bluuebunny/crossref_metadata_2025 huggingface dataset:
Adult Child-Parent Dyadic Interactions at the End of Life: A Scoping Review
Authors: Herbst Franziska A , Gawinski Laura , Schneider Nils , Stiel Stephanie
Published: August 2019

Background

Being terminally ill affects not only the life of patients but also that of their loved ones. Dyads of adult children and their parents at the end of life may face specific challenges with regard to their relationship and interactions that need to be further examined.

Aim

The aim was to identify, describe and summarise available evidence on adult child–parent interaction and psychosocial support needs at the end of life. Research gaps in the existing literature are disclosed and recommendations for future research are presented.

Design

A type 4 scoping review according to Arksey and O’Malley’s (2005) methodological framework was conducted. The review includes studies regardless of study design and provides a descriptive account of foci of available research.

Data sources

The PubMed, PsycINFO, CINAHL, Google Scholar and Web of Science databases were searched from inception to 16 August 2018. An additional hand search was conducted. A highly sensitive search strategy was employed to cover all potentially relevant results.

Results

The authors screened 1832 records by title and abstract, retrieved 216 full-text articles and included 15 studies from the database search. One study was identified by way of hand search. The review identified six major themes: (1) adult child–parent relationship, (2) adult child–parent communication, (3) involvement in caregiving, (4) benefit and burden of caregiving, (5) coping strategies and (6) support and information for caregivers.

Conclusions

The scoping review accentuates the paucity of studies that address both patients’ and their parent/adult child caregivers’ relationship, interaction and psychosocial support needs.
Current controversies and irresolvable disagreement: the case of Vincent Lambert and the role of ‘dissensus’
Authors: Wilkinson Dominic , Savulescu Julian
Published: August 2019

Controversial cases in medical ethics are, by their very nature, divisive. There are disagreements that revolve around questions of fact or of value. Ethical debate may help in resolving those disagreements. However, sometimes in such cases, there are opposing reasonable views arising from deep-seated differences in ethical values. It is unclear that agreement and consensus will ever be possible. In this paper, we discuss the recent controversial case of Vincent Lambert, a French man, diagnosed with a vegetative state, for whom there were multiple court hearings over a number of years. Both family and health professionals were divided about whether artificial nutrition and hydration should be withdrawn and Lambert allowed to die. We apply a ‘dissensus’ approach to his case and argue that the ethical issue most in need of scrutiny (resource allocation) is different from the one that was the focus of attention.
A module to simulate the impact of western gall rust (Cronartium harknessii) on merchantable volume and lumber yields for lodgepole pine (Pinus contorta var. latifolia) stands in British Columbia
Authors: Sattler Derek F. , Goudie James W. , Reich Richard W.
Published: August 2019

Western gall rust (Cronartium harknessii (J.P. Moore) E. Meinecke) is a pathogen that affects lodgepole pine (Pinus contorta Douglas ex Loudon var. latifolia Engelm. ex S. Watson) and has the potential to reduce lumber product yields derived from stands managed for the commercial production of timber. A dataset containing repeated measurements from 7775 trees located within the province of British Columbia, Canada, was used to develop equations that predict annual rates of stem infection, post-infection mortality, and the location of large stem galls. Results showed that annual rates of infection peaked between 3 and 5 years following stand establishment. Few new infections were predicted to occur beyond the stand age of 15 years. For an individual tree, the probability of first infection increased as its height increased relative to stand top height. The rate of mortality increased with the number of stem infections and was highest among trees infected within the first 3 years following planting. Mortality rates decreased thereafter, with many trees likely to survive to rotation. The equations predicting rust incidence and mortality were added to the Tree and Stand Simulator (TASS), an individual-tree growth model used within the province. A final equation predicting the location of large galls was added and allows TASS to account for losses due to the removal of stem defects during lumber manufacturing.
Effects of non-commutative phase-space on prolate nuclei in the presence of Coulomb interaction
Authors: Sobhani Hadi , Hassanabadi Hassan , Chung Won Sang
Published: August 2019

In this paper, we have shown how ultra-fine structures in prolate nuclei can be seen. Ultra-fine structures can be interpreted as a nuclear version of the Zeeman effect in atomic physics. Because this effect is so tiny, we called it Ultra-Fine Structures in the nuclei. This effect appears while non-commutative phase-space is considered. After considering non-commutative phase-space for Davydov–Chaban Hamiltonian for prolate nuclei, the effects of Coulomb interaction are studied.
Flavons and LFV decays and productions of pseudoscalar mesons
Authors: Li Tian-Qi , Yue Chong-Xing
Published: August 2019

Flavons are the dynamic agent of flavor symmetry breaking and have flavor changing couplings to the Standard Model (SM) fermions. We consider their contributions to the lepton flavor violating (LFV) decays [Formula: see text] and [Formula: see text] with [Formula: see text], [Formula: see text] or [Formula: see text] and [Formula: see text] in the simplest flavon model without Higgs-flavon mixing. We find that flavons can produce significant contributions to some of these LFV decay processes.
Optimal Design of Reliability Acceptance Sampling Plan Based on Data Obtained from Partially Accelerated Life Test (PALT)
Authors: Kumar M. , Bajeel P. N. , Ramyamol P. C.
Published: August 2019

