bluuebunny/crossref_metadata_2025 huggingface dataset:
ErMiao San Inhibits Angiogenesis in Rheumatoid Arthritis by Suppressing JAK/STAT Signaling Pathways
Authors: He Lianhua , Qin Qingxia , He Juan , Wang Han , Hu Yiping , He Wencheng , Xu Bihua , Zhou Gengmin , Shan Hongying , Yang Bo , Wang Qingwen
Published: February 2020

ErMiao San (EMS) is composed of the Cortex Phellodendri chinensis and Atractylodes lancea, and it has the function of eliminating heat and excreting dampness in terms of traditional Chinese medicine to damp heat syndrome. Previous reports indicate that EMS possesses anti‐inflammatory activity; however, its action on angiogenesis of rheumatoid arthritis (RA) has not been clarified. The present study aims to determine the antiangiogenic activity of EMS in collagen‐induced arthritis (CIA) mice and in various angiogenesis models. Our data showed that EMS (5 g/kg) markedly reduced the immature blood vessels in synovial membrane tissues of inflamed joints from CIA mice. It also inhibited vascular endothelial growth factor (VEGF)‐induced microvessel sprout formation ex vivo. Meanwhile, EMS suppressed VEGF‐induced migration, invasion, adhesion, and tube formation of human umbilical vein endothelial cells (HUVECs). Moreover, EMS significantly reduced the expression of angiogenic activators including interleukin (IL)‐1β, IL‐6, and tumor necrosis factor‐alpha (TNF‐α) in synovium of CIA mice. More interestingly, EMS blocked the autophosphorylation of VEGF‐induced JAK1, STAT1, and STAT6 in CIA mice and VEGF‐induced HUVECs. These findings suggest for the first time that EMS possesses the antiangiogenic effect in RA in vivo, ex vivo, and in vitro by interrupting the targeting of JAK/STAT activation.
Anisotropy Effect of Masonry on the Behaviour and Bearing Capacity of Masonry Walls
Authors: Smilović Zulim M. , Radnić J.
Published: February 2020

Firstly, an updated numerical model for the numerical analysis of planar unreinforced and confined masonry walls is presented. The model can simulate the main nonlinear material effects of masonry and reinforced concrete. A simplified anisotropic constitutive model for masonry is developed and presented. The criteria for the limit bearing capacity and collapse of masonry are separately defined for normal stresses only and for normal and shear stresses. The presented numerical model is verified and used to analyse the anisotropy effect of masonry on the behaviour of unreinforced and confined two‐story anisotropic masonry walls with different coefficients of anisotropy, wall lengths, and quality of masonry under horizontal static forces. The influence of the anisotropy coefficient of the masonry on the response of the walls is discussed in detail, and the main conclusions are given.
Visualizing the Knowledge Domain of Project Governance: A Scientometric Review
Authors: Zhai Zhao , Shan Ming , Darko Amos , Le Yun
Published: February 2020

Over the past two decades, project governance has attracted increasing attention from researchers and practitioners worldwide and has become an important research area of project management. However, an inclusive quantitative and systematic analysis of the state‐of‐the‐art recently available research in this field is still missing. This study attempts to map the global research on project governance through a state‐of‐the‐art review. A total of 285 bibliographic records were retrieved from the Web of Science Core Collection database and analyzed by the visual analytic tool—CiteSpace. The results indicated that there has been an increasing research interest in project governance. The most productive and the most highly cited author in the area of project governance is Müller R., and most of the existing project governance research achievements are from Australia, China, USA, and Norway. By synthetically analyzing the keywords, future research might focus on governance of megaprojects and project success. Additionally, 9 knowledge domains of project governance were identified, including conceptual framework, public projects, governance structure, governance context, megaproject governance, contractual and relational governance, sustainability, portfolio governance, and project success. This study contributes to the body of knowledge by mapping the existing project governance research. It is particularly helpful to new and early‐stage researchers who plan to do research on project governance, as it can provide them an overview of project governance research, including key authors, main institutions, hot topics, and knowledge domains. Moreover, the findings from the study are beneficial to industry practitioners as well, as they can help industry practitioners understand the latest development of governance theory and practice and thereby help them locate the best governance strategies for project management.
Successful Management of Ludwig’s Angina due to Dental Implant Displacement: A Rare Case Report
Authors: Cardoso Lincoln Lara , Gasperini Giovanni , Cardoso Leandro Carvalho , Scartezini Guilherme Romano , Campos Annika Ingrid Maria Soderberg , Marão Heloisa Fonseca
Published: February 2020

