bluuebunny/crossref_metadata_2025 huggingface dataset:
The metalloproteinase inhibitor Prinomastat reduces AML growth, prevents stem cell loss and improves chemotherapy effectiveness
Authors: Pirillo Chiara , Haltalli Myriam , Anton Sara Gonzalez , Tini Valentina , Kong Isabella , Hawkins Edwin , Falini Brunangelo , Marra Andrea , Duarte Delfim , Celso Cristina Lo
Published: December 2020

Acute myeloid leukemia (AML) is a blood cancer of the myeloid lineage. Its prognosis remains poor, highlighting the need for new therapeutic and precision medicine approaches. AML symptoms often include cytopenias, linked to loss of healthy hematopoietic stem and progenitor cells (HSPCs). The mechanism behind HSPC decline is complex and still poorly understood. Here, intravital microscopy (IVM) of a well-established experimental model of AML allows direct observation of the interactions between healthy and malignant cells in the bone marrow (BM), suggesting that physical dislodgment of healthy cells by AML through damaged vasculature may play an important role. Numerous human leukemia types, particularly MLL-AF9 samples, show high expression levels of multiple matrix metalloproteinases (MMPs). Therefore, we evaluate the therapeutic potential of the MMP inhibitor (MMPI) prinomastat. IVM analyses of treated mice reveal reduced vascular permeability and healthy cell clusters in circulation, and lower AML cell speed. Furthermore, treated mice have decreased BM infiltration, increased retention of healthy HSPCs in the BM and increased survival following chemotherapy. Overall, our results suggest that MMPIs could be a promising complementary therapy to reduce AML growth and limit the loss of HSPC and BM vascular damage caused by MLL-AF9 and possibly other AML subtypes.
Primary school design: co-creation with children
Authors: Ghaziani Rokhshid
Published: November 2020

Purpose

The school environment affects children's health, emotions and learning. The good design of school buildings makes these places more pleasant and more functional. Children's views are important and need to be more effectively integrated in the school design project, especially after the pandemic as many schools had to re-design their spaces. However, there are challenges for academics, designers and policymakers in determining which methods are appropriate for listening to children's views and ensuring their effective participation. The study aims to evaluate the different ways in which children could get involved in designing schools, and to identify spatial design trends from the perspective of the children.

Design/methodology/approach

For this study, qualitative and quantitative research methods were used. Various data collection techniques were drawings, model making and questionnaires. The empirical study was undertaken by 120 children (8–10 years old), who designed three spaces in two Primary Schools in England.

Findings

This paper discusses the change in use of spaces for current and future (post-COVID) school design and the need for multi-purpose spaces that can flip form one to another. The findings highlight the importance of involving children in the school design process that could then inform the decision-making processes of architects and designers. The findings would have implications for school design practice, demonstrating how research can be embedded in primary schools to evaluate the quality of indoor and outdoor spaces.

Research limitations/implications

More research focusing on diverse spaces, various age groups and in different primary schools would provide reliable and age-appropriate guideline for future school design. It is recommended to gather children's and teachers' views related to the changes that primary schools in the UK have applied in response to the pandemic since June 2020 to assess the impact of social distancing in various indoor and outdoor spaces.

Originality/value

The study is a response to effective involvement of children in school design process as the main user. By identifying appropriate methods to gather children's views, the gap between academics, designers and policymakers can be bridged, especially for innovative post-COVID design of primary schools with radical changes. The study also highlights children's views for design of outdoor and indoor multi-functional spaces and suggests some post-pandemic design considerations to respond to children's preferences as well as their health and well-being.
Internet users beware, you follow online health rumors (more than counter-rumors) irrespective of risk propensity and prior endorsement
Authors: Pal Anjan , Banerjee Snehasish
Published: November 2020

Purpose

The Internet is a breeding ground for rumors. A way to tackle the problem involves the use of counter-rumor messages that refute rumors. This paper analyzes users' intention to follow rumors and counter-rumors as a function of two factors: individuals' risk propensity and messages' prior endorsement.

Design/methodology/approach

The paper conducted an online experiment. Complete responses from 134 participants were analyzed statistically.

Findings

Risk-seeking users were keener to follow counter-rumors compared with risk-averse ones. No difference was detected in terms of their intention to follow rumors. Users' intention to follow rumors always exceeded their intention to follow counter-rumors regardless of whether prior endorsement was low or high.

Research limitations/implications

This paper contributes to the scholarly understanding of people's behavioral responses when, unknowingly, exposed to rumors and counter-rumors on the Internet. Moreover, it dovetails the literature by examining how risk-averse and risk-seeking individuals differ in terms of intention to follow rumors and counter-rumors. It also shows how prior endorsement of such messages drives their likelihood to be followed.

Originality/value

The paper explores the hitherto elusive question: When users are unknowingly exposed to both a rumor and its counter-rumor, which entry is likely to be followed more than the other? It also takes into consideration the roles played by individuals' risk propensity and messages' prior endorsement.
Level of Maqāsid ul-Shari’āh’s in financial reporting standards for Islamic financial institutions
Authors: Mukhlisin Murniati
Published: November 2020

Purpose

This study aims to measure levels of Sharīʿah-compliance in Islamic financial institutions (IFIs) financial reporting standards with the objective to investigate the application of Maqāsid ul-Sharīʿah as a compliance measure reflected in the reporting standards.