In this paper, constant–stress partially accelerated life tests (PALT) are considered for a product with the assumption that the lifetime of the product follows Weibull distribution with known shape parameter and unknown scale parameter. Based on data obtained using Type-II censoring, the maximum likelihood estimates (MLEs) of the Weibull parameters and acceleration factor are obtained assuming linear and Arrhenius relationships with the lifetime characteristics and stress. Exact distributions of the MLEs of the parameters of Weibull distribution are also obtained. Optimal acceptance sampling plans are developed using both linear and Arrhenius relationships. Some numerical results are also presented to illustrate the resulted test plans.
Release Time Problem Incorporating the Effect of Imperfect Debugging and Fault Generation: An Analysis for Multi-Upgraded Software System
Authors: Das Subhrata , Anand Adarsh , Agarwal Mohini , Ram Mangey
Published: August 2019

In the field of software engineering, optimal scheduling of software is a well-studied concept. However, attention to cost analysis in the field of multi-upgradation is still limited to certain well- known works. In the present work, a mathematical framework for multi-upgraded software under the concept of imperfect debugging has been analyzed. With due consideration of the fact that upgraded version might contain some newly generated bugs and few latent bugs of its preceding version, the cost components have been designed in accordance. The parameter estimates of multi-upgraded software under the influence of imperfect fault removal process are used for optimal determination of release time. For validation purpose, a numerical illustration has been carried out on three releases of software and the optimal release time is estimated accordingly.
Reliability Prediction of Computing Network with Software and Hardware Failures
Authors: Shekhar Chandra , Kumar Neeraj , Jain Madhu , Gupta Amit
Published: August 2019

In this paper, we investigate the reliability and queueing performance indices for the fault-tolerant computing network having a finite number of unreliable operating components with the provision of warm standby components. Operating and standby components are governed by dedicated software which is also prone to random failure. On failure of operating components, available standby component(s) may switch from the standby state to operating state with negligible switchover time. The switchover process may also fail due to some automation hindrance. The computing network is also subjected to common cause failure in lieu of external cause. The studied redundant fault-tolerant computing network is framed as a Markovian machine interference model with exponentially distributed inter-failure times and service times. For the reliability prediction of the computing network, various performance measures, namely, mean-time-to-failure (MTTF), reliability/availability, failure frequency, etc., have been formulated in terms of transient-state probabilities which we have obtained using the spectral method. To show the practicability of the developed model, numerical simulation has been done. Sensitivity analysis of reliability and other indices of the computing network with respect to different network parameters has been presented, and results are summarized in the tables and graphs. Finally, future scope and concluding remarks have been included.
Failure-Correlated Opportunity-based Age Replacement Models
Authors: Dohi Tadashi , Okamura Hiroyuki
Published: August 2019

In this paper, we extend the existing opportunity-based age replacement policies by taking account of dependency between the failure time and the arrival time of a replacement opportunity for one-unit system. Based on the bivariate probability distribution function of the failure time and the arrival time of the opportunity, we focus on two opportunity-based age replacement problems and characterize the cost-optimal age replacement policies which minimize the relevant expected costs, with the hazard gradient, which is a vector-valued bivariate hazard rate. Through numerical examples with the Farlie–Gumbel–Morgenstern bivariate copula and the Gaussian bivariate copula having the general marginal distributions, we investigate the dependence of correlation between the failure time and the opportunistic replacement time on the age replacement policies.
The Implementation of the Colored Abstract Simplicial Complex and Its Application to Mesh Generation
Authors: Lee Christopher T. , Moody John B. , Amaro Rommie E. , Mccammon J. Andrew , Holst Michael J.
Published: August 2019

We introduce the Colored Abstract Simplicial Complex library (CASC): a new, modern, and header-only C++ library that provides a data structure to represent arbitrary dimension abstract simplicial complexes (ASC) with user-defined classes stored directly on the simplices at each dimension. This is accomplished by using the latest C++ language features including variadic template parameters introduced in C++11 and automatic function return type deduction from C++14. Effectively, CASC decouples the representation of the topology from the interactions of user data. We present the innovations and design principles of the data structure and related algorithms. This includes a metadata-aware decimation algorithm, which is general for collapsing simplices of any dimension. We also present an example application of this library to represent an orientable surface mesh.
Learning Click-Based Deep Structure-Preserving Embeddings with Visual Attention
Authors: Li Yehao , Pan Yingwei , Yao Ting , Chao Hongyang , Rui Yong , Mei Tao
Published: August 2019

One fundamental problem in image search is to learn the ranking functions (i.e., the similarity between query and image). Recent progress on this topic has evolved through two paradigms: the text-based model and image ranker learning. The former relies on image surrounding texts, making the similarity sensitive to the quality of textual descriptions. The latter may suffer from the robustness problem when human-labeled query-image pairs cannot represent user search intent precisely. We demonstrate in this article that the preceding two limitations can be well mitigated by learning a cross-view embedding that leverages click data. Specifically, a novel click-based Deep Structure-Preserving Embeddings with visual Attention (DSPEA) model is presented, which consists of two components: deep convolutional neural networks followed by image embedding layers for learning visual embedding, and a deep neural networks for generating query semantic embedding. Meanwhile, visual attention is incorporated at the top of the convolutional neural network to reflect the relevant regions of the image to the query. Furthermore, considering the high dimension of the query space, a new click-based representation on a query set is proposed for alleviating this sparsity problem. The whole network is end-to-end trained by optimizing a large margin objective that combines cross-view ranking constraints with in-view neighborhood structure preservation constraints. On a large-scale click-based image dataset with 11.7 million queries and 1 million images, our model is shown to be powerful for keyword-based image search with superior performance over several state-of-the-art methods and achieves, to date, the best reported NDCG@25 of 52.21%.
Improving the Flexibility and Robustness of Model-based Derivative-free Optimization Solvers
Authors: Cartis Coralia , Fiala Jan , Marteau Benjamin , Roberts Lindon
Published: August 2019

