bluuebunny/crossref_metadata_2025 huggingface dataset:
Granzyme B is an essential mediator in CD8+ T cell killing ofTheileria parva-infected cells
Authors: Yang Jie , Pemberton Alan , Morrison W. Ivan , Connelley Tim
Published: May 2018

There is established evidence that cytotoxic CD8+ T cells are important mediators of immunity against the bovine intracellular protozoan parasiteT. parva.However, the mechanism by which the specific CD8+ T cells kill parasitized cells is not understood. Although the predominant pathway used by human and murine CD8+ T cells to kill pathogen-infected cells is granule exocytosis, involving release of perforin and granzyme B, there is to date a lack of published information on the biological activities of bovine granzyme B. The present study set out to define the functional activities of bovine granzyme B and determine its role in mediating killing ofT. parva-parasitized cells. DNA constructs encoding functional and non-functional forms of bovine granzyme B were produced and the proteins expressed in Cos-7 cells were used to establish an enzymatic assay to detect and quantify expression of functional granzyme B protein. Using this assay, the levels of killing of differentT. parva-specific CD8+ T cell clones were found to be significantly correlated with levels of granzyme B protein, but not mRNA transcript, expression. Experiments using inhibitors specific for perforin and granzyme B confirmed that CD8+ T cell killing of parasitized cells is dependent on granule exocytosis and specifically granzyme B. Further studies showed that granzyme B-mediated death of parasitized cells is independent of caspases, but involves activation of the pro-apoptotic molecule Bid.
Crystal structure and Hirshfield surface analysis of 4-phenyl-3-(thiophen-3-ylmethyl)-1H-1,2,4-triazole-5(4H)-thione
Authors: Vu Quoc Trung , Nguyen Ngoc Linh , Do Ba Dai , Pham Chien Thang , Nguyen Huy Hung , Van Meervelt Luc
Published: May 2018

In the title compound, C13H11N3S2, the phenyl ring is twisted from the 1,2,4-triazole plane by 63.35 (9)° and by 47.35 (9)° from the thiophene plane. In the crystal, chains of molecules running along the c-axis direction are formed by N—H...S interactions [graph-set motif C(4)]. The 1,2,4-triazole and phenyl rings are involved in π–π stacking interactions [centroid–centroid distance = 3.4553 (10) Å]. The thiophene ring is involved in C—H...S and C—H...π interactions. The intermolecular interactions in the crystal packing were further analysed using Hirshfield surface analysis, which indicates that the most significant contacts are H...H (35.8%), followed by S...H/H...S (26.7%) and C...H/H...C (18.2%).
Made in Vietnam
Authors: Phung Minh Thu Thuy , Knoben Joris , Vermeulen Patrick , Tran Dat Tho
Published: May 2018

Purpose

The purpose of this paper is to simultaneously test the association between three different sources of knowledge (internal, collaborative and regional) and innovation. This study aims to expand the insights by assessing these associations in the context of a rapidly developing and liberalizing economy; Vietnam. By conducting this study with Vietnamese data, the authors can assess whether the association between different sources of knowledge and innovation shows systematic differences to those in advanced economies.

Design/methodology/approach

In this study, the authors utilize data from two main sources: The World Bank Enterprise Survey and the Innovation Capabilities Survey. These firm-level surveys comprise non-agricultural formal and private sector firms. For Vietnam, 300 manufacturing firms have been included in the sample. The authors use a series of binary logistic regression models to analyze the data.

Findings

The analyses reveal that internal R&D has a strong positive association with product innovation. In contrast to findings in Western economies, not all kinds of collaborative knowledge sources have a significant association with innovation. Only collaborative knowledge gained from inside the supply chain is positively related to product innovation. Unexpectedly, negative effects from using too much external knowledge were also found.

Research limitations/implications

Due to the cross-sectional nature of the data causality could not be inferred from the study. Moreover, a relatively large number of the measures were dichotomous due the large number of missing observations for more detailed measurements of the variables.

Practical implications

When developing their innovation strategy firms in developing countries should take into account that collaborating with partners useful, but only if they collaborate within the supply chain. As such, firms should increase their interaction with suppliers and customers and put their efforts on the development of customized solutions for them.

Social implications

The Vietnamese Government could implement policies that help to enhance the quality of universities and research institutes. In most developed countries, universities and research institutes are vital sources of knowledge for innovation whereas they are not in Vietnam.

Originality/value

This paper contributes to the growing body of literature on firm-level innovation in developing countries. It identifies several core differences between the drivers of innovation in developed and developing contexts. Surprisingly, a feature that was expected to differ, the negative effect of over-search of external knowledge on innovation, was also found in Vietnam.
Ten commandments of Lean Six Sigma: a practitioners’ perspective
Authors: Antony Jiju , Gupta Sandeep , Sunder M. Vijaya , Gijo E.V.
Published: May 2018

Purpose

The purpose of this paper is to provide lean and six sigma professionals and researchers of tomorrow with Ten Commandments of Lean Six Sigma (LSS).

Design/methodology/approach

The Ten Commandments of LSS are based on several years’ experience of four authors who act as researchers, LSS Master Black Belts, consultants, practitioners and trainers on various topics of Lean, Six Sigma and general quality management and continuous improvement.