Design/methodology/approach

This paper adopts Maqāsid ul-Sharīʿah’s model to measure levels of Sharīʿah-compliance amongst three available financial reporting frameworks and presentation standards; international financial reporting standards (IFRS), accounting and auditing organization for Islamic financial institutions (AAOIFI), Pernyataan Standar Akuntansi Keuangan (PSAK) Syariah. NVivo 10 software is used in this paper to help measure quantitatively the compliance level of each standard.

Findings

The findings suggest that the use of Maqāsid ul-Sharīʿah leads to a more complete understanding of how the meaning of Sharīʿah and its values can be integrated into the demands of financial reporting, and hence, offering greater convergence between ethics and accounting regulations amongst IFIs.

Originality/value

It documents different context of content analysis that takes examples of Islamic financial reporting studies and uses both classical and contemporary theoretical bases. The main outputs are designed for standard setters and policymakers with expectation for Sharīʿah objectives (i.e. Maqāsid ul-Sharīʿah), to be embedded in the preparation of financial reporting standards for the IFIs. Hence, they will be able to show their full accountability then gain better trust from the stakeholders.
Determinants and market performance of Fortune 100 best companies: evidence from Islamic perspective
Authors: Bhaskaran Rajesh Kumar , Ting Irene Wei Kiong , Azizan Noor Azlinna , Yelubolu Kranthi Vidhatha
Published: November 2020

Purpose

Islam is valid for every place and time, and it promotes fair and equitable employees’ relations as an essential corporate social responsibility (CSR) policy for successful organisations such as Fortune 100 companies. Whence, this study aims to explore Fortune 100 best companies exhibit better market performance and capitalisation relative to other companies in relation to their employees’ satisfaction as a significant contributor to better performance.

Design/methodology/approach

This study conducts two-stage robust least square regressions analyses on Fortune’s best a sample of Fortune companies list in 2017.

Findings

Tests of differences in mean indicate that Fortune listed companies have superior profitability, liquidity and firm size compared with the control sample data set. The regression results are also robust to the use of different measures of market performance, such as market capitalisation, price/earnings ratio and price/book ratio, as well as to the potential endogeneity problem. This study also reveals the top 10 employers with the highest number of employees with their number of times being ranked in Fortune best companies. The result is in line and compatible with the concept of CSR in Islam perspective which encompasses legal, economic, ethical and philanthropic responsibilities (Maruf, 2013). Islamic CSR promotes the behaviour of brotherhood and justice to balance employee rights and better coherence between self-interest and altruism. With that, satisfied employees contribute to firm performance.

Practical implications

Overall, this study extends the insight that satisfied employees may, in turn, mean better market performances for a company.

Originality/value

The findings corroborate human relations theories, as well as from the Islamic perspective, employee satisfaction results in greater market performances.
Cooperation and novelty innovation: a study for Argentina
Authors: Pasciaroni Carolina , Barbero Andrea
Published: November 2020

Purpose

This paper aims to analyse the influence of cooperation on the degree of novelty of technological innovations introduced by industrial firms in Argentina. This influence is analysed from three perspectives: cooperation by partner type [business partners or scientific and technological centres (S&T) partners]; cooperation by number of partner types, from no cooperation to cooperation with two partner types; and cooperation by goals pursued by firms.

Design/methodology/approach

The data come from one of the last national innovation surveys conducted in Argentina. The study controls for endogeneity, using instrumental variable procedures within the conditional mixed-process (CMP) framework.

Findings

The main result is the influence of cooperation with universities and S&T centres on the introduction of more novel innovations, which was found both in estimations with and without endogeneity correction. This influence was verified for more complex goals (R&D, technology transfer and industrial design and engineering) as well as for less complex ones (tests and trials, human resources training, quality management and certification). Business cooperation seems to impact only on a lower degree of novelty for more complex goals. The increase in the number of partners that the firm cooperates with, from no cooperation to joint cooperation with two partner types, influences more novel innovations.

Research limitations/implications

Limitations and proposals for future research are discussed at the end of the study.

Practical implications

The results of this study contrast with the high propensity to cooperate with business partners shown by firms in Argentina and other Latin American countries. Therefore, this paper may help formulate more effective policies to promote cooperation conducive to firm innovation performance. Limitations and proposals for future research are discussed at the end of the study.

Originality/value

Although there is empirical evidence on this topic for developed countries, firm-level studies on cooperation and degree of novelty are scarce for Latin America. In addition, this paper analyses cooperation not only by type of partner but also by type of goal. This study attempted to control for endogeneity by using instrumental variables within the CMP framework.
Management in times of crisis: Can collective plans prepare teams to make and implement good decisions?
Authors: Thürmer J. Lukas , Wieber Frank , Gollwitzer Peter M.
Published: November 2020

Purpose

Crises such as the Coronavirus pandemic pose extraordinary challenges to the decision making in management teams. Teams need to integrate available information quickly to make informed decisions on the spot and update their decisions as new information becomes available. Moreover, making good decisions is hard as it requires sacrifices for the common good, and finally, implementing the decisions made is not easy as it requires persistence in the face of strong counterproductive social pressures.

Design/methodology/approach

We provide a “psychology of action” perspective on making team-based management decisions in crisis by introducing collective implementation intentions (We-if-then plans) as a theory-based intervention tool to improve decision processes. We discuss our program of research on forming and acting on We-if-then plans in ad hoc teams facing challenging situations.