We present two software packages for derivative-free optimization (DFO): DFO-LS for nonlinear least-squares problems and Py-BOBYQA for general objectives, both with optional bound constraints. Inspired by the Gauss-Newton method, DFO-LS constructs simplified linear regression models for the residuals and allows flexible initialization for expensive problems, whereby it can begin making progress after as few as two objective evaluations. Numerical results show DFO-LS can gain reasonable progress on some medium-scale problems with fewer objective evaluations than is needed for one gradient evaluation. DFO-LS has improved robustness to noise, allowing sample averaging, regression-based model construction, and multiple restart strategies with an auto-detection mechanism. Our extensive numerical experimentation shows that restarting the solver when stagnation is detected is a cheap and effective mechanism for achieving robustness, with superior performance over sampling and regression techniques. The package Py-BOBYQA is a Python implementation of BOBYQA (Powell 2009), with novel features such as the implementation of robustness to noise strategies. Our numerical experiments show that Py-BOBYQA is comparable to or better than existing general DFO solvers for noisy problems. In our comparisons, we introduce an adaptive accuracy measure for data profiles of noisy functions, striking a balance between measuring the true and the noisy objective improvement.
Scheduling Mutual Exclusion Accesses in Equal-Length Jobs
Authors: Kagaris Dimitri , Dutta Sourav
Published: August 2019

A fundamental problem in parallel and distributed processing is the partial serialization that is imposed due to the need for mutually exclusive access to common resources. In this article, we investigate the problem of optimally scheduling (in terms of makespan) a set of jobs, where each job consists of the same number
L
of unit-duration tasks, and each task either accesses exclusively one resource from a given set of resources or accesses a fully shareable resource. We develop and establish the optimality of a fast polynomial-time algorithm to find a schedule with the shortest makespan for any number of jobs and for any number of resources for the case of
L
= 2. In the notation commonly used for job-shop scheduling problems, this result means that the problem
J
|
d

ij

=1,
n

j

=2|
C
max
is polynomially solvable, adding to the polynomial solutions known for the problems
J
2 |
n

j

≤ 2 |
C
max
and
J
2 |
d

ij

= 1 |
C
max
(whereas other closely related versions such as
J
2 |
n

j

≤ 3 |
C
max
,
J
2 |
d

ij

∈ { 1,2} |
C
max
,
J
3 |
n

j

≤ 2 |
C
max
,
J
3 |
d

ij

=1 |
C
max
, and
J
|
d

ij

=1,
n

j

≤ 3|
C
max
are all known to be NP-complete). For the general case
L
> 2 (i.e., for the job-shop problem
J
|
d

ij

=1,
n

j

=
L
> 2|
C
max
), we present a competitive heuristic and provide experimental comparisons with other heuristic versions and, when possible, with the ideal integer linear programming formulation.
Slug and Snail have differential effects in directing colonic epithelial wound healing and partially mediate the restitutive effects of butyrate
Authors: Swain Steve D. , Grifka-Walk Heather N. , Gripentrog Jeannie , Lehmann Margaret , Deuling Benjamin , Jenkins Brittany , Liss Hailey , Blaseg Nathan , Bimczok Diane , Kominsky Douglas J.
Published: August 2019

Restitution of wounds in colonic epithelium is essential in the maintenance of health. Microbial products, such as the short-chain fatty acid butyrate, can have positive effects on wound healing. We used an in vitro model of T84 colonic epithelial cells to determine if the Snail genes Slug ( SNAI2) and Snail ( SNAI1), implemented in keratinocyte monolayer healing, are involved in butyrate-enhanced colonic epithelial wound healing. Using shRNA-mediated Slug/Snail knockdown, we found that knockdown of Slug (Slug-KD), but not Snail (Snail-KD), impairs wound healing in scratch assays with and without butyrate. Slug and Snail had differential effects on T84 monolayer barrier integrity, measured by transepithelial resistance, as Snail-KD impaired the barrier (with or without butyrate), whereas Slug-KD enhanced the barrier, again with or without butyrate. Targeted transcriptional analysis demonstrated differential expression of several tight junction genes, as well as focal adhesion genes. This included altered regulation of Annexin A2 and ITGB1 in Slug-KD, which was reflected in confocal microscopy, showing increased accumulation of B1-integrin protein in Slug-KD cells, which was previously shown to impair wound healing. Transcriptional analysis also indicated altered expression of genes associated with epithelial terminal differentiation, such that Slug-KD cells skewed toward overexpression of secretory cell pathway-associated genes. This included trefoil factors TFF1 and TFF3, which were expressed at lower than control levels in Snail-KD cells. Since TFFs can enhance the barrier in epithelial cells, this points to a potential mechanism of differential modulation by Snail genes. Although Snail genes are crucial in epithelial wound restitution, butyrate responses are mediated by other pathways as well.