Findings

The Ten Commandments in our opinion include: alignment of LSS initiative with organisational strategy, LSS project selection and prioritisation, selection of top talent for the project execution, leadership for LSS, effective training and design of appropriate curriculum for different LSS roles, development of reward and recognition system, LSS sustainability, Linking LSS with Organisational Learning and Innovation, Linking LSS with Environmental Management System Standards and finally LSS and Big Data.

Research limitations/implications

The key features outlined in this paper are based on the practitioners of LSS. The authors of this article are planning to pursue a global study to critically evaluate these commandments by various practitioners of LSS.

Originality/value

The senior managers and executives of various businesses can use these commandments of LSS as a guide to achieve and sustain competitive advantage.
The teaching of information communication in Namibian schools
Authors: Wilfred Chanakira Tonderayi
Published: May 2018

Purpose

The study is a survey covering the Ohangwena, Khomas and Otjozondjupa regions highlighting developments in the teaching of information literacy in Namibian schools through the subject Basic Information Science (BIS). This paper aims to provide an update on previous related studies which have been conducted in Namibia led by Nengomasha et al. (2012), Namibia Library Council (NLIC) Report (2007) and Smith et al.’s Baseline Study (2008).

Design/methodology/approach

The main objective of this study is to find reasons for non-compliance in the effective teaching of BIS in Namibian schools focus sing on the three regions. The data collection methods were questionnaires and focus group discussions.

Findings

A major finding from the study is that 80 per cent school principals are supporting the teaching of the subject BIS in the Ohangwena region, while 20 per cent are non-compliant in the teaching of BIS. The compliance levels in the Otjozondjupa region is that 75 per cent school principals support the teaching of BIS whilst 25 per cent school principals are non-compliant. In total, 60 teachers were randomly sampled in the Otjozondjupa region, while 75 school principals out of a population of 157 were also randomly sampled in the Ohangwena region. In the Khomas (100) region, 52 school principals were randomly sampled out of a population of a 108. The study recommends that it is critical for school principals in Namibia to fully support the development of young learners to be critical thinkers for lifelong learning challenges through the teaching of information literacy.

Originality/value

This study is original.
Exploring the dual-role of cognitive heuristics and the moderating effect of gender in microblog information credibility evaluation
Authors: Yin Chunxiao , Sun Yongqiang , Fang Yulin , Lim Kai
Published: May 2018

Purpose

Although microblogs have become an important information source, the credibility of their postings is still a critical concern due to the open and unregulated nature. To understand the antecedents of microblog information credibility, the purpose of this paper is to investigate the dual-role of cognitive heuristics (i.e. the additivity and bias roles) and the effect of gender differences.

Design/methodology/approach

This study collected data via an online field survey of active microblog users, and a total of 204 valid responses was received.

Findings

This study demonstrates the dual-role of source credibility and vividness, the additivity role of microblog platform credibility, and the bias role of social endorsement. Furthermore, this study also found out gender difference that the additivity role of cognitive heuristics was stronger for men while bias role was stronger for women.

Research limitations/implications

This research enriches the microblog literature by examining the cognitive heuristic determinants as key predictors of microblog information credibility, and contributes to the information credibility literature by identifying and analyzing the dual-role effect of cognitive heuristics and corresponding gender differences.

Practical implications

This study can help organizations better manage their reputation, especially during the reputation crises, and also serves as a reminder to microblog platform operators of the importance of their microblog platform credibility.

Social implications

This study can help organizations better manage their reputation, especially during the reputation crises, and serves as a reminder to the microblog platform operators of the importance of their microblog platform credibility.

Originality/value

This study investigates the dual-role effect of cognitive heuristics (i.e. the additivity role and bias role) and corresponding gender differences that are less touched on before, and thus provides a more nuanced understanding of the more complex effects of cognitive heuristics.
Exploring effective work unit knowledge management (KM): roles of network, task, and KM strategies
Authors: Song Seokwoo , Sun Jonghak
Published: May 2018

Purpose

This paper aims to explore the potential contribution of inter-unit network structure and intra-unit task environment to the overall knowledge management (KM) effectiveness of an organization through different KM strategies.

Design/methodology/approach

The survey method was used to empirically test the hypotheses. The authors administered two survey forms: a member-survey form that obtained responses from members of each work unit and a leader-survey form issued only to the leader of each unit to obtain his/her perception on inter-unit communications.

Findings

The findings indicate that both a unit’s boundary-spanning role and its extensive interaction with other units help promote the unit’s overall KM effectiveness. In addition, the authors found that task variety was significantly related to the use of both personalization and codification of KM strategies in the unit, and that a unit’s KM strategy played a mediating role between intra-unit task characteristics and KM effectiveness.

Originality/value

Few studies have attempted to address what makes some work units within an organization more effective in their use of knowledge than others. This study provides an understanding of the influence of inter-unit social network structure on KM effectiveness, as well as the influence of intra-unit task environment and KM strategies on KM effectiveness. The findings suggest that inter-unit knowledge exchange and a unit’s brokering role can be a vital component of a work unit’s KM strategy, and that for successful KM in a work unit, an organization should not only establish appropriate inter-unit relationship but also develop the unit’s own KM strategies.
Hospital unit understaffing and missed treatments: primary evidence
Authors: Metcalf Ashley Y. , Wang Yong , Habermann Marco
Published: May 2018

Purpose

Hospitals throughout the USA are facing increasing patient demand and employee shortages. This capacity issue has led to understaffing in some hospital areas. The purpose of this paper is to examine the understaffing in hospital-unit respiratory care and the impact to error rates, specifically missed treatments rates. The moderating effects of teamwork and standardized, integrated information systems are also considered.