Dental implant surgery is a common procedure in oral and maxillofacial surgery practices. Extensive training, skill, and experience allow this procedure to be performed with an atraumatic approach, but like any surgical technique, it is subject to accidents and complications. This is an unusual clinical case of an accidental displacement of an implant into the submandibular space that progressed to Ludwig’s angina, and it has not yet been described in the literature. This case report describes a clinical case of dental implant displaced into the submandibular space after healing cap removal. After seven days, it progressed to Ludwig’s angina. The removal was performed through extraoral access in the submandibular area by using hemostatic forceps and radioscopic technique. After implant removal, the clinical case showed a satisfactory repair emphasizing the importance of a meticulous clinical planning to achieve an appropriate treatment plan, which is essential for a favorable prognosis. Therefore, prevention and management of displaced objects requires proper planning and surgical technique.
A Strength Design Method of Cemented Backfill with a High Aspect Ratio
Authors: Wang Zhi-zhihui , Wu Ai-xiang , Wang Hong-jiang
Published: February 2020

To calculate the required strength of a cemented backfill with high aspect ratio, the confirmation of lateral pressure is fundamental and needs to be determined first. As for the backfill with a high aspect ratio of height to length, the shape of the slip surface is not straight when in the active state due to the limited space, which is different from the general backfill. For this reason, a formulation of the slip surface with a curved shape and a lateral pressure calculation method based on this curved slip surface were proposed. The proposed equation of the slip surface is affected by the geometry parameters of the backfill, internal friction angle of the backfill, and the friction angle of the backfill‐rock interface. Then, by the combination of the minor principal stress trajectory method and the horizontal slice method, an ordinary differential equation of stresses was established and then solved numerically. Finally, the method based on Mitchell’s three‐dimensional limit equilibrium model was used to calculate the required strength of the cemented backfill. The calculated results were compared with previous studies and validated with numerical models. The results showed good consistency for the backfills with high aspect ratios.
Inhibition of SHP-1 Expands the Repertoire of Antitumor T Cells Available to Respond to Immune Checkpoint Blockade
Authors: Snook Jeremy P. , Soedel Ashleigh J. , Ekiz H. Atakan , O'Connell Ryan M. , Williams Matthew A.
Published: February 2020

The presence and activity of CD8+ T cells within the tumor microenvironment are essential for the control of tumor growth. Utilizing B16-F10 melanoma tumors that express altered peptide ligands of chicken ovalbumin, OVA257-264, we measured high- and low-affinity OVA-specific responses following adoptive transfer of OT-I CD8+ T cell into mice subsequently challenged with tumors. T-cell receptor (TCR) affinity positively correlated with the frequency of OT-I tumor-infiltrating lymphocytes (TIL). Differences in TCR affinity inversely corresponded to in vivo tumor growth rate. Blockade of the PD-1 and CTLA-4 checkpoints preferentially increased the frequency and antitumor function of TIL responding to high-affinity antigens, while failing to enhance the antitumor activity of low-affinity T cells. To determine whether lowering the TCR activation threshold could enhance the breadth and magnitude of the antitumor T-cell response, we inhibited Src homology region 2 domain–containing phosphatase 1 (SHP-1) in OT-I T cells prior to tumor antigen exposure. SHP-1 knockdown increased the cytokine-producing potential of high- and low-affinity T cells but failed to enhance control of tumor growth. In contrast, when SHP-1 knockdown of OT-I T cells was combined with immunotherapy, we observed a significant and long-lasting suppression of tumor growth mediated by low-affinity T cells. We conclude that lowering the TCR activation threshold by targeting SHP-1 expands the repertoire of T cells available to respond to conventional checkpoint blockade, leading to enhanced control of tumor growth.
Publication Patterns of Presentations at the 16th Quadrennial Meeting of the World Society for Stereotactic and Functional Neurosurgery
Authors: Sarica Can , Kucuk Furkan , Ozen Ali , Aksu Sayman Ozden
Published: February 2020