NEW & NOTEWORTHY Although butyrate can promote colonic mucosal healing, not all of its downstream pathways are understood. We show that the Snail genes Snail and Slug are mediators of butyrate responses. Furthermore, these genes, and Slug in particular, are necessary for efficient restitution of wounds and barriers in T84 epithelial cells even in the absence of butyrate. These effects are achieved in part through effects on regulation of β1 integrin and cellular differentiation state.
Physiologically driven, altitude-adaptive model for the interpretation of pediatric oxygen saturation at altitudes above 2,000 m a.s.l.
Authors: Tüshaus Laura , Moreo Monica , Zhang Jia , Hartinger Stella Maria , Mäusezahl Daniel , Karlen Walter
Published: August 2019

Measuring peripheral oxygen saturation ([Formula: see text]) with pulse oximeters at the point of care is widely established. However, since [Formula: see text] is dependent on ambient atmospheric pressure, the distribution of [Formula: see text] values in populations living above 2000 m a.s.l. is largely unknown. Here, we propose and evaluate a computer model to predict [Formula: see text] values for pediatric permanent residents living between 0 and 4,000 m a.s.l. Based on a sensitivity analysis of oxygen transport parameters, we created an altitude-adaptive [Formula: see text] model that takes physiological adaptation of permanent residents into account. From this model, we derived an altitude-adaptive abnormal [Formula: see text] threshold using patient parameters from literature. We compared the obtained model and threshold against a previously proposed threshold derived statistically from data and two empirical data sets independently recorded from Peruvian children living at altitudes up to 4,100 m a.s.l. Our model followed the trends of empirical data, with the empirical data having a narrower healthy [Formula: see text] range below 2,000 m a.s.l. but the medians never differed more than 2.3% across all altitudes. Our threshold estimated abnormal [Formula: see text] in only 17 out of 5,981 (0.3%) healthy recordings, whereas the statistical threshold returned 95 (1.6%) recordings outside the healthy range. The strength of our parametrized model is that it is rooted in physiology-derived equations and enables customization. Furthermore, as it provides a reference [Formula: see text], it could assist practitioners in interpreting [Formula: see text] values for diagnosis, prognosis, and oxygen administration at higher altitudes.

NEW & NOTEWORTHY Our model describes the altitude-dependent decrease of [Formula: see text] in healthy pediatric residents based on physiological equations and can be adapted based on measureable clinical parameters. The proposed altitude-specific abnormal [Formula: see text] threshold might be more appropriate than rigid guidelines for administering oxygen that currently are only available for patients at sea level. We see this as a starting point to discuss and adapt oxygen administration guidelines.
Individuals have unique muscle activation signatures as revealed during gait and pedaling
Authors: Hug François , Vogel Clément , Tucker Kylie , Dorel Sylvain , Deschamps Thibault , Le Carpentier Éric , Lacourpaille Lilian
Published: August 2019

Although it is known that the muscle activation patterns used to produce even simple movements can vary between individuals, these differences have not been considered to prove the existence of individual muscle activation strategies (or signatures). We used a machine learning approach (support vector machine) to test the hypothesis that each individual has unique muscle activation signatures. Eighty participants performed a series of pedaling and gait tasks, and 53 of these participants performed a second experimental session on a subsequent day. Myoelectrical activity was measured from eight muscles: vastus lateralis and medialis, rectus femoris, gastrocnemius lateralis and medialis, soleus, tibialis anterior, and biceps femoris -long head. The classification task involved separating data into training and testing sets. For the within-day classification, each pedaling/gait cycle was tested using the classifier, which had been trained on the remaining cycles. For the between-day classification, each cycle from day 2 was tested using the classifier, which had been trained on the cycles from day 1. When considering all eight muscles, the activation profiles were assigned to the corresponding individuals with a classification rate of up to 99.28% (2,353/2,370 cycles) and 91.22% (1,341/1,470 cycles) for the within-day and between-day classification, respectively. When considering the within-day classification, a combination of two muscles was sufficient to obtain a classification rate >80% for both pedaling and gait. When considering between-day classification, a combination of four to five muscles was sufficient to obtain a classification rate >80% for pedaling and gait. These results demonstrate that strategies not only vary between individuals, as is often assumed, but are unique to each individual.

NEW & NOTEWORTHY We used a machine learning approach to test the uniqueness and robustness of muscle activation patterns. We considered that, if an algorithm can accurately identify participants, one can conclude that these participants exhibit discernible differences and thus have unique muscle activation signatures. Our results show that activation patterns not only vary between individuals, but are unique to each individual. Individual differences should, therefore, be considered relevant information for addressing fundamental questions about the control of movement.
Laparoscopic Treatment of an Incarcerated Meckel’s Diverticulum in a Femoral Hernia
Authors: Paasch Christoph , De Santo Gianluca , Look Peter , Boettge Katherina , Hünerbein Michael
Published: August 2019

Meckel’s diverticulum (MD) is the persistence of the omphalomesenteric duct. It is usually asymptomatic but may present with bleeding, infections, and intestinal obstruction. It also may be a content of a hernia sac, a so-called Littre hernia. Herein, we will present the case of a 75-year-old female, who suffered from a painful swelling of the right inguinal region. Ultrasound imaging detected an inguinal hernia with incarcerated blind ending small bowel. Immediately, a laparoscopy was conducted. We diagnosed a right femoral hernia with an incarcerated MD. A TAPP (transabdominal preperitoneal) procedure was performed and the MD tangential stapled. Due to an uneventful postoperative course, the patient left the hospital after two days. An incarceration of a MD in a femoral hernia is rare. Tangential resection of the MD with simultaneous hernia repair in a TAPP technique seems to be a sufficient approach, when it is conducted by an experienced surgeon.
A Numerical Study of Initiation and Migration of Trapped Oil in Capillaries with Noncircular Cross Sections
Authors: Long Long , Li Yajun , Gong Houjian , Dong Mingzhe
Published: August 2019