Design/methodology/approach

Survey methodology is used for data collection of respiratory care managers within hospital units. Regression is used to test the hypotheses in this study.

Findings

The regression results show that higher rates of understaffing are associated with more missed treatments. In addition, both teamwork and integrated information systems are associated with lower missed treatments. Finally, the moderating effect of teamwork is also highly significant within the model while integrated information systems are not a significant moderator.

Practical implications

Managers working within understaffed hospital units can try to reduce missed treatment rates by both integrated information systems and teamwork among employees. Additional benefits can be gained from teamwork due to the indirect effects (moderating effects) as well. This indicates teamwork training can be useful for quality initiatives.

Originality/value

Understaffing is associated with higher missed treatments in hospital units. Standardized, integrated information systems within a hospital are associated with less missed treatments. Furthermore, employee teamwork within a hospital unit is associated with a direct effect on missed treatment rates as well as an indirect effect by weakening the negative impact of understaffing.
Strategic orientation for failure recovery and performance behavior
Authors: Ladeira Wagner Junior , de Oliveira Santini Fernando , da Costa Janaína Raquel Andrade , Ribeiro Lucas Endrigo Severo
Published: May 2018

Purpose

The purpose of this paper is to analyze the moderating effect of salesperson environmental and goal orientation on the relationship between strategic orientation for failure recovery and performance behavior.

Design/methodology/approach

In total, 287 usable samples were collected from surveying sales representatives. The data were analyzed using structural equation modeling.

Findings

The results indicated that the recovery strategy has a positive and significant impact on performance behavior. However, this relationship can be influenced by high levels of competitiveness to generate a smaller commitment in the sales team in behavioral performance and by the fact that salespeople who have a high learning goal orientation ascribed stronger relationships between the recovery strategy and performance goal.

Originality/value

Academically, this research has several purposes. In the sales area, the authors analyze the strategic orientation for failure recovery. The authors believe that this approach is necessary to improve the scientific quality of the studies in the sales area.
Optimization of mixed aonla-guava fruit bar using response surface methodology
Authors: Mahawar Manoj Kumar , Jalgaonkar Kirti , Bibwe Bhushan , Kulkarni Tushar , Bhushan Bharat , Meena Vijay Singh
Published: May 2018

Purpose

This paper aims to optimize the quantum of aonla pulp that could be mixed with guava pulp to make a nutritional rich fruit bar. The developed fruit bar will not only help in the improvement of processing value of both Guava and underused but highly nutritional Aonla but also serve the purpose of improvement in nutritional status of consumers.

Design/methodology/approach

Response surface methodology (RSM) using Box–Behnken design was used with the process variables as aonla and guava pulp ratio, PR (30:70, 40:60, 50:50); pectin concentration, PC (0, 0.15, 0.30%); and drying temperature, DT (50, 60, 70°C) for optimization of process conditions. The prepared mixed fruit leather was evaluated for physico-chemical, textural and sensory properties such as titratable acidity (TA), ascorbic acid content (AA), L value (lightness), cutting force (CF), taste and overall acceptability (OAA).

Findings

Second-order regression models fitted for TA, AA, L value (lightness), CF, taste and OAA were highly significant (P = 0.01) with the coefficient of determination (R2 = 0.85). The TA and AA of mixed fruit bar increased whereas L value, CF, taste and OAA decreased with increasing level of aonla pulp in the blend formulation. The optimum process conditions for mixed aonla-guava bar with desirable characteristics were 40:60 (PR), 0.02% (PC) and 56°C (DT). The corresponding optimum values of TA, AA, L value, CF, taste and OAA were 1.00%, 164 mg/100 g, 50, 5066 g, 7.83 and 7.92, respectively. The design formulation and data analysis using RSM validated the optimum solution.

Originality/value

This paper demonstrates that optimum blending of aonla and guava pulp has improved the overall nutritional characteristics and acceptability of the final product. This will not only help in reducing the associated post-harvest losses but also encourage the cultivators/local processing industries by stabilizing the price during glut sea.
Medical records management framework to support public healthcare services in Limpopo province of South Africa
Authors: Marutha Ngoako Solomon , Ngoepe Mpho
Published: May 2018

Purpose

This study aims to develop a framework for the management of medical records in support of health-care service delivery in the hospitals in the Limpopo province of South Africa.

Design/methodology/approach

The study was predominantly quantitative and has used the questionnaires, system analysis, document analysis and observation to collect data in 40 hospitals of Limpopo province. The sample of 49 per cent (306) records management officials were drawn out of 622 (100 per cent) total population. The response rate was 71 per cent (217) out of the entire sample.

Findings

The study discovered that a framework for management of medical records in the public hospitals is not in place because of several reasons and further demonstrates that public health-care institutions need an integrative framework for the proper management of medical records of all forms and in all media.