Background: The quality of a scientific meeting can be quantified by the rate of full publications arising from the presented abstracts and the impact factor of the journals in which the studies were published. Objectives: The aim of this study was to investigate the publication rates of presentations from the 2013 World Society for Stereotactic and Functional Neurosurgery (WSSFN) quadrennial meeting. Methods: Scopus and PubMed databases were searched for the authors of the presentations to identify full publications arising from the relevant abstracts. Author and content matching were used to match an abstract with a full publication. Mann-Whitney U and Kruskal-Wallis tests were used for statistical analysis. Results: In total, 77% (57/74), 56% (44/79), and 50% (79/157) of the paper, flash, and poster presentations, respectively, have been published, with an overall publication rate of 58% (180/310). Articles received a total of 5,227 citations, with an average of 29 ± 64.1 citations per article. The first authors who published their studies had a significantly higher h-index than those who did not publish (p = 0.003). The most preferred journals for publication were Journal of Neurosurgery, Acta Neurochirurgica, and Stereotactic and Functional Neurosurgery. The majority of the articles (117/180 [65%]) were published in a quartile 1 or 2 journal. The average journal impact factor (JIF) was 4.5 for all presentations, and 7.8 for paper session presentations. Studies presented in paper sessions were published in significantly higher-impact factor journals than those presented in poster sessions (p < 0.001). Conclusions: The WSSFN Congress had a relatively high overall publication rate (58%) compared to both other neurosurgical congresses and congresses in other scientific fields. The average JIF of 7.8 is a reflection of the high quality and high impact of the paper session presentations.
Association of Disease Subtype and Duration with Echocardiographic Evidence of Pulmonary Hypertension in Myeloproliferative Neoplasm
Authors: Yaylali Yalin Tolga , Yilmaz Samet , Akgun-Cagliyan Gulsum , Kilic Oguz , Kaya Emrah , Senol Hande , Ozen Furkan
Published: February 2020

Background: Pulmonary hypertension (PH) can complicate the course of myeloproliferative neoplasms (MPNs). Echocardiography is a useful noninvasive screening test for PH in populations at risk. We aimed to investigate the echocardiographic evidence of PH and clinical characteristics of patients with MPNs. Methods: This study included 197 patients with MPNs (mean age, 59 ± 14 years; females, 53%; mean disease duration, 3.4 ± 2.8 years). Clinical and laboratory characteristics, including JAK2V617F mutation status, were obtained. All participants underwent a comprehensive transthoracic echocardiographic examination. The echocardiographic evidence of PH was defined as systolic pulmonary artery pressure (SPAP) ≥40 mm Hg. Results: Overall, 11 patients (5.5%) with SPAP ≥40 mm Hg had echocardiographic evidence of PH. Patients with myelofibrosis had echocardiographic evidence of PH more often than patients with other MPNs (p < 0.001). Disease duration since the diagnosis of MPNs was 6.7 ± 4.6 years in the PH group and 3.1 ± 2.5 years in the non-PH group (p < 0.001). There was a weak positive correlation between SPAP values and time since diagnosis (r = 0.236, p =0.001). JAK2V617F mutation was not associated with PH. In multivariate logistic regression analysis, the presence of myelofibrosis (odds ratio [OR]: 22.177, 95% CI: 4.480–109.790, p < 0.001), long disease duration (OR: 1.217, 95% CI: 1.024–1.447, p = 0.026), and high uric acid levels (OR: 1.868, 95% CI: 1.049–3.328, p = 0.034) were found to be related with the echocardiographic evidence of PH. Survival was worse in the PH group (p = 0.0001). Conclusion: Our results suggest that patients with myelofibrosis are more likely to develop PH than other MPNs patients. Disease duration may predict the development of PH in MPN patients.
Soviet-Brazilian Relations and the Cuban Missile Crisis
Authors: Hershberg James G.
Published: February 2020