To clarify the initiation and migration mechanisms of a discontinuous oil phase in pores, a numerical study was performed to interpret the starting phenomenon and flowing rules of oil trapped in capillaries that have noncircular cross sections. In this study, capillaries with three different cross sections were used to investigate the deformation law of oil and the pressure drop across these microchannels at different displacement velocities by computational fluid dynamics (CFD). The geometrical structure of the microchannels was precisely controlled, and the migration process of the oil, which is too small to be observed by direct experimentation, was assessed and quantitatively analyzed. By analyzing the shape of the trapped oil after reaching a steady state at different velocities, the nonstart and start conditions could be distinguished and the accuracy of the numerical method was verified by a comparison with an analytical method (the MS-P method). Two aspects of oil migration in noncircular microchannels were observed in combination with previous studies: there is a driving force on the cross section of the oil drop and a viscous force at the oil-water interface in the corners, and the more irregular the pore section is, the more easily the trapped oil will migrate. Additionally, the influence of the microchannel cross-sectional shape on the non-Darcy flow of a discontinuous oil phase was clarified. It can be concluded that the presence of the non-Darcy flow in pores arises because trapped oil, as a discontinuous phase, cannot be separated from the capillary wall without reaching critical velocity.
Influences of Saturation and Wetting-Drying Cycle on Mechanical Performances of Argillaceous Limestones from Liupanshan Tunnel, China
Authors: Meng Bo , Jing Hongwen , Zhu Wenxin , Su Haijian
Published: August 2019

Water-rock interaction is a vital factor to affect the stabilities of rock projects. This paper conducted a series of experiments on argillaceous limestones to investigate the influences of saturation and wetting-drying cycle on the physical and mechanical performances of rocks. The results show that the increasing saturation increases the dissolution of clay minerals and lubrication among mineral grains, resulting in an obvious reduction effect on the strength and deformation performances of argillaceous limestones. Wetting-drying cycle increases the porosity and changes the pore structure of argillaceous limestones, leading to the pore transformation from small pore (0.01∼0.1 μm) to relatively large pore (0.1∼1.0 μm). Both the physical and mechanical performances of argillaceous limestones are weakened by the wetting-drying cycle. Besides, the variation process of the physical and mechanical parameters, including mass loss, density, ultrasonic velocity, compression strength, peak strain, elasticity modulus, and secant modulus, can be divided into two stages: 0∼6th wetting-drying cycle, gently changing, and 6th∼12th wetting-drying cycle, drastically changing. The whole change process of these physical and mechanical parameters with the increase in the wetting-drying cycle number can be expressed with the exponential function in general.
Baseline Triglyceride Level Affected the Efficacy of Vildagliptin in Treating Type 2 Diabetes: A Post Hoc Analysis of the VISION Study
Authors: Zhou Lingli , Cai Xiaoling , Luo Yingying , Zhang Fang , Ji Linong
Published: August 2019

Identifying factors that may impact vildagliptin’s efficacy could contribute to individualized treatment for patients with type 2 diabetes. In the current study, we aimed to assess the correlation between patient baseline triglyceride (TG) and efficacy of vildagliptin in Chinese patients with type 2 diabetes in a post hoc analysis of the VISION study. TG-based subgroup analysis was performed to evaluate baseline TG’s impact on the decrease of glycated hemoglobin (HbA1c) in patients receiving vildagliptin plus low-dose metformin (VLDM) vs. high-dose metformin (HDM). Additionally, multivariate linear regression was performed to assess the association between baseline TG and HbA1c reduction at weeks 12 and 24 for patients receiving VLDM vs. HDM. For patients receiving VLDM, baseline TG≤2.03 mmol/L was associated with significantly greater HbA1c reduction vs. TG>2.03 mmol/L at week 12, but not at week 24. Additionally, multivariate linear regression analysis revealed a significant independent association and an association short of statistical significance between patient baseline TG and the HbA1c-reducing efficacy of VLDM at weeks 12 (P<0.001) and 24 (P=0.082), respectively, while such association was absent for HDM. Collectively, baseline TG was an independent predictive factor for the efficacy of a dipeptidyl peptidase-IV in treating type 2 diabetes during its initial use.
An Allosteric PRC2 Inhibitor Targeting EED Suppresses Tumor Progression by Modulating the Immune Response
Authors: Dong Hongping , Liu Shaojun , Zhang Xuejie , Chen Sheng , Kang Lijing , Chen Yanni , Ma Shichao , Fu Xianlei , Liu Yanchao , Zhang Hailong , Zou Bin
Published: August 2019

Aberrant activity of polycomb repressive complex 2 (PRC2) is involved in a wide range of human cancer progression. The WD40 repeat-containing protein EED is a core component of PRC2 and enhances PRC2 activity through interaction with H3K27me3. In this study, we report the discovery of a class of pyrimidone compounds, represented by BR-001, as potent allosteric inhibitors of PRC2. X-ray co-crystallography showed that BR-001 directly binds EED in the H3K27me3-binding pocket. BR-001 displayed antitumor potency in vitro and in vivo. In Karpas422 and Pfeiffer xenograft mouse models, twice daily oral dosing with BR-001 resulted in robust antitumor activity. BR-001 was also efficacious in syngeneic CT26 colon tumor-bearing mice; oral dosing of 30 mg/kg of BR-001 led to 59.3% tumor growth suppression and increased frequency of effector CD8+ T-cell infiltrates in tumors. Pharmacodynamic analysis revealed that CXCL10 was highly upregulated, suggesting that CXCL10 triggers the trafficking of CD8+ T cells toward tumor sites. Our results demonstrate for the first time that inhibition of EED modulates the tumor immune microenvironment to induce regression of colon tumors and therefore has the potential to be used in combination with immune-oncology therapy.