Originality/value

The study develops and suggests a framework to embed medical records management into the health-care service delivery workflow for effective records management and ease of access. It is hoped that such a framework will help hospitals in South Africa and elsewhere to improve their medical records management to support health-care service provision.
What does it take to stress a word? Digital manipulation of stress markers in ataxic dysarthria
Authors: Lowit Anja , Ijitona Tolulope , Kuschmann Anja , Corson Stephen , Soraghan John
Published: May 2018

Background

Stress production is important for effective communication, but this skill is frequently impaired in people with motor speech disorders. The literature reports successful treatment of these deficits in this population, thus highlighting the therapeutic potential of this area. However, no specific guidance is currently available to clinicians about whether any of the stress markers are more effective than others, to what degree they have to be manipulated, and whether strategies need to differ according to the underlying symptoms.

Aims

In order to provide detailed information on how stress production problems can be addressed, the study investigated (1) the minimum amount of change in a single stress marker necessary to achieve significant improvement in stress target identification; and (2) whether stress can be signalled more effectively with a combination of stress markers.

Methods & Procedures

Data were sourced from a sentence stress task performed by 10 speakers with ataxic dysarthria and 10 healthy matched control participants. Fifteen utterances perceived as having incorrect stress patterns (no stress, all words stressed or inappropriate word stressed) were selected and digitally manipulated in a stepwise fashion based on typical speaker performance. Manipulations were performed on F0, intensity and duration, either in isolation or in combination with each other. In addition, pitch contours were modified for some utterances. A total of 50 naïve listeners scored which word they perceived as being stressed.

Outcomes & Results

Results showed that increases in duration and intensity at levels smaller than produced by the control participants resulted in significant improvements in listener accuracy. The effectiveness of F0 increases depended on the underlying error pattern. Overall intensity showed the most stable effects. Modifications of the pitch contour also resulted in significant improvements, but not to the same degree as amplification. Integration of two or more stress markers did not result in better results than manipulation of individual stress markers, unless they were combined with pitch contour modifications.

Conclusions & Implications

The results highlight the potential for improvement of stress production in speakers with motor speech disorders. The fact that individual parameter manipulation is as effective as combining them will facilitate the therapeutic process considerably, as will the result that amplification at lower levels than seen in typical speakers is sufficient. The difference in results across utterance sets highlights the need to investigate the underlying error pattern in order to select the most effective compensatory strategy for clients.
A review of test protocols for the evaluation of teat disinfectants
Authors: Fitzpatrick Sarah , Garvey Mary , Gleeson David
Published: May 2018

The prevention of mastitis is the most important part of a mastitis control programme. Postmilking disinfection is considered the most effective procedure for preventing new intramammary infections in dairy herds. This article reviews the different protocols used to evaluate the efficacy of teat disinfectant products. These protocols include experimental challenge, natural exposure and excised teat, along with agar diffusion assays and teat swabbing. The experimental designs, limitations, positive and negative aspects of each protocol were compared and discussed throughout this article.
On the Opportunity Cost of Crop Diversification
Authors: Ang Frederic , Mortimer Simon M. , Areal Francisco J. , Tiffin Richard
Published: May 2018

Distance functions are increasingly being augmented, with environmental goods treated as conventional outputs. A common approach to evaluate the opportunity cost of providing an environmental good is the exploitation of the distance function's dual relationship to the value function. This implies that the opportunity cost is assumed to be non‐negative. This approach also requires a convex technology set. Focusing on crop diversification for a balanced sample of 44 cereal farms in the East of England for the years 2007–2013, this paper develops a novel opportunity cost measure that does not depend on these strong assumptions. We find that the opportunity cost of crop diversification is negative for most farms.
Evaluation of HOXC8 in crested Swiss chicken
Authors: Joller S. , Ammann P. , Flury C. , Drögemüller C.
Published: May 2018

The crest in chicken consists of elongated and upraised feathers, as seen in various breeds such as the Silkie chicken. Recently, the still unknown causative mutation for the crest phenotype was assigned to chromosome 33 and an ectopic expression of HOXC8 was shown. The aim this study was to evaluate whether the crest phenotype in a local Swiss chicken breed, the Appenzeller Spitzhaubenhuhn, is associated with HOXC8. Three previously reported crest‐associated flanking markers at the HOXC8 locus were genotyped in cohorts of this breed and two other local breeds without the crest phenotype. For the Appenzeller Spitzhaubenhuhn chicken showing the crest phenotype, no clear association of the reported markers could be revealed. Furthermore, the two exons of HOXC8 were sequenced in crested chicken of the Appenzeller Spitzhaubenhuhn and Silkie breeds and revealed no evidence of polymorphisms within the coding region of HOXC8. Therefore, the molecular genetic etiology for the crest phenotype in the investigated breeds remains unclear.
Dipeptidyl peptidase‐4 inhibitor use is associated with decreased risk of fracture in patients with type 2 diabetes: a population‐based cohort study
Authors: Hou Wen‐Hsuan , Chang Kai‐Cheng , Li Chung‐Yi , Ou Huang‐Tz
Published: May 2018

Aims

The aim of this study was to investigate the putative link between dipeptidyl peptidase‐4 inhibitor (DPP‐4i) use and the risk of fracture in patients with type 2 diabetes.