Using materials from the Russian Foreign Ministry archive in Moscow (combined with previously obtained Brazilian and U.S. sources), this research note presents fresh evidence about Soviet-Brazilian relations and the October 1962 Cuban missile crisis, supplementing a detailed, two-part article published in the Journal of Cold War Studies in 2004 exploring Brazil's secret mediation between John F. Kennedy and Fidel Castro at the height of the crisis. The new evidence illuminates a previously hidden “double game” that Brazil's president, João Goulart, played during the crisis as he alternated between meetings with the U.S. ambassador and Nikita Khrushchev's recently arrived envoy (Brazil and the Soviet Union had just restored diplomatic relations after a fifteen-year break). The new evidence from Moscow suggests that Goulart, who vowed solidarity with Washington and even toasted Kennedy's “victory” when talking to the U.S. ambassador, took a completely different approach when speaking to Soviet officials, expressing strong sympathy and even support for Khrushchev.
Spatial Neuronal Integration Supports a Global Representation of Visual Numerosity in Primate Association Cortices
Authors: Viswanathan Pooja , Nieder Andreas
Published: February 2020

Our sense of number rests on the activity of neurons that are tuned to the number of items and show great invariance across display formats and modalities. Whether numerosity coding becomes abstracted from local spatial representations characteristic of visual input is not known. We mapped the visual receptive fields (RFs) of numerosity-selective neurons in the pFC and ventral intraparietal area in rhesus monkeys. We found numerosity selectivity in pFC and ventral intraparietal neurons irrespective of whether they exhibited an RF and independent of the location of their RFs. RFs were not predictive of the preference of numerosity-selective neurons. Furthermore, the presence and location of RFs had no impact on tuning width and quality of the numerosity-selective neurons. These findings show that neurons in frontal and parietal cortices integrate abstract visuospatial stimuli to give rise to global and spatially released number representations as required for number perception.
New species and records of the genus Syllis Savigny in Lamarck, 1818 (Annelida: Syllidae) from Socotra Archipelago (Indian Ocean)
Authors: RODRÍGUEZ YOLANDA LUCAS , SAN MARTÍN GUILLERMO , FIEGE DIETER
Published: February 2020

Based on a census of the polychaete fauna of the Socotra Archipelago in the Indian Ocean we report here new findings on the genus Syllis Savigny in Lamarck, 1818. These ten species are newly recorded from this area: Syllis alternata Moore, 1908; Syllis bouvieri Gravier, 1900; Syllis broomensis (Hartmann-Schröder, 1979); Syllis compacta Gravier, 1900; Syllis crassicirrata (Treadwell, 1925); Syllis gerlachi (Hartmann-Schröder, 1960); Syllis hyalina Grube, 1863; Syllis lutea (Hartmann-Schröder, 1960); Syllis schulzi (Hartmann-Schröder, 1960); Syllis ypsiloides Aguado, San Martín & Ten Hove, 2008. Additionally, Syllis qamhiyn sp. nov. is described as a new species, characterized by its conspicuously thick and short dorsal cirri filled with a gelatinous substance and reduced number of compound chaetae from medium to posterior parapodia, with enlarged shafts and short blades which become almost unidentate and do not fuse with shafts. Following an examination of the holotype of S. bouvieri, its status as a valid species and not as synonym of Syllis prolifera Krohn, 1852, as considered by some authors (see Licher 1999) is confirmed, and a redescription is included.
Presentation of BK polyomavirus–associated hemorrhagic cystitis after allogeneic hematopoietic cell transplantation
Authors: Imlay Hannah , Xie Hu , Leisenring Wendy M. , Duke Elizabeth R. , Kimball Louise E. , Huang Meei-Li , Pergam Steven A. , Hill Joshua A. , Jerome Keith R. , Milano Filippo , Nichols W. Garrett , Pang Phillip S. , Hirsch Hans H. , Limaye Ajit P. , Boeckh Michael
Published: February 2020