Significance:

BR-001, a potent inhibitor of the EED subunit of the PRC2 complex, suppresses tumor progression by modulating the tumor microenvironment.
Relationship between Diabetes and Diabetes Medications and Risk of Different Molecular Subtypes of Breast Cancer
Authors: Chen Hongjie , Cook Linda S. , Tang Mei-Tzu C. , Hill Deirdre A. , Wiggins Charles L. , Li Christopher I.
Published: August 2019

Background:

Type II diabetes and certain diabetes treatments have been observed to impact breast cancer risk. However, their associations with different breast cancer molecular subtype defined by estrogen receptor (ER)/progesterone receptor (PR)/HER2 status are unclear.

Methods:

We conducted a retrospective multi-center population-based case–case study consisting of 4,557 breast cancer cases to evaluate the impact of type II diabetes and diabetes medications on the risk of different breast cancer molecular subtypes [ER+/HER2−, ER+/HER2+, triple negative (ER−/PR−/HER2−), and HER2 overexpressing (H2E, ER−/PR−/HER2+)]. Using ER+/HER2− cases as the reference group, we estimated ORs and corresponding 95% confidence intervals (CI) for each subtype using polytomous logistic regression.

Results:

Compared with those without a diabetes history, women with type II diabetes had a 38% (95% CI, 1.01–1.89) increased odds of triple-negative breast cancer (TNBC). Current and longer term recent metformin use (13–24 months of treatment within the 24-month period prior to breast cancer diagnosis) was associated with elevated odds of TNBC (OR = 1.54; 95% CI, 1.07–2.22 and OR = 1.80; 95% CI, 1.13–2.85, respectively).

Conclusions:

The odds of having a triple-negative rather than ER+/HER2− breast cancer is greater for women with type II diabetes, and particularly for those who were users of metformin. This finding is supported by some preclinical data suggesting that diabetes may be more strongly associated with risk of triple-negative disease.

Impact:

Our study provides novel evidence regarding potential differential effects of type II diabetes and metformin use on risk of different molecular subtypes of breast cancer.
Evidence for Etiologic Subtypes of Breast Cancer in the Carolina Breast Cancer Study
Authors: Benefield Halei C. , Zabor Emily C. , Shan Yue , Allott Emma H. , Begg Colin B. , Troester Melissa A.
Published: August 2019

Background:

Distinctions in the etiology of triple-negative versus luminal breast cancer have become well established using immunohistochemical surrogates [notably estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)]. However, it is unclear whether established immunohistochemical subtypes are the sole or definitive means of etiologically subdividing breast cancers.

Methods:

We evaluated clinical biomarkers and tumor suppressor p53 with risk factor data from cases and controls in the Carolina Breast Cancer Study, a population-based study of incident breast cancers. For each individual marker and combinations of markers, we calculated an aggregate measure to distinguish the etiologic heterogeneity of different classification schema. To compare schema, we estimated subtype-specific case–control odds ratios for individual risk factors and fit age-at-incidence curves with two-component mixture models. We also evaluated subtype concordance of metachronous contralateral breast tumors in the California Cancer Registry.

Results:

ER was the biomarker that individually explained the greatest variability in risk factor profiles. However, further subdivision by p53 significantly increased the degree of etiologic heterogeneity. Age at diagnosis, nulliparity, and race were heterogeneously associated with ER/p53 subtypes. The ER−/p53+ subtype exhibited a similar risk factor profile and age-at-incidence distribution to the triple-negative subtype.

Conclusions:

Clinical marker–based intrinsic subtypes have established value, yet other schema may also yield important etiologic insights.

Impact:

Novel environmental or genetic risk factors may be identifiable by considering different etiologic schema, including cross-classification based on ER/p53.
Anti–B-cell Maturation Antigen Chimeric Antigen Receptor T cell Function against Multiple Myeloma Is Enhanced in the Presence of Lenalidomide
Authors: Works Melissa , Soni Neha , Hauskins Collin , Sierra Catherine , Baturevych Alex , Jones Jon C. , Curtis Wendy , Carlson Patrick , Johnstone Timothy G. , Kugler David , Hause Ronald J. , Jiang Yue , Wimberly Lindsey , Clouser Christopher R. , Jessup Heidi K. , Sather Blythe , Salmon Ruth A. , Ports Michael O.
Published: August 2019

Anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells have shown promising clinical responses in patients with relapsed/refractory multiple myeloma. Lenalidomide, an immunomodulatory drug, potentiates T cell functionality, drives antimyeloma activity, and alters the suppressive microenvironment; these properties may effectively combine with anti-BCMA CAR T cells to enhance function. Using an anti-BCMA CAR T, we demonstrated that lenalidomide enhances CAR T cell function in a concentration-dependent manner. Lenalidomide increased CAR T effector cytokine production, particularly under low CAR stimulation or in the presence of inhibitory ligand programmed cell death 1 ligand 1. Notably, lenalidomide also enhanced CAR T cytokine production, cytolytic activity, and activation profile relative to untreated CAR T cells in chronic stimulation assays. This unique potentiation of both short-term CAR T activity and long-term functionality during chronic stimulation prompted investigation of the molecular profile of lenalidomide-treated CAR T cells. Signatures from RNA sequencing and assay for transposase-accessible chromatin using sequencing indicated that pathways associated with T-helper 1 response, cytokine production, T cell activation, cell-cycle control, and cytoskeletal remodeling were altered with lenalidomide. Finally, study of lenalidomide and anti-BCMA CAR T cells in a murine, disseminated, multiple myeloma model indicated that lenalidomide increased CAR T cell counts in blood and significantly prolonged animal survival. In summary, preclinical studies demonstrated that lenalidomide potentiated CAR T activity in vivo in low-antigen or suppressive environments and delayed onset of functional exhaustion. These results support further investigation of lenalidomide and anti-BCMA CAR T cells in the clinic.
The β2-Adrenergic Receptor Is a Molecular Switch for Neuroendocrine Transdifferentiation of Prostate Cancer Cells
Authors: Braadland Peder R. , Ramberg Håkon , Grytli Helene Hartvedt , Urbanucci Alfonso , Nielsen Heidi Kristin , Guldvik Ingrid Jenny , Engedal Andreas , Ketola Kirsi , Wang Wanzhong , Svindland Aud , Mills Ian G. , Bjartell Anders , Taskén Kristin Austlid
Published: August 2019

The incidence of treatment-related neuroendocrine prostate cancer (t-NEPC) is rising as more potent drugs targeting the androgen signaling axis are clinically implemented. Neuroendocrine transdifferentiation (NEtD), an putative initial step in t-NEPC development, is induced by androgen-deprivation therapy (ADT) or anti-androgens, and by activation of the β2-adrenergic receptor (ADRB2) in prostate cancer cell lines. Thus, understanding whether ADRB2 is involved in ADT-initiated NEtD may assist in developing treatment strategies that can prevent or reverse t-NEPC emergence, thereby prolonging therapeutic responses. Here we found that in primary, treatment-naïve prostate cancers, ADRB2 mRNA was positively correlated with expression of luminal differentiation markers, and ADRB2 protein levels were inversely correlated with Gleason grade. ADRB2 mRNA was upregulated in metastatic prostate cancer, and progressively downregulated during ADT and t-NEPC emergence. In androgen-deprivated medium, high ADRB2 was required for LNCaP cells to undergo NEtD, measured as increased neurite outgrowth and expression of neuron differentiation and neuroendocrine genes. ADRB2 overexpression induced a neuroendocrine-like morphology in both androgen receptor (AR)-positive and -negative prostate cancer cell lines. ADRB2 downregulation in LNCaP cells increased canonical Wnt signaling, and GSK3α/β inhibition reduced the expression of neuron differentiation and neuroendocrine genes. In LNCaP xenografts, more pronounced castration-induced NEtD was observed in tumors derived from high than low ADRB2 cells. In conclusion, high ADRB2 expression is required for ADT-induced NEtD, characterized by ADRB2 downregulation and t-NEPC emergence.

Implications:

This data suggest a potential application of β-blockers to prevent cancer cells committed to a neuroendocrine lineage from evolving into t-NEPC.
Neonatal Soft Tissue Sarcoma with YWHAE-NUTM2B Fusion
Authors: Guizard Maylis , Karanian Marie , Dijoud Frédérique , Bouhamama Amine , Faure-Conter Cécile , Hameury Frédéric , Tirode Franck , Corradini Nadège
Published: August 2019

Neonatal soft tissues sarcoma is a rare entity that comprises heterogeneous types of tumors. In this article we describe a neonatal case of round-cell sarcoma with an YWHAE-NUTM2B fusion gene. The patient was treated just after birth with neoadjuvant chemotherapy, then surgical resection, but evolution was quickly fatal. This fusion transcript has been reported in endometrial stromal sarcomas and clear cells renal sarcomas but its description in small round-cell sarcomas is recent. To our knowledge, this is the first case report describing this translocation in a newborn patient with soft tissues sarcoma and its clinical tumoral evolution.
Hypercalcaemia due to Sarcoidosis during Treatment with Avelumab for Metastatic Merkel Cell Carcinoma
Authors: Tun Min Sandy , Nordman Ina I.C. , Tran Huy A.
Published: August 2019

Merkel cell carcinoma is a rare but aggressive skin cancer. Response to chemotherapy is not durable but avelumab, an anti-PD-L1 inhibitor, showed promising ongoing response in a phase II trial. Checkpoint inhibitors including avelumab are known to cause overactivation of the immune system, leading to immune-related adverse events (irAE). We describe the first reported case of hypercalcaemia secondary to reactivation of sarcoidosis in a patient with metastatic Merkel cell carcinoma on avelumab. Hypercalcaemia was managed with corticosteroids to full resolution and avelumab therapy was safely continued.
ВПЛИВ МЕТФОРМІНУ НА ЕКСПРЕСІЮ α- ТА β-MHC ГЕНІВ ПІСЛЯ ІНФАРКТУ МІОКАРДА У МИШЕЙ
Authors: Loi H. Ya. , Oleshchuk O. М. , Korda M. M.
Published: August 2019