Methods

This propensity‐score‐matched population‐based cohort study was performed between 2009 and 2013 on patients with type 2 diabetes who were stable metformin users. A total of 3996 patients with type 2 diabetes used DPP‐4i as a second‐line antidiabetic drug. The same number of matched non‐DPP‐4i users were followed up until fracture occurrence, health insurance policy termination, or the end of 2013. The incidence rates of overall and cause‐specific fractures were estimated based on the Poisson assumption. A multiple Cox proportional hazard model was used to estimate the covariate‐adjusted hazard ratio (HR) and 95% confidence interval (CI) to determine the association between DPP‐4i use and overall and cause‐specific fractures stratified by age and sex.

Results

Over a maximum follow‐up period of 5 years, 340 DPP‐4i users and 419 non‐DPP‐4i users were newly diagnosed with fractures, yielding incidence rates of 28.03 and 32.04 per 1000 people per year, respectively. The Cox proportional hazard model revealed that DPP‐4i use significantly reduced the risk of all‐cause fractures and upper extremity fractures, with adjusted HRs of 0.86 (95% CI: 0.74–0.99) and 0.75 (95% CI: 0.59–0.95), respectively. The aforementioned associations of DDP‐4i use with fracture were sustained across sex and age stratifications.

Conclusions

The results of this study supported the premise that DPP‐4i usage is associated with a reduced risk of all‐cause fractures and upper extremity fractures in patients with type 2 diabetes.
Patient involvement is essential in identifying drug‐related problems
Authors: Kari Heini , Kortejärvi Hanna , Airaksinen Marja , Laaksonen Raisa
Published: May 2018

Aims

The aim of this study is to evaluate how critical patient involvement is in pharmacist‐led clinical medication reviews and in identifying the most significant clinical drug‐related problems (DRPs).

Methods

Pharmacist‐led clinical medication reviews were conducted with 161 consenting patients aged ≥75 years with at least seven prescribed medicines, living independently at home in Finland. A pharmacist, a nurse and a physician evaluated the clinical significance of the DRPs identified during the patient interview at an interprofessional case conference. It was evaluated whether the most significant clinical DRPs could also have been identified through reviewing the medication list only or the medication list and certain patient details.

Results

Altogether, the 111 most significant clinical DRPs were evaluated. Only 6% could have been identified through reviewing the medication list only, and 16% through reviewing the medication list and certain patient details. Hence, 84% of the most significant clinical DRPs could only have been identified with patient involvement. The most common DRPs were: poor therapy control (25%); nonoptimal drug (22%); intentional nonadherence (12%); and additional drug needed (11%). patient involvement was critical when identifying DRPs related to additional drug needed, unintentional nonadherence, use of over‐the‐counter medicines or dietary supplements, or contradictions in counselling.

Conclusion

Patient involvement is essential when identifying clinical DRPs. Indeed, poor therapy control, nonoptimal drug use, intentional or unintentional nonadherence might otherwise be missed.
Expression of ribosomal and actin network proteins and immunochemotherapy resistance in diffuse large B cell lymphoma patients
Authors: Bram Ednersson Susanne , Stenson Martin , Stern Mimmie , Enblad Gunilla , Fagman Henrik , Nilsson‐Ehle Herman , Hasselblom Sverker , Andersson Per‐Ola
Published: May 2018

Diffuse large B cell lymphoma (DLBCL) patients with early relapse or refractory disease have a very poor outcome. Immunochemotherapy resistance will probably, also in the era of targeted drugs, remain the major cause of treatment failure. We used proteomic mass spectrometry to analyse the global protein expression of micro‐dissected formalin‐fixed paraffin‐embedded tumour tissues from 97 DLBCL patients: 44 with primary refractory disease or relapse within 1 year from diagnosis (REF/REL), and 53 who were progression‐free more than 5 years after diagnosis (CURED). We identified 2127 proteins: 442 were found in all patients and 102 were differentially expressed. Sixty‐five proteins were overexpressed in REF/REL patients, of which 46 were ribosomal proteins (RPs) compared with 2 of the 37 overexpressed proteins in CURED patients (P = 7·6 × 10−10). Twenty of 37 overexpressed proteins in CURED patients were associated with actin regulation, compared with 1 of 65 in REF/REL patients (P = 1·4 × 10−9). Immunohistochemical staining showed higher expression of RPS5 and RPL17 in REF/REL patients while MARCKS‐like protein, belonging to the actin network, was more highly expressed in CURED patients. Even though functional studies aimed at individual proteins and protein interactions to evaluate potential clinical effect are needed, our findings suggest new mechanisms behind immunochemotherapy resistance in DLBCL.
MEK1/2 inhibition by binimetinib is effective as a single agent and potentiates the actions of Venetoclax and ABT‐737 under conditions that mimic the chronic lymphocytic leukaemia (CLL) tumour microenvironment
Authors: Crassini Kyle , Shen Yandong , Stevenson William S. , Christopherson Richard , Ward Chris , Mulligan Stephen P. , Best O. Giles
Published: May 2018