Findings

Teams with We-if-then plans consistently made more informed decisions when information was socially or temporally distributed, when decision makers had to make sacrifices for the common good, and when strong social pressures opposed acting on their decisions. Preliminary experimental evidence indicates that assigning simple We-if-then plans had similar positive effects as providing a leader to steer team processes.

Originality/value

Our analysis of self-regulated team decisions helps understand and improve how management teams can make and act on good decisions in crises such as the Coronavirus pandemic.
Commentary on a “unified approach to behaviours that challenge”: against consensus – why we need a new field of challenging behaviour studies
Authors: Clifford Simplican Stacy
Published: November 2020

Purpose

This paper challenges the value of consensus within the field of learning disability. In this commentary, the author argues that consensus threatens to silence multiple viewpoints, hides how power operates and stifles creativity.

Design/methodology/approach

The author focuses on two articles within this special issue to suggest that the consensus celebrated is more about a set of shared values, rather than a set of shared practices. This should make us question the depth of the field’s consensus.

Findings

The presumption that multiple paradigms can be “unified” actually hides how power operates to resolve disagreements among positive behaviour support, active support and human rights approaches. A similar erasure occurs in the language of “capable environments,” which the author argues obscures the role of individuals, relationships and organizational cultures in impacting quality of life.

Research limitations/implications

We need to create and build a new interdisciplinary field of challenging behaviour studies that is willing to embrace conflict and disagreement in research, policy and practice.

Practical implications

The author believes that this approach is more likely to empower people, including people with learning disabilities whose behaviour challenges, family members, and direct support workers because it is more likely to recognize their experiences and expertise.

Originality/value

A new multidisciplinary field of challenging behaviour studies may encourage more theoretical diversity that makes us challenge the value of consensus and embrace creativity.
Urbanization‐driven climate change increases invertebrate lipid demand, relative to protein—A response to dehydration
Authors: Becker Jamie E. , McCluney Kevin E.
Published: November 2020

Climatic change alters not only animal energy balance but also water balance, but this latter topic has received less attention. Water can be obtained through consumption of moist food and metabolism of dry food. The breakdown of carbohydrates, lipids and proteins can produce metabolic water. Metabolism of lipids produces large amounts of water, whereas excretion of nitrogenous waste related to protein metabolism requires water losses.

Here we tested the hypothesis that climatic shifts associated with urbanization influences animal lipid demand relative to protein, due to shifts in water balance.

We placed artificial diets high in lipid or protein, and either with or without supplemented water, at 16 pairs of sites along an urbanization gradient in Toledo, OH, USA.

Lipid consumption, relative to protein, increased with urbanization and mean temperature, but water supplementation reduced the magnitude of this association. Ants were ~50% of the observed consumers.

These results suggest that shifts in nutritional demand with climatic change are partially predictable from physiological first principles related to water balance and nutrient metabolism. Because ants and other arthropods play key roles in many food webs and ecosystems, increased demand for lipids with urbanization or climate change could have major consequences for ecosystem services (e.g. urban waste removal, seed predation). Overall, our results suggest that warming related to urbanization increases animal demand for lipids, in part to maintain water balance, and this could have important implications for both animal health and ecosystem services.

A free Plain Language Summary can be found within the Supporting Information of this article.
Do Forests have The Capacity for 1 Trillion Extra Trees?
Authors: Russell Matthew
Published: December 2020

Matthew Russell asks whether Earth's existing forestland has the space and resources necessary to enable 1 trillion additional trees to survive and thrive
Claiming Digital Technology for Health Equity: Early Lessons from Promising Practices in India
Authors: Dasgupta Jashodhara
Published: November 2020

The recent proliferation of digital technologies for development has led to a new paradigm of state‐citizen relations in which technology mediates the citizens' interactions with the agencies of government. The use of digital technologies has enabled the state to effectively distinguish between the “deserving” and “undeserving” poor, so as to parse the digital subject that is worthy of the state’s projects of governmentality. However, the top‐down use of technology occurs within a specific value system that is oblivious to contextual reality and does not question existing power asymmetries. Recent initiatives in northern India have questioned the state’s use of such technologies to devalue the agency of the poor and their autonomous capacity to contribute to development policy and practice. This Commentary will briefly examine two examples from India, where citizens’ movements have reshaped the terms of engagement through the medium of digital technologies, towards creating a more responsive state. Such initiatives have the potential to reframe the very objectives from the perspective of the affected people, and to reclaim digital technologies towards promoting equity.
Postoperative radiotherapy for pathological stageIIIA‐N2 non‐smallcell lung cancer with positive surgical margins
Authors: Yuan Meng , Men Yu , Kang Jingjing , Sun Xin , Zhao Maoyuan , Bao Yongxing , Yang Xu , Sun Shuang , Ma Zeliang , Wang Jianyang , Deng Lei , Wang Wenqing , Zhai Yirui , Liu Wenyang , Zhang Tao , Wang Xin , Bi Nan , Lv Jima , Liang Jun , Feng Qinfu , Chen Dongfu , Xiao Zefen , Zhou Zongmei , Wang Luhua , Hui Zhouguang
Published: November 2020

Background

The aim of this study was to evaluate the efficacy of postoperative radiotherapy (PORT) in stage pIIIA‐N2 non‐small cell lung cancer (NSCLC) patients with positive surgical margins.