BK polyomavirus (BKPyV) has been associated with hemorrhagic cystitis (HC) after allogeneic hematopoietic cell transplantation (HCT), but the natural history of HC and factors associated with the clinical course are incompletely understood. We retrospectively analyzed allogeneic HCT patients transplanted from 2007-2017 who presented after platelet engraftment or after day 28 post-HCT with BKPyV-associated HC (BKPyV-HC), which was defined as a positive urine BKPyV PCR, ≥1 plasma BKPyV viral load result, and macroscopic hematuria (Bedi grade ≥2). Factors associated with resolution of macroscopic hematuria and resolution of all cystitis symptoms within 90 days after HC diagnosis were investigated in multivariable models. In 128 patients with BKPyV-HC, the median times from diagnosis to resolution of all symptoms, macroscopic hematuria, and urinary clots (present in 55% [71/128]) were 24 days (15-44), 17 days (10-30), and 14 days (5-26), respectively. Ninety percent of patients had BKPyV viremia at the onset of HC with a median viral load of 1850 copies/mL (interquartile range, 240-8550). In multivariable models, high plasma viral load (≥10 000 copies/mL) and cytopenias at the beginning of BKPyV-HC were significantly associated with longer macroscopic hematuria and cystitis symptoms. Use of cidofovir was not associated with shorter duration of illness. In conclusion, BKPyV-HC after allogeneic HCT is characterized by prolonged and severe symptoms and requires improved management strategies. High-grade viremia and cytopenias were associated with a longer duration of BKPyV-associated HC. Accurate descriptions of disease and factors associated with prolonged recovery will inform end points of future clinical trials.
Curdione ameliorates bleomycin-induced pulmonary fibrosis by repressing TGF-β-induced fibroblast to myofibroblast differentiation
Authors: Liu Peng , Miao Kang , Zhang Lei , Mou Yong , Xu Yongjian , Xiong Weining , Yu Jun , Wang Yi
Published: February 2020

Background

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible disease characterized by excessive fibroblast to myofibroblast differentiation with limited therapeutic options. Curdione, a sesquiterpene compound extracted from the essential oil of Curcuma aromatica Salisb, has anti-inflammatory and anti-tumor effects. However, the role of curdione in IPF is still unclear.

Methods

The effects of curdione were evaluated in a bleomycin (BLM)-induced pulmonary fibrosis mouse model. C57BL/6 mice were treated with BLM on day 0 by intratracheal injection and intraperitoneal administered curdione or vehicle. In vitro study, expression of fibrotic protein was examined and the transforming growth factor (TGF)-β-related signaling was evaluated in human pulmonary fibroblasts (HPFs) treated with curdione following TGF-β1 stimulation.

Results

Histological and immunofluorescent examination showed that curdione alleviated BLM-induced lung injury and fibrosis. Specifically, curdione significantly attenuated fibroblast to myofibroblast differentiation in the lung in BLM induced mice. Furthermore, curdione also decreased TGF-β1 induced fibroblast to myofibroblast differentiation in vitro, as evidenced by low expression of α-SMA, collagen 1 and fibronectin in a dose dependent manner. Mechanistically, curdione suppressed the phosphorylation of Smad3 following TGF-β1 treatment, thereby inhibiting fibroblast differentiation.

Conclusions

Overall, curdione exerted therapeutic effects against pulmonary fibrosis via attenuating fibroblast to myofibroblast differentiation. As curdione had been shown to be safe and well-tolerated in BLM-induced mouse model, curdione might be useful for developing novel therapeutics for IPF.
Unveiling synapse pathology in spinal bulbar muscular atrophy by genome-wide transcriptome analysis of purified motor neurons derived from disease specific iPSCs
Authors: Onodera Kazunari , Shimojo Daisuke , Ishihara Yasuharu , Yano Masato , Miya Fuyuki , Banno Haruhiko , Kuzumaki Naoko , Ito Takuji , Okada Rina , de Araújo Herculano Bruno , Ohyama Manabu , Yoshida Mari , Tsunoda Tatsuhiko , Katsuno Masahisa , Doyu Manabu , Sobue Gen , Okano Hideyuki , Okada Yohei
Published: February 2020