The survival and proliferation of chronic lymphocytic leukaemia (CLL) cells is driven by multiple signalling pathways, including those mediated by the B cell, Toll‐like and chemokine receptors. Many of these pathways converge on the same signalling molecules, including those involved in the Raf‐1/MEK/Erk1/2‐MAPK pathway. We investigated the effects of the MEK1/2 (also termed MAP2K1/2) inhibitor, binimetinib, against CLL cells cultured under conditions that mimic aspects of the tumour microenvironment. Binimetinib blocked CLL cell survival induced by stroma‐conditioned media and phorbol myristylate (PMA). Binimetinib was also significantly more toxic towards CLL cells cultured in the presence of either anti‐IgM antibody or stroma‐derived factor‐1α (SDF‐1α) and reduced CLL cell cycle progression and proliferation. Furthermore, binimetinib significantly increased the sensitivity of CLL cells co‐cultured with CD40 ligand (CD40L)‐expressing fibroblasts to the BH3‐mimetics ABT‐737 and Venetoclax (ABT‐199) via a mechanism involving down‐regulation of Mcl‐1 (MCL1) activity and Bim (BCL2L11) and Bcl‐xL (BCL2L1) expression. Collectively, these data suggest that binimetinib may have both cytotoxic and cytostatic effects on CLL cells by blocking microenvironment‐derived signals known to drive survival and proliferation. The combination of binimetinib with a BH3 mimetic may be an effective treatment strategy for CLL, particularly against the proliferative fraction of the disease within the tumour microenvironment.
Central adenosine A1 receptors inhibit cough via suppression of excitatory glutamatergic and tachykininergic neurotransmission
Authors: El‐Hashim Ahmed Z , Mathews Seena , Al‐Shamlan Fajer
Published: May 2018

Background and Purpose

The adenosine A1 receptor is reported to mediate several excitatory effects in the airways and has inhibitory effects in the CNS. In this study, we investigated the role of peripheral and central A1 receptors in regulating cough and airway obstruction.

Experimental Approach

Drugs were administered to guinea pigs via inhalation or i.c.v. infusion. Following the administration of different drugs, cough was induced by exposing guinea pigs to aerosolized 0.4 M citric acid. An automated analyser recorded both cough and airway obstruction simultaneously using whole‐body plethysmography.

Key Results

The A1 receptor agonist, cyclopentyladenosine (CPA, administered by inhalation), dose‐dependently inhibited cough and also inhibited airway obstruction. Similarly, CPA, administered i.c.v., inhibited both the citric acid‐induced cough and airway obstruction; this was prevented by pretreatment with the A1 receptor antagonist DPCPX (i.c.v.). Treatment with DPCPX alone dose‐dependently enhanced the citric acid‐induced cough and airway obstruction. This effect was reversed following treatment with either the glutamate GluN1 receptor antagonist D‐AP5 or the neurokinin NK1 receptor antagonist FK‐888.

Conclusions and Implications

These findings suggest that activation of either peripheral or central adenosine A1 receptors inhibits citric acid‐induced cough and airway obstruction. The data also suggest that tonic activation of central adenosine A1 receptors serves as a negative regulator of cough and airway obstruction, secondary to inhibition of excitatory glutamatergic and tachykininergic neurotransmission.
Early increase of neutrophil‐to‐lymphocyte ratio predicts 30‐day mortality in patients with spontaneous intracerebral hemorrhage
Authors: Wang Fei , Xu Feng , Quan Ye , Wang Li , Xia Jian‐Jun , Jiang Ting‐Ting , Shen Li‐Juan , Kang Wen‐Hui , Ding Yong , Mei Li‐Xia , Ju Xue‐Feng , Hu Shan‐You , Wu Xiao
Published: May 2018

Aims

To examine whether early rise of neutrophil‐to‐lymphocyte ratio (NLR) after patient hospitalization correlates with 30‐day mortality in patients with spontaneous intracerebral hemorrhage (ICH).

Methods

This retrospective study included all patients receiving treatment for spontaneous ICH between January 2015 and September 2016 at the Jiading District Central Hospital Affiliated Shanghai University of Medicine & Health Sciences in Shanghai, China. NLR was determined at admission (T1), at 24‐48 hours (T2) and 5‐7 days (T3). NLR and clinicopathologic features were compared between those who survived for >30 days vs not. Multivariate regression was used to identify risk factors for 30‐day mortality.

Results

A total of 275 subjects were included in the analysis: 235 survived for at least 30 days; the remaining 40 subjects died within 30 days. The patients who died within 30 days had higher ICH score, larger ICH volume, and lower GCS score (all P < 0.05). In comparison with the baseline (NLRT1), NLR at 24‐48 hours (NLRT2) and 5‐7 days (NLRT3) was significantly higher in patients who died within 30 days (P < 0.05), but not in patients surviving for >30 days. In the multivariate analysis, the 30‐day mortality was associated with both NLRT2 (OR 1.112, 95%CI 1.032‐1.199, P = 0.006) and NLRT3 (OR 1.163, 95%CI 1.067‐1.268, P = 0.001). Spearman correlation analysis showed that both NLRT2 and NLRT3 correlated inversely with GCS score and positively with ICH score and ICH volume at the baseline.