Methods

Between January 2003 and December 2015, patients who had undergone lobectomy or pneumonectomy plus mediastinal lymph node dissection or systematic sampling in our single institution were retrospectively reviewed. Those with pIIIA‐N2 NSCLC and positive surgical margins were enrolled into the study. The Kaplan‐Meier method was used for survival analysis, and the log‐rank test was used to analyze differences between the groups. Univariate and multivariate analyses using Cox proportional hazards regression models were performed to evaluate potential prognostic factors for OS. Statistically significant difference was set asP < 0.05.

Results

Of all the 1547 patients with pIIIA‐N2 NSCLC reviewed, 113 patients had positive surgical margins, including 76 patients with R1 resection and 37 with R2 resection. The median overall survival (OS) was 28.3 months in the PORT group and 22.6 months in the non‐PORT group (P= 0.568). Subset analysis showed that for patients with R1 resection, the median OS was 52.4 months in the PORT group which was nonsignificantly longer than that of 22.6 months in the non‐PORT group (P= 0.127), whereas PORT combined with chemotherapy could significantly improve OS, with a median OS of 52.4 months versus 17.2 months (P= 0.027). For patients with R2 resection, PORT made no significant difference in OS (17.6 vs. 63.8 months,P= 0.529).

Conclusions

For pIIIA‐N2 NSCLC patients with positive surgical margins, PORT did not improve OS, but OS was improved in those patients who underwent R1 resection combined with chemotherapy.

Key points

Significant findings of the study

Significant findings of the study: Postoperative radiotherapy (PORT) has been recommended to treat patients with positive surgical margins. However, the existing evidence is controversial and high‐level evidence is lacking.

What this study adds

What this study adds: The PORT group had markedly, but not statistically significant, longer median OS compared with the non‐PORT group in patients with R1 resection. OS was significantly longer in the patients with R1 resection receiving adjuvant CRT than the surgery alone group.
Do National and International Ethics Documents Accord With the Consent Substitute Model for Emergency Research?
Authors: Langlois Adèle , Armstrong Stephanie , Siriwardena Aloysius Niroshan
Published: November 2020

In 2010 Largent, Wendler, and Emanuel proposed the “consent substitute model” for emergency research with incapacitated participants. The model provides a means to enroll participants in emergency research without consent, if five conditions are met: 1) the research addresses the patients’ urgent medical needs, 2) the risk–benefit ratio is favorable, 3) there are no known conflicts with patients’ values or interests, 4) cumulative net risk is minimal, and 5) consent is given as soon as possible. We review national and international ethics laws, regulations, and guidelines to determine 1) whether they accord with the consent substitute model’s five conditions and 2) the level of congruence across these documents. We find that only one document meets all five conditions and that there is significant disparity among the documents, particularly between national and international ones. These differences may have stymied international collaboration in emergency research. We recommend that the two international documents used most, the International Council for Harmonization’s Guideline for Good Clinical Practice and the World Medical Association’s Declaration of Helsinki, are revised to include more specific provisions on emergency medical research.
Five‐year mortality of severely malnourished patients with chronic anorexia nervosa admitted to a medical unit
Authors: Guinhut Marie , Godart Nathalie , Benadjaoud Mohamed‐Amine , Melchior Jean‐Claude , Hanachi Mouna
Published: November 2020

Objective

Anorexia nervosa (AN) is associated with one of the highest mortality rates of any psychiatric disorder but limited mortality data were reported for those with extremely severe malnutrition. This study aimed to estimate standardized mortality ratio (SMR), investigate predictive factors of mortality and causes of death among a sample of patients with AN admitted to a specialized clinical nutrition unit (CNU) because of extremely severe malnutrition.

Methods

Between 11/27/1997 and 01/15/2014, vital status was determined for 384 patients admitted for AN at the first time in the CNU. Sociodemographic, anamnestic, and clinical data were collected. We calculated the SMR. Univariate and multivariate Cox regression analyses were performed to identify mortality predictors.

Results

Crude mortality rate was 11.5%. (44 deaths) and SMR 15.9 [CI 95% (11.6–21.4)], 5.2 years post inpatient treatment. Mortality predictors at the time of hospitalization were as follows: older age, occurrence of an in‐hospital suicide attempt, transfer to medical intensive care unit and the following somatic complications: frank anemia, dysnatremia, infectious and cardiac complications. Other predictors of mortality were: past or present history of discharge against medical advice, hematological comorbidities (not related to AN). A longer inpatient length of stay was a protective factor.

Conclusion

Very severely malnourished patients with AN hospitalized in a medical unit because of extremely severe somatic issues have a medium‐term mortality rate higher than the general population and even higher than patients in tertiary specialized ED units. This study highlights predictive factors of mortality that will help clinicians in recognizing and managing patients at risk of death.
Canal transportation using Mani GPR or HyFlex NT during the retreatment of curved root canals: A micro‐computed tomographic study
Authors: Gomes Isabelle Luise Lima , Alves Flávio Rodrigues Ferreira , Marceliano‐Alves Marília F. , Silveira Stephanie B. , Provenzano José Claudio , Gonçalves Lucio Souza
Published: November 2020

