responsive tumors, the therapeutic-to-toxic range of these interventions remains quite narrow, such that side effects of therapy are substantial. Targeted therapies, such as adoptive T-cell transfer, not only spare normal tissues but also use alternative killing mechanisms to which the tumor cells are usually not immune. Adoptive T-cell transfer for solid tumors faces unique challenges because of the inherent heterogeneity of tumor parenchyma, the complexity of the tumor microenvironment, and tumor occurrence in areas with limited therapeutic accessibility. In this review, we examine the recent evolution of various T-cell–based immunotherapeutics, the mechanisms of action behind their antitumor activity, their increasing complexity, and the prospect of building on previous successes in the treatment of solid tumors. Clin Cancer Res; 21(15); 3384–92. ©2015 AACR.
Preclinical Efficacy and Safety Assessment of an Antibody–Drug Conjugate Targeting the c-RET Proto-Oncogene for Breast Carcinoma
Authors: Nguyen Minh , Miyakawa Shuichi , Kato Junichi , Mori Toshiyuki , Arai Toshimitsu , Armanini Mark , Gelmon Karen , Yerushalmi Rinat , Leung Samuel , Gao Dongxia , Landes Gregory , Haak-Frendscho Mary , Elias Kathleen , Simmons Andrew D. 
Published: August 2015

Abstract
Purpose: The RET proto-oncogene has been implicated in breast cancer, and the studies herein describe the preclinical and safety assessment of an anti-RET antibody–drug conjugate (ADC) being developed for the treatment of breast cancer.
Experimental Design: RET protein expression was analyzed in breast tumor samples using tissue microarrays. The fully human anti-RET antibody (Y078) was conjugated to the DM1 and DM4 derivatives of the potent cytotoxic agent maytansine using thioether and disulfide linkers, respectively. The resulting compounds, designated Y078-DM1 and Y078-DM4, were evaluated for antitumor activity using human breast cancer cell lines and established tumor xenograft models. A single-dose, 28-day, safety study of Y078-DM1 was performed in cynomolgus monkeys.
Results: By immunohistochemistry, RET expression was detected in 57% of tumors (1,596 of 2,800 tumor sections) and was most common in HER2-positive and basal breast cancer subtypes. Potent in vitro cytotoxicity was achieved in human breast cancer cell lines that have expression levels comparable with those observed in breast cancer tissue samples. Dose-response studies in xenograft models demonstrated antitumor activity with both weekly and every-3-weeks dosing regimens. In cynomolgus monkeys, a single injection of Y078-DM1 demonstrated dose-dependent, reversible drug-mediated alterations in blood chemistry with evidence of on-target neuropathy.
Conclusions: RET is broadly expressed in breast cancer specimens and thus represents a potential therapeutic target; Y078-DM1 and Y078-DM4 demonstrated antitumor activity in preclinical models. Optimization of the dosing schedule or an alternate cytotoxic agent with a different mechanism of action may reduce the potential risk of neuropathy. Clin Cancer Res; 21(24); 5552–62. ©2015 AACR.