Conclusions

Early rise of NLR predicts 30‐day mortality in patients with spontaneous ICH.
Using consumer preferences to characterize the trade of wild‐collected ornamental orchids in China
Authors: Williams Sophie J. , Gale Stephan W. , Hinsley Amy , Gao Jiangyun , St. John Freya A. V.
Published: May 2018

Overexploitation of wildlife for trade threatens taxa globally. Interest in demand‐side approaches to address this problem has grown but understanding of how consumer preferences shape demand remains limited. To quantify the role of consumer preferences for wild orchids in China's horticultural market, we used conjoint analysis to determine which attributes are preferred by orchid owners and nonowners in two socioeconomically contrasting areas of South China. Across all respondents, price was the most important attribute followed by flower color. While Xishuangbanna participants exhibited a slight preference for wild over cultivated plants, origin (wild/cultivated) was of minimal importance. We also measured awareness of orchid import regulations. Most did not recognize the CITES logo, and knowledge of import laws was significantly lower in Hong Kong than in Xishuangbanna. Our findings suggest that trade in wild ornamental orchids in South China is supply‐driven, and strengthened regulations might be effective in reducing overexploitation.
Pancreas transplantation using compatible but non‐identical ABO blood group donors
Authors: Nagaraju Santosh , Mangus Richard S. , Powelson John A. , Fridell Jonathan A.
Published: May 2018

Background

There are limited data on the outcomes of pancreas transplants using ABO non‐identical but compatible (NIC) donors.

Methods

A review of all pancreas transplants from a single institution from 01/2003 to 07/2016 (n = 606) revealed 41 recipients of a NIC donor pancreas which were matched for age, race, gender, year, and type of transplant with 41 ABO identical cases. Groups were compared for allograft survival, incidence of acute cellular rejection (ACR), length of hospital stay, 3‐month readmissions and transfusion requirements. Serum haptoglobin and lactate dehydrogenase were used to identify hemolysis in patients requiring repeated transfusions without overt blood loss.

Results

The 1‐year graft survival was 100% and 88% in the study and control groups. In the study group, 6/41(14%) developed hemolysis, all of which were ABO O into A. All responded to donor blood type specific transfusions.

Discussion

There are limited data on outcomes of solid organ transplant using NIC donors with almost none specifically addressing pancreas transplantation. In this study, graft survival was similar but 14% developed hemolysis, which was transient and treated with transfusion of donor blood type specific blood.

Conclusion

Non‐identical but compatible pancreas transplants have similar graft survival compared to ABO identical. Hemolysis may occur so some caution is required.
Evaluation of current strategies for surveillance and management of donor‐specific antibodies: Single‐center study
Authors: Sullivan Daniel , Ahn Chul , Gao Ang , Lacelle Chantale , Torres Fernando , Bollineni Srinivas , Banga Amit , Mullins Jessica , Mohanka Manish , Ring Steve , Wait Michael , Peltz Matthias , Duddupudi Pavan , Surapaneni Dhiraj , Kaza Vaidehi
Published: May 2018

Background

Although the presence of donor‐specific antibodies (DSA) is known to impact lung allograft, limited data exist regarding DSA management.

Methods

We did a retrospective study at our center evaluating DSA management in adult lung transplant recipients undergoing lung transplantation between January 1, 2010 and June 30, 2014. Study follow‐up was completed through October 2017. All recipients were stratified into 2 groups based on the presence or absence of DSA. Those with DSA were evaluated for the impact of treatment of DSA. The primary outcomes were postlung transplant survival and freedom from bronchiolitis obliterans syndrome (BOS), subset of chronic lung allograft dysfunction (CLAD). Simon‐Makuch method was used to estimate overall survival and BOS‐free survival to account for DSA as time‐dependent covariate. Survival differences between the groups were analyzed using time‐dependent Cox proportional hazards model.

Results

Sixty‐four percent of 194 total subjects developed post‐lung transplant DSA. Overall survival was different with worse survival in the DSA positive group that never cleared DSA (P = .002). BOS‐free survival was lower, but did not reach significance in this group. Response to treatment was poor, with only 12 of 47 (25.5%) who received treatment demonstrating clearance of DSA.

Conclusions

Donor‐specific antibodies prevalence is high after lung transplantation. Clearance of DSA correlated with improved outcomes. Current therapeutic strategies against DSA are relatively ineffective. Multicenter collaborative studies will be required to evaluate current treatment strategies and other innovative modalities.
Comprehensive, Multimodal Characterization of an Imiquimod‐Induced Human Skin Inflammation Model for Drug Development
Authors: van der Kolk Tessa , Assil Salma , Rijneveld Rianne , Klaassen Erica S. , Feiss Gary , Florencia Edwin , Prens Errol P. , Burggraaf Jacobus , Moerland Matthijs , Rissmann Robert , van Doorn Martijn B.A.
Published: May 2018

Imiquimod (IMQ) is often used as a topical challenge agent to provoke local skin inflammation. The objective of this study was to develop and refine a rapid, temporary, and reversible human skin inflammation model with IMQ for application in clinical drug development. A randomized, vehicle‐controlled, open‐label, dose‐ranging study was conducted in 16 healthy male subjects. IMQ (5 mg) was applied once daily for 72 hours under occlusion to intact skin (n = 8) or tape stripped (TS) skin (n = 8). Although IMQ alone induced limited effects, TS+IMQ treatment showed larger responses in several domains, including erythema and perfusion (P < 0.0001), mRNA expression of inflammatory markers (P < 0.01), and inflammatory cell influx compared with vehicle. In conclusion, a rapid, human IMQ skin inflammation challenge model was successfully developed with a clear benefit of TS prior to IMQ application. Future interaction studies will enable proof‐of‐pharmacology of novel compounds targeting the innate immune system.
A comparison of different thicknesses of mouthguards according to the groove shape of sheets
Authors: Son Ho‐Jung , Sim Ji‐Young , Kim Ji‐Hwan , Kim Woong‐Chul
Published: May 2018

Background/aims

Previous studies have compared the thickness of the device with and without grooves. The result was a difference in thickness of the device along the groove. The aim of this study was to assess the differences in thickness of mouthguards that result from different groove shapes of ethylene vinyl acetate sheets used to make these appliances.