This study assessed the apical transportation using Mani GPR or HyFlex NT during the retreatment of curved root canals. Thirty‐eight roots were analysed using micro‐CT for the comparison of apical transportation produced by two retreatment systems. Longitudinal transportation, horizontal transportation, variation in the canal angle of curvature and variation in the canal/root width ratio were analysed. Longitudinal transportation was frequently observed, regardless of the system used. The canals retreated with Mani GPR showed a significantly higher horizontal transportation at 1 mm from the root apex (P < 0.01) and greater variation of the canal curvature angle (P < 0.01). The canal/root width ratio was similar between groups (P > 0.05). In conclusion, longitudinal transportation occurred more frequently in the mesial canal walls. Mani GPR showed greater horizontal transportation at 1 mm short of the apex, and higher variation of the canal curvature angle compared with HyFlex NT.
Prevalence of potentially inappropriate prescribing in older adults in Jordan: Application of the STOPP criteria
Authors: Abu Hammour Khawla , Abdel jalil Mariam , AlHabeis Sara , Abu Hammour Ghayda' , Manaseer Qusai
Published: November 2020

Objectives

To measure the prevalence of cases of potentially inappropriate prescribing (PIP) for older patients and to identify the risk factors for identified cases of PIP.

Methods

STOPP criteria version 2 were used for identifying cases of PIP for older patients (>65 years) who were admitted to a tertiary hospital in Jordan over a period of 18 months. Data were collected by prospectively reviewing the clinical and prescription records of included patients. Descriptive analysis, univariate analysis and multiple linear regression were used to analyse the results.

Results

Upon admission, during hospitalisation and on discharge, 144, 182 and 156 cases of PIP were identified, respectively. There was a statistically significant association between the number of prescribed medications and cases of PIP during the hospital journey (P < .05).

Conclusion

Inappropriate prescribing of medications is highly prevalent among older patients. Application of validated (STOPP) criteria can help to detect and direct development of interventions to prevent PIP occurrence among older patients.
Serum levels of soluble Fas and Fas ligand in pregnant women who smoke
Authors: Hasan Sean , Alshaikh Belal , Yusuf Kamran
Published: November 2020

Problem

Cigarette smoking during pregnancy is associated with reduced incidence of preeclampsia. Mechanisms of this association are poorly understood. Cytokines, angiogenic, and anti‐angiogenic factors are involved in the pathogenesis of preeclampsia. During normal pregnancy, Fas ligand (FasL) present on trophoblasts induces apoptosis of Fas bearing maternal immune cells. In preeclampsia, trophoblasts show increased apoptosis with reduced expression of FasL. We determined serum levels of cytokines, angiogenic (placental growth factor), anti‐angiogenic factors (soluble endoglin, soluble fms‐like tyrosine kinase‐1), soluble Fas (sFas), and soluble FasL (sFasL) in smoking and non‐smoking pregnant women.

Methods

Using enzyme‐linked immunosorbent and multiplex assays, we prospectively analyzed serum levels of angiogenic, anti‐angiogenic factors, cytokines, sFas and sFasL in normotensive smoking and non‐smoking mothers. Exclusion criteria included maternal hypertension, auto‐immune disorders, rupture of membranes, evidence of labor, and drug use.

Results

Of 100 women recruited to the study, 51 were in the non‐smoking and 49 in the smoking group. Except for lower maternal age in the smoking group, there was no difference in gestation, BMI, gravidity, or ethnicity between the two groups. Levels of angiogenic, anti‐angiogenic factors, cytokines, and sFas were similar between the two groups but sFasL levels were significantly higher in smoking group (38 pg/ml vs. 16 pg/ml, p < .001) and remained significant after controlling for confounders.

Conclusion

Our study demonstrates higher sFasL levels in pregnant women who smoke. Higher sFasL may explain the reduced incidence of preeclampsia in pregnant mothers who smoke by inducing apoptosis of immune cells which may otherwise induce trophoblast apoptosis.
Oral berotralstat for the prophylaxis of hereditary angioedema attacks in patients in Japan: A phase 3 randomized trial
Authors: Ohsawa Isao , Honda Daisuke , Suzuki Yusuke , Fukuda Tomoo , Kohga Keisuke , Morita Eishin , Moriwaki Shinichi , Ishikawa Osamu , Sasaki Yoshihiro , Tago Masaki , Chittick Greg , Cornpropst Melanie , Murray Sharon C. , Dobo Sylvia M. , Nagy Eniko , Van Dyke Sharon , Reese Lacy , Best Jessica M. , Iocca Heather , Collis Phil , Sheridan William P. , Hide Michihiro
Published: November 2020

Background

With no approved treatments in Japan for the prevention of hereditary angioedema (HAE) attacks, there is a significant unmet need for long‐term prophylactic therapies for Japanese patients with HAE. Berotralstat (BCX7353) is an oral, once‐daily, highly selective inhibitor of plasma kallikrein in development for prophylaxis of angioedema attacks in HAE patients.

Methods

APeX‐J is a phase 3, randomized, double‐blind, placebo‐controlled, parallel‐group, 3‐part trial conducted in Japan (University Hospital Medical Information Network identifier, UMIN000034869; ClinicalTrials.gov identifier, NCT03873116). Patients with a clinical diagnosis of type 1 or 2 HAE underwent a prospective run‐in period of 56 days to determine eligibility, allowing enrollment of those with ≥2 expert‐confirmed angioedema attacks. Patients were randomly assigned (1:1:1) and stratified by baseline attack rate (≥2 vs. <2 expert‐confirmed attacks/month between screening and randomization) to receive once‐daily berotralstat 110 mg, berotralstat 150 mg, or placebo. The primary endpoint was the rate of expert‐confirmed angioedema attacks during dosing in the 24‐week treatment period.