Spinal bulbar muscular atrophy (SBMA) is an adult-onset, slowly progressive motor neuron disease caused by abnormal CAG repeat expansion in the androgen receptor (AR) gene. Although ligand (testosterone)-dependent mutant AR aggregation has been shown to play important roles in motor neuronal degeneration by the analyses of transgenic mice models and in vitro cell culture models, the underlying disease mechanisms remain to be fully elucidated because of the discrepancy between model mice and SBMA patients. Thus, novel human disease models that recapitulate SBMA patients’ pathology more accurately are required for more precise pathophysiological analysis and the development of novel therapeutics. Here, we established disease specific iPSCs from four SBMA patients, and differentiated them into spinal motor neurons. To investigate motor neuron specific pathology, we purified iPSC-derived motor neurons using flow cytometry and cell sorting based on the motor neuron specific reporter, HB9e438::Venus, and proceeded to the genome-wide transcriptome analysis by RNA sequences. The results revealed the involvement of the pathology associated with synapses, epigenetics, and endoplasmic reticulum (ER) in SBMA. Notably, we demonstrated the involvement of the neuromuscular synapse via significant upregulation of Synaptotagmin, R-Spondin2 (RSPO2), and WNT ligands in motor neurons derived from SBMA patients, which are known to be associated with neuromuscular junction (NMJ) formation and acetylcholine receptor (AChR) clustering. These aberrant gene expression in neuromuscular synapses might represent a novel therapeutic target for SBMA.
Effect of transcranial direct current stimulation and multicomponent training on functional capacity in older adults: protocol for a randomized, controlled, double-blind clinical trial
Authors: Costa Glaucio Carneiro , Corrêa João Carlos Ferrari , Silva Soraia Micaela , Corso Simone Dal , da Cruz Stefany Ferreira , de Souza Cunha Micaelly , Souza Paulo Henrique Leite , Saldanha Marcella Leiva , Corrêa Fernanda Ishida
Published: February 2020

Introduction

When physical activity contains training of at least three components such as balance, coordination and strength, among others, it is called multicomponent training. This type of training is recommended for improving the functional capacity in elderly individuals but has no lasting effects. The association of transcranial direct current stimulation (tDCS) with other types of therapy has been shown to facilitate the enhancement and prolongation of therapy outcomes.

Aim

The objective of this study is to evaluate the effect of multicomponent training associated with active or sham tDCS on the performance of functional capacity in the elderly before treatment, after treatment and 30 days after the end of treatment. The secondary objective will be to correlate the performance of the primary outcome (functional capacity assessed by the Glittre Daily Life Activity Test) with walking capacity (by 6-min walk test), balance (with the mini-Balance Evaluation Systems Test), functional independence (by the Functional Independence Measure) and quality of life (with the World Health Organization Quality of Life Instrument).

Methods

Twenty-eight elderly people from the community will participate in the study, and will be randomized into two groups: 1) multicomponent training associated with active tDCS; and 2) multicomponent training associated with sham tDCS. The multicomponent training sessions will be held twice a week for 12 weeks, totaling 24 sessions. The tDCS will be administered over the dominant dorsolateral prefrontal cortex at the same time as multicomponent training, with an intensity of 2 mA, for 20 min. The evaluations will be made pretraining, after 24 training sessions and 30 days after the end of the training.

Discussion

We hypothesize that tDCS, when associated with multicomponent training, can potentiate and prolong the effects of this training on the functional capacity of the elderly. If this hypothesis is confirmed, this protocol may contribute to a longer-lasting physical rehabilitation of the elderly, encouraging them to maintain their independent daily activities for longer.

Trial registration

The study was registered in the Brazilian Clinical Trial Registry (RBR-2crd42) and received approval from the Human Research Ethics Committee of University Nove de Julho, São Paulo, Brazil (process number 3.077.953).
Time series classification based on statistical features
Authors: Lei Yuxia , Wu Zhongqiang
Published: February 2020