Materials and Method

Mouthguards were made using a 3‐dimensional printer, and produced by softening 4 mm transparent circular sheets. Four different shapes of sheets were evaluated: normal sheets, sheets with anterior V‐shaped grooves, sheets with anterior A‐shaped grooves, and sheets with posterior A‐shaped grooves. The groove was 3 mm deep and 5 mm wide. The thickness of the appliance was assessed with respect to the anterior incisal edge, labial surface, palatal surface, posterior cusp, buccal surface, and palatal surface. The Kruskal‐Wallis test was used to analyze differences in thickness among the different groove shapes.

Results

No significant difference was detected between the thickness of mouthguards made using sheets with grooves and that of mouthguards made using sheets without grooves (P > .05).

Conclusion

The presence of grooves on the sheets did not influence mouthguard thickness.
Treatment of haemoperitoneum secondary to ruptured granulosa cell tumours in two mares
Authors: Worsman F. C. F. , Barakzai S. Z. , de Bont M. P. , Turner S. , Rubio‐Martínez L. M.
Published: May 2018

This report describes two cases of successful surgical management of granulosa cell tumours (GCT) in mares presenting with haemoperitoneum (HP). Controlled abdominal drainage was initially attempted in Case 1 but was not successful. A ventral midline exploratory laparotomy allowed removal of a haemorrhaging 13 kg GCT. The mare made a full recovery and returned to normal work as a driving pony 11 months post‐operatively. In Case 2 controlled abdominal drainage was followed by standing left flank laparoscopic visualisation of the bleeding ovary and transection of the ovarian pedicle by electrocautery. The GCT was then removed via a ventral midline incision due to its large size. Haemoperitoneum can be associated with GCTs and in some cases is severe enough to prompt emergency treatment. Stabilisation of the patient and removal of the haemorrhaging GCT can lead to a successful outcome.
Phosphorylation alters Bim‐mediated Mcl‐1 stabilization and priming
Authors: Conage‐Pough Jason E. , Boise Lawrence H.
Published: May 2018

Mcl‐1 is a highly labile protein, subject to extensive post‐translational regulation. This distinguishes Mcl‐1 from other antiapoptotic proteins and necessitates further study to better understand how interactions with proapoptotic Bcl‐2 proteins affect its regulation. One such protein, Bim, is known to stabilize Mcl‐1, and Bim phosphorylation has been associated with increased Mcl‐1 binding. Consequently, we investigated the potential impact of Bim phosphorylation on Mcl‐1 stability. We found that Bim stabilizes and primes Mcl‐1 in RPCI‐WM1 cells and is constitutively phosphorylated. Additionally, introduction of several phospho‐mimetic and unphosphosphorylateable Bim mutations resulted in altered Mcl‐1 stability and distinct Bim binding to antiapoptotic proteins. These findings suggest Bim phosphorylation not only regulates Mcl‐1 stability but also is a potential mechanism for enforcing Mcl‐1 dependence.
Mannosylinositol phosphorylceramides and ergosterol coodinately maintain cell wall integrity in the yeast Saccharomyces cerevisiae
Authors: Tanaka Seiya , Tani Motohiro
Published: May 2018

In the yeast Saccharomyces cerevisiae, complex sphingolipids have three types of polar head group, and breakdown of their normal composition causes several cellular dysfunctions. Previously we found that loss of biosynthesis of mannosylinositol phosphorylceramide (MIPC) causes a defect in cell wall integrity (CWI). In this study, we screened for multicopy suppressor genes that rescue the defect in CWI in cells lacking MIPC synthases (Sur1 and Csh1), and found that the defect is partly suppressed by upregulation of ergosterol biosynthesis. In addition, repression of expression of ERG9, which encodes squalene synthase in the ergosterol biosynthesis pathway, in sur1∆ csh1∆ cells caused a strong growth defect and enhancement of the defect in CWI. The repression of ERG9 and/or the deletion of SUR1 and CSH1 caused an increase in the phosphorylated form of Slt2, a mitogen‐activated protein kinase activated through impairment of CWI. Moreover, the deletion of SLT2 or WSC1/2, encoding a sensor protein recognizing CWI, enhanced the growth defect in the ERG9‐repressed sur1∆ csh1∆ cells. On the other hand, the ERG9‐repressed sur1∆ csh1∆ cells also exhibited an increase in the cell wall chitin level in a Slt2‐ and Wsc1/2‐independent manner. These results suggested that MIPC and ergosterol are coordinately involved in maintenance of CWI, and the activation of Slt2 suppressed the CWI defect caused by these metabolic defects.