Results

Nineteen patients were randomized to receive once‐daily berotralstat 110 mg (n = 6), berotralstat 150 mg (n = 7), or placebo (n = 6). Treatment with berotralstat 150 mg significantly reduced HAE attacks relative to placebo (1.11 vs. 2.18 attacks/month, p = .003). The most frequently reported treatment‐emergent adverse events (TEAEs) in berotralstat‐treated patients (n = 13) were nasopharyngitis (n = 4, 31%), abdominal pain, cough, diarrhea, and pyrexia (n = 2 each, 15%).

Conclusions

Orally administered, once‐daily berotralstat 150 mg significantly reduced the frequency of HAE attacks and was safe and well tolerated, supporting its use as a prophylactic therapy in patients with type 1 or 2 HAE in Japan.
Maternal N‐acetyl‐cysteine prevents neonatal brain injury associated with necrotizing enterocolitis in a rat model
Authors: Zmora Osnat , Gutzeit Ola , Segal Linoy , Boulos Sari , Millo Zvika , Ginsberg Yuval , Khatib Nizar , Fainaru Ofer , Ross Michael G. , Weiner Zeev , Beloosesky Ron
Published: November 2020

Introduction

Preterm infants with necrotizing enterocolitis (NEC) are at increased risk of cerebral injury and neurodevelopmental dysfunction. N‐acetyl‐cysteine (NAC) is a known anti‐inflammatory and antioxidant agent. Currently, there is no prophylactic treatment in clinical use to prevent NEC and its neurodevelopmental sequelae. We sought to determine whether brain inflammation/apoptosis accompanies NEC systemic inflammation, and whether it can be attenuated by maternal NAC treatment during pregnancy and/or in the neonatal period in a rat model.

Material and methods

An established NEC newborn model (hypoxia 5% O2 for 10 min and formula feeding thrice daily, beginning on day 1 for 4 days) was used in Sprague‐Dawley rat pups (n = 32). An additional group of pups (n = 33) received NAC (300 mg/kg intraperitoneal thrice daily) in addition to NEC conditions (NEC‐NAC). Control pups (n = 33) were nursed and remained with the dam in room air. Two additional groups included pups of dams treated once daily with NAC (300 mg/kg intravenous) in the last 3 days of pregnancy. After birth, pups were randomized into NAC‐NEC (n = 33) with NEC conditions and NAC‐NEC‐NAC (n = 36) with additional postnatal NAC treatment. Pups were sacrificed on the fifth day of life. Pup serum interleukin (IL)‐6 protein levels, and brain nuclear factor kappa B (NF‐κB) p65, neuronal nitric oxide synthase (nNOS), Caspase 3, tumor necrosis factor alpha (TNF‐α), IL‐6 and IL‐1β protein levels were determined by ELISA, western blot and TUNEL staining, and the groups were compared using analysis of variance (ANOVA).

Results

NEC pups had significantly increased serum IL‐6 levels compared with the control group as well as increased neuronal apoptosis and brain protein levels of NF‐κB, nNOS, Caspase 3, TNF‐α, IL‐6 and IL‐1β compared with control. In all NAC treatment groups, levels of serum IL‐6, neuronal apoptosis and brain NF‐κB, nNOS, Caspase 3, TNF‐α, IL‐6 and IL‐1β protein levels were significantly reduced compared with the NEC group. The most pronounced decrease was demonstrated within the NAC‐NEC‐NAC group.

Conclusions

NAC treatment can attenuate newborn inflammatory response syndrome and decrease offspring brain neuroapoptosis and inflammation in a rat model of NEC by inhibition of NF‐κB, nNOS and Caspase 3 pathways.
National Current Care Guidelines for paediatric lower respiratory tract infections reduced the use of chest radiographs but local variations were observed
Authors: Poutanen Roope , Virta Tuija , Heikkilä Paula , Pauniaho Satu‐Liisa , Csonka Peter , Korppi Matti , Renko Marjo , Palmu Sauli
Published: November 2020

Aim

Our aim was to evaluate the impact of the 2014 Finnish Current Care Guidelines for paediatric lower respiratory tract infections (LRTIs), particularly on taking of chest radiographs.

Methods

This study used official national data and regional (Pirkanmaa) data on children aged 0‐16 years who underwent chest radiographs in 2011 and 2015. We also collected data for LRTI diagnoses from local registers, including prescribed antibiotics and taking of chest radiographs. The local cohort comprised children aged 0‐15 who presented to the primary care emergency room or to the hospital emergency department (Tampere university hospital) in November‐December 2012‐2015.

Results

Chest radiographs for Finnish children aged 0‐16 fell from 2011 to 2015: by 15.9% nationally and by 16.9% in Pirkanmaa. When asylum seekers with chest radiographs for tuberculosis screening were excluded, the estimated national reduction was 29.9%. In the local cohort, chest radiographs increased from 82 to 139 (69.5%) between 2012/2013 and 2014/2015 as the occurrence of community‐acquired pneumonia (CAP) increased. However, the proportion of patients with CAP who had chest radiograph taken tended to decrease from 84.6% to 71.3% (p = 0.078).