This paper presents a statistical feature approach in fully convolutional time series classification (TSC), which is aimed at improving the accuracy and efficiency of TSC. This method is based on fully convolutional neural networks (FCN), and there are the following two properties: statistical features in data preprocessing and fine-tuning strategies in network training. The key steps are described as follows: firstly, by the window slicing principle, dividing the original time series into multiple equal-length subsequences; secondly, by extracting statistical features on each subsequence, in order to form a new sequence as the input of the neural network, and training neural network by the fine-tuning idea; thirdly, by evaluating the classification performance about test sets; and finally, by comparing the sample sequence complexity and network classification loss accuracy with the FCN using the original sequence. Our experimental results show that the proposed method improved the classification effects of FCN and the residual network (ResNet), which means that it has a generalization ability to the network structures.
Statistical analysis of the interaction between irradiation-induced defects and triple junctions
Authors: Zarnas Patrick , Dingreville Rémi , Muntifering Brittany , Hattar Khalid , Boyce Brad L. , Qu Jianmin
Published: February 2020

By using a generalized, spatially resolved rate theory, we systematically studied the irradiation-induced diffusion and segregation of point defects near triple junctions. Our model captured not only the formation, growth, and recombination of point defects but also the interaction of these defects with pre-existing defects. We coupled the stress field of the triple junction with defect diffusion via a modified chemical potential. The residual stress fields of grain boundaries and triple junctions are modeled via disclination mechanics theory. By assessing the behavior of 144 triple junctions with vacancy and interstitial defects, we correlated defect-sink efficiencies with key characteristics of triple junctions. For vacancies, the geometric configuration of triple junctions dominated sink efficiency, suggesting that equiaxed grains would resist the accumulation of vacancies more than elongated grains. For interstitials, the sink density of the grain boundaries composing the triple junctions dominated sink efficiency. Hence, the interstitial concentration may be managed by adjusting the structure of the grain boundaries. Overall, we illustrated the complex coupling between pre-existing defects and radiation-induced defects through interaction of their stress fields. This theoretical framework provides an efficient tool to rapidly assess defect management in microstructures.
Improving patient flow in acute psychiatric wards: enhanced bed management and trusted assessment
Authors: Turkington Douglas , Moorhead Steve , Turkington Gordon D. , King Carla , Bell Leigh , Pickersgill Denise
Published: February 2020

Aims and method

In three localities in a mental health trust in England, an enhanced bed management team was established to improve patient flow and reduce out-of-area placements. Trusted assessments were provided to support risk management and conflict resolution. Two measures of flow were compared before and after the team was established.

Results

The trusted assessment recommendation was for discharge in 70% of cases. The number of out-of-area placements was significantly reduced (P < 0.05), saving £616 876 over a 12-month period. Patient flow was significantly improved in one of the three localities as measured by patients/bed/6-month period (P < 0.05). In one of the other localities increased use of trusted assessment input and reduced numbers of patients being transferred in are recommended to improve flow.

Clinical implications

Mental health trusts should consider the establishment of an enhanced bed management team, including trusted assessment, as a safe and cost-effective approach to improving patient flow and reducing the need for out-of-area placement.
Discontinuing psychotropic drug treatment
Authors: Tondo Leonardo , Baldessarini Ross J.
Published: February 2020

Interruption of ongoing treatment with benzodiazepines, antidepressants, antipsychotics and mood stabilisers including lithium can be followed by clinically significant withdrawal reactions within hours or days, as well as later increases in relapses or recurrences of the illness being treated. Such observations support the view that stopping treatment is not equivalent to being untreated. With lithium, antipsychotics and antidepressants, there is consistent evidence that abrupt or rapid discontinuation is followed by earlier clinical worsening than with more gradual removal of treatment. Moreover, treatment discontinuation can complicate interpretation of responses to changes in treatment, including in clinical practice and in experimental treatment trials. Notably, terminating preceding treatments can lead to both discontinuation and carry-over effects that can have an impact on the interpretation of observed outcomes.
KEYNOTE-365 cohort C updated results: Pembrolizumab (pembro) plus enzalutamide (enza) in abiraterone (abi)-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC).
Authors: Berry William R. , Fong Peter C.C. , Piulats Josep M. , Appleman Leonard Joseph , Conter Henry Jacob , Feyerabend Susan , Shore Neal D. , Gravis Gwenaelle , Laguerre Brigitte , Gurney Howard , Retz Margitta , Romano Emanuela , Mourey Loic , De Bono Johann S. , Kam Audrey E. , Emmenegger Urban , Wu Helen , Schloss Charles , Poehlein Christian Heinrich , Yu Evan Y.
Published: February 2020

102

Background: KEYNOTE-365 (NCT02861573) is a phase 1b/2 study evaluating pembro in combination with other agents in mCRPC. An earlier report of cohort C showed activity and acceptable safety with pembro + enza. Updated results from cohort C are reported. Methods: Pts who failed or became intolerant to ≥4 wks of abi in prechemotherapy mCRPC state and whose disease progressed within 6 mo of screening per PSA progression or radiologic bone or soft tissue progression enrolled. Pts received pembro 200 mg IV Q3W with enza 160 mg/day PO. Primary end points: safety, PSA response rate (confirmed PSA decline ≥50%), and objective response rate (ORR) per blinded independent central review. Key secondary end points: disease control rate (DCR), duration of response (DOR), time to PSA progression, rPFS, and OS. Results: Of 102 treated pts, 73 discontinued, primarily due to progression (60%). Median age was 70 y (range, 43-87), 29% were PD-L1+, 17% had visceral disease, and 39% had measurable disease. Median follow up was 13 mo for all patients (n=102) and 17 mo for patients with ≥27 wks’ follow-up (n=69). See Table for efficacy outcomes. Treatment-related AEs occurred in 92 pts (90%); most frequent (≥20%) were fatigue (38%), nausea (22%), and rash (20%). Grade 3-5 treatment-related AEs occurred in 40 pts (39%). Three pts died of AEs (1 AE was treatment related [cause unknown]). Conclusions: With additional follow-up, pembro + enza continued to show activity in pts with abi-pretreated mCRPC. Safety of the combination was consistent with known profiles of pembro and enza. Clinical trial information: NCT02861573. [Table: see text]
Association of tumor burden with the eligibility of upfront therapy in patients with castration-naive prostate cancer: A multicenter retrospective study.
Authors: Iwamura Hiromichi , Hatakeyama Shingo , Narita Shintaro , Sakurai Toshihiko , Kawamura Sadafumi , Hoshi Senji , Saito Fumitada , Kawaguchi Toshiaki , Mitsuzuka Koji , Ito Akihiro , Tsuchiya Norihiko , Arai Yoichi , Habuchi Tomonori , Ohyama Chikara
Published: February 2020

107

Background: Although several large-scale studies reported a robust benefit of upfront therapy for mHNPC, not all patients with mHNPC experienced mCRPC progression. As there is a concern for overtreatment in patients with low-risk/volume disease, we aimed to identify potential candidates for upfront therapy in patients with metastatic hormone-naïve prostate cancer (mHNPC). Methods: We retrospectively evaluated 679 patients with mHNPC who were initially treated with conventional androgen deprivation therapy. We defined the patients with progression to metastatic castration-resistant prostate cancer (mCRPC) as potential candidates for upfront therapy. To estimate the suitable candidate for upfront therapy, we retrospectively compared mCRPC progression rate, mCRPC-free survival, and overall survival (OS) after castration-resistance (OS-CR) between the low- and high-volume disease groups. Furthermore, we tried to develop a novel prediction model using deep learning algorithm. Results: The number of patients with mCRPC progression (potential candidates for upfront therapy) was 119 (52%) and 319 (71%) in the low- and high-volume disease groups. The mCRPC progression rate and CRPC-free survival were significantly worse in high-volume disease group ( P < 0.01), but no difference was found for OS-CR. Multivariate Cox regression analysis showed no significant association between tumor volume and OS-CR (HR 1.14, P=0.52). The deep learning model showed not high accuracy of mCRPC prediction (AUC 0.66). Conclusions: Approximately a half of patients with low-volume disease had progression to mCRPC. As the OS-CR in the patients with low-volume disease showed poor prognosis as well as those with high-volume disease, upfront therapy may be needed for a half of patients with low-volume disease.
Docetaxel (DOC) versus new androgen receptor-targeted agent (ART) in metastatic castrate-resistant prostate cancer (mCRPC) patients (pts) having received abiraterone (ABI) or enzalutamide (