Цукровий діабет 2 типу діагностовано у понад 65 % пацієнтів, які помирають у результаті кардіоваскулярної патології. “Метформін” – препарат вибору для лікування цукрового діабету 2 типу, який проявляє виражені кардіопротективні ефекти. Проте молекулярні механізми захисту кардіоміоцитів потребують подальшого вивчення. Гіпертрофія кардіоміоцитів відіграє провідну роль у розвитку серцевої недостатності та вважається результатом дисбалансу між прогіпертрофічними та антигіпертрофічними факторами та їх механізмами, які контролюють ріст клітин. При серцевій недостатності та гіпертрофії виникає дисфункція генів α-MHC і β-MHC. У нормі α-MHC є домінантною ізоформою, проте при кардіальній дисфункції виникає апрегуляція β-MHC гена.

Мета дослідження – вивчити вплив препарату “Метформін” на гіпертрофію кардіоміоцитів та експресію генів α-MHC і β-MHC після інфаркту міокарда у мишей.

Матеріали і методи. Мишам типу C57BI/6J змодельовано ішемію/реперфузію. Щоб оцінити трансляційний потенціал метформіну, лікування було розпочато через 15 хв після ішемії/реперфузії у дозі 5 мг/кг/добу інтраперитонеально та тривало 14 днів. Серцеві кріосекції забарвлено за допомогою гематоксиліну та еозину. Площі клітин визначено за допомогою програми ImageJ. Аналіз рівнів експресії генів α-MHC та β-MHC здійснено за допомогою полімеразної ланцюгової реакції в реальному часі.

Результати досліджень та їх обговорення. Ішемія/реперфузія спровокувала виражену гіпертрофію клітин серця. У групі тварин, пролікованих метформіном після інфаркту міокарда, виявлено достовірне зменшення розмірів кардіоміоцитів, порівняно з групою тварин, які отримували ін’єкції PBS. Крім того, ішемія/реперфузія спричинила апрегуляцію β-MHC, хоча достовірних змін в експресії α-MHC не відбулося. Встановлено, що на експресію генів α- та β-MHC препарат “Метформін” не чинить ніякого впливу.

Висновки. Препарат “Метформін” захищає кардіоміоцити від гіпертрофічного ремоделювання після інфакту міокарда у мишей. Антигіпертрофічний ефект метформіну реалізується незалежно від експресії α- та β-MHC генів.
ОСОБЛИВОСТІ АНГІОАРХІТЕКТОНІКИ ПЕЧІНКОВИХ ВЕН ЩУРА ТА ЇХ РЕМОДЕЛЮВАННЯ ПРИ ОТРУЄННІ АЦЕТИЛСАЛІЦИЛОВОЮ КИСЛОТОЮ
Authors: Klantsa M.P.
Published: August 2019

Проблема розвитку токсичного ураження печінки в останні роки стає все більш актуальною. Все частіше зустрічається явище медикаментозного (токсичного) гепатиту, що розвивається в результаті прийому разової великої дози препарату чи тривалого вживання як під наглядом лікаря, так і без нього. Нестероїдні протизапальні препарати (НПЗП) фармакологічної групи, що поряд із протимікробними засобами масово фігурують у призначеннях лікарів у всьому світі. Серед даної групи ацетилсаліцилову кислоту виділяють як одну з найпоширеніших речовин, що буває у складі багатьох препаратів, які можна придбати чи отримати без рецепта.

Мета дослідження – вивчити, описати і проілюструвати особливості просторової організації печінкових вен інтактних статевозрілих щурів та їх реорганізацію при отруєнні ацетилсаліциловою кислотою.

Матеріали і методи. Експерименти проведено на 42 білих лабораторних статевозрілих щурах-самцях: інтрактні (n=6), гостре отруєння (n=6), хронічне отруєння (n=30). Гостре отруєння моделювали одноразовим внутрішньошлунковим введенням ацетилсаліцилової кислоти у дозі 500 мг на 1 кг маси тіла. Хронічну інтоксикацію – щоденним внутрішньошлунковим введенням ацетилсаліцилової кислоти у дозі 150 мг на 1 кг маси тіла. Оцінювали розміри і площу венозного колектора печінки, діаметри основних венозних магістралей (D), довжину їх сегментів між двома сусідніми розгалуженнями (L), діаметрально-довжинні співвідношення (L/D) та величину кутів злиття (φ). Методи дослідження: контрастна рентгенолографія, макроморфометрія. Контрольні терміни дослідження – 1; 3; 7; 14 і 28 діб від початку експерименту.

Результати досліджень та їх обговорення. При моделюванні тяжкого ступеня токсичності у першу добу експерименту гинули усі тварини. При цьому на їх контрастних рентгенангіограмах спостерігали значні зміни ангіоархітектоніки вен печінки. Вони проявлялися вираженим розширенням просвіту вен усіх контрастованих порядків, що візуально підтверджувалося посиленням судинного рисунка за рахунок більш глибокого контрастування дрібних гілок, а також результатами їх кількісного аналізу.

Висновки. Найбільші зміни виникають при гострому отруєнні великими дозами ацетилсаліцилової кислоти. При хронічному отруєнні зміни дещо менш виражені й у своєму перебігу проходять у декілька етапів. Отримані кількісні показники печінкових вен і венозного колектора можуть скласти основу для порівняння і встановлення ступеня змін у печінці щурів при експериментальному моделюванні патологічних процесів.