Conclusion

Decreases in national and regional chest imaging trends were observed after the 2014 guidance for children`s LRTI was introduced.
Role of TDM‐based dose adjustments for taxane anticancer drugs
Authors: Muth Marsilla , Ojara Francis Williams , Kloft Charlotte , Joerger Markus
Published: November 2020

The classical taxanes (paclitaxel, docetaxel), the newer taxane cabazitaxel and the nanoparticle‐bound nab‐paclitaxel are among the most widely used anticancer drugs. Still, the optimal use and the value of pharmacological personalization of the taxanes is still controversial. We give an overview on the pharmacological properties of the taxanes, including metabolism, pharmacokinetics‐pharmacodynamic relations and aspects in the clinical use of taxanes. The latter includes the ongoing debate on the most effective and safe regimen, the recommended initial dose, and pharmacological dosing individualization. The taxanes are among the most widely used anticancer drugs in patients with solid malignancies. Despite their longtime use in clinical routine, the optimal dosing strategy (weekly versus 3‐weekly) or optimal average dose (cabazitaxel, nab‐paclitaxel) has not been fully resolved, as it may differ according to tumour entity and line of treatment. The value of pharmacological individualization of the taxanes (TDM, TCI) has been partly explored for 3‐weekly paclitaxel and docetaxel, but remains mostly unexplored for cabazitaxel and nab‐paclitaxel at present.
Fit for addressing grand challenges? A process model for effective accountability relationships within multi‐stakeholder initiatives in developing countries
Authors: Hennchen Esther , Schrempf‐Stirling Judith
Published: November 2020

Business is expected to contribute to grand challenges (GC) such as poverty within their corporate social responsibilities. Multi‐stakeholder initiatives (MSIs) have developed to a popular governance model to address GC. While existing scholarship has discussed the positive and negative aspects of MSIs, we know relatively little about how corporations within MSIs are held accountable. The objective of the study is to analyze the dynamics of accountability relationships between the corporate actor and the accountability forum to conceive a process model for effective accountability relationships in developing countries. We conducted an inductive study which explored the tensions the accountability forum perceives in MSI accountability relationships and the criteria to meet the forum's accountability claims. Our study identified four accountability criteria: transparency, inclusion, procedural fairness, and efficacy. Our main theoretical claim is that considering the four accountability criteria in the process of facilitating, dialoguing, and evaluating allows affected stakeholders to validate and match legitimacy claims with their own expectations, and thus, manage MSIs more effectively. Our contribution to existing scholarship on MSIs in developing countries is that we offer a novel perspective on analyzing the effectiveness of MSIs to address GC through our focus on one element of MSIs––specifically accountability. Beyond academic theorizing, this perspective may well hold value for nongovernmental organizations, policymakers, and business managers as it advances a concept of responsibility based on a set of accountability criteria which have the potential to become a cornerstone for how MSI members can organize to effectively address GC in developing countries.
Distinct circular RNA expression profiles in pediatric ependymomas
Authors: Ahmadov Ulvi , Bendikas Meile M. , Ebbesen Karoline K. , Sehested Astrid M. , Kjems Jørgen , Broholm Helle , Kristensen Lasse S.
Published: November 2020

Pediatric ependymomas frequently develop in the cerebellum and are currently treated using non‐specific therapies, in part, because few somatically mutated driver genes are present, and the underlying pathobiology is poorly described. Circular RNAs (circRNAs) constitute as a large class of primarily non‐coding RNAs with important roles in tumorigenesis, but they have not been described in pediatric ependymomas. To advance our molecular understanding of ependymomas, we performed Next Generation Sequencing of rRNA‐depleted total RNA of 10 primary ependymoma and three control samples. CircRNA expression patterns were correlated to disease stage, outcome, age, and gender. We found a profound global downregulation of circRNAs in ependymoma relative to control samples. Many differentially expressed circRNAs were discovered and circSMARCA5 and circ‐FBXW7, which are described as tumor suppressors in glioma and glioblastomas in adults, were among the most downregulated. Moreover, patients with a dismal outcome clustered separately from patients with a good prognosis in unsupervised hierarchical cluster analyses. Next, NanoString nCounter experiments were performed, using a custom‐designed panel targeting 66 selected circRNAs, on a larger cohort that also included medulloblastomas and pilocytic astrocytomas. These experiments indicated that circRNA expression profiles are different among distinct pediatric brain tumor subtypes. In particular, circRNAs derived from RMST, LRBA, WDR78, DRC1 and BBS9 genes were specifically upregulated in ependymomas. In conclusion, circRNAs have different expression profiles in ependymomas relative to controls and between survivors and patients with a dismal outcome, suggesting that circRNAs could be exerted as diagnostic and prognostic biomarkers in the future if further validated in larger cohorts.
Activation of trace amine‐associated receptor 1 selectively attenuates the reinforcing effects of morphine
Authors: Liu Jianfeng , Seaman Robert , Johnson Bernard , Wu Ruyan , Vu Jimmy , Tian Jingwei , Zhang Yanan , Li Jun‐Xu
Published: November 2020

Background and Purpose

Trace amine‐associated TA1 receptors play critical roles in regulating dopamine transmission. Previous studies showed that pharmacologically or genetically manipulating the activity of TA1 receptors modulates addiction‐like behaviours associated with psychostimulants. However, little is known about whether TA1 receptor modulation would regulate the behavioural effects of opioids.

Experimental Approach

Effects of the selective TA1 receptor partial agonist RO5263397 on the addiction‐related and antinociceptive effects of morphine were systematically assessed in male rats and mice.

Key Results

RO5263397 attenuated the expression of morphine‐induced behavioural sensitization in wildtype but not TA1 receptor knockout mice. RO5263397 shifted the dose‐effect curve of morphine self‐administration downward and reduced the breakpoint in a progressive ratio schedule of reinforcement but did not affect food self‐administration in rats. RO5263397 decreased the cue‐ and drug‐induced reinstatement of morphine‐seeking behaviour in rats. RO5263397 alone did not trigger reinstatement of morphine‐seeking behaviour or change locomotor activity in rats with a history of morphine self‐administration. However, RO5263397 did not affect the expression of morphine‐induced conditioned place preference in mice or rats. RO5263397 did not affect naltrexone‐precipitated jumping behaviour or naltrexone‐induced conditioned place aversion in morphine‐dependent mice. Furthermore, RO5263397 did not affect the analgesic effects of morphine in an acute nociception model in mice and a chronic pain model in rats.

Conclusion and Implications

These results indicated that TA1 receptor activation selectively attenuated the reinforcing, but not withdrawal or antinociceptive effects of morphine, suggesting that selective TA1 receptor agonists might be useful to combat opioid addiction, while sparing the analgesic effects.
c‐KIT‐ERK1/2 signaling activated ELK1 and upregulated carcinoembryonic antigen expression to promote colorectal cancer progression
Authors: Ma Jian , Liu Xiaohui , Chen Hong , Abbas Muhammad Khawar , Yang Liu , Sun Haimei , Sun Tingyi , Wu Bo , Yang Shu , Zhou Deshan
Published: November 2020

Carcinoembryonic antigen (CEA) is highly expressed in embryo and colorectal cancer (CRC) and has been widely used as a marker for CRC. Emerging evidence has demonstrated that elevated CEA levels promote CRC progression. However, the mechanism of the increased CEA expression in patients with primary and recurrent CRC is still an open question. In this study, we showed that c‐KIT, ELK1, and CEA were hyperexpressed in patients with CRC, especially patients with recurrent disease. From bioinformatics analysis, we picked ELK1 as a candidate transcription factor (TF) for CEA; the binding site of ELK1 within the CEA promoter was confirmed by chromatin immunoprecipitation and dual luciferase reporter assays. Overexpression of ELK1 increased CEA expression in vitro, while knockdown of ELK1 decreased CEA. Upregulated ELK1 promoted the adhesion, migration, and invasion of CRC cells, however knockdown of CEA blocked the activities of ELK1‐overexpressed CRC cells. Furthermore, we explored the role of c‐KIT‐ERK1/2 signaling in activation of ELK1. Blocking c‐KIT signaling using Imatinib or ISCK03 reduced p‐ELK1 expression and consequently decreased CEA levels in CRC cells, as did blocking the ERK1/2 pathway by U0126. Compared with wild type littermates, the c‐kit loss‐of‐functional Wadsm/m mice showed lowered c‐KIT, ELK1, and CEA expression. In conclusion, our study revealed that ELK1, which was activated by c‐KIT‐ERK1/2 signaling, was a key TF for CEA expression. Blocking ELK1 or its upstream signaling could be an alternative way to decelerate CRC progression. Besides being a biomarker for CRC, CEA could be used for guiding targeted therapy.
Long‐term swallowing outcomes of radiotherapy and transoral laser microsurgery for T1 glottic cancer treatment
Authors: Ozturk Kerem , Turhal Goksel , Durusoy Duygu , Sahin Emre , Akagunduz Ozlem , Eyigor Sibel , Akyildiz Serdar , Esassolak Mustafa
Published: November 2020

Introduction

Both CO2 transoral laser microsurgery (CO2 TOLMS) and radiotherapy (RT) are standard of care in early glottic carcinoma. However, previous studies focus on voice outcomes rather than swallowing outcomes. This study aimed to compare the late post‐treatment effects of CO2 TOLMS and RT treatment on swallowing function in T1 glottic carcinoma.

Methods

Forty patients (20 CO2 TOLMS and 20 RT) with T1 glottic cancer between May 2015 and January 2019 were included. Certain types of foods triggering dysphagia, any difficulties in bolus control, need to clean the throat, the sensation of lumping in the throat, choking, cough and xerostomia were questioned. Also, functional oral intake scale (FOIS), functional outcome swallowing scale (FOSS), Eating Assessment Tool‐10 test (EAT‐10) and flexible fiberoptic endoscopic examination of swallowing (FEES) findings were assessed.

Results

CO2 TOLMS patients performed significantly better than the RT group regarding penetration and aspiration with 10 and 20 mL water according to the Penetration and Aspiration Scale (P < .05). The mean EAT‐10 Score was found 0 in the CO2 TOLMS group, and 3.20 ± 3.24 in the RT group (P < .05) (lower score indicates a better outcome). According to the Yale Pharyngeal Residue Severity Scale for vallecula, there was no statistically significant difference in vallecular residue between the groups (P > .05). A significantly lesser residue in piriform sinus was detected in the CO2 TOLMS group compared to the RT group with 5 mL and 10 mL water, 5 mL and 20 mL honey consistency food and yogurt according to Yale Pharyngeal Residue Severity Scale (P < .05).

Conclusion

It is suggested that in the long term, CO2 TOLMS is more advantageous regarding swallowing function in the treatment of T1 glottic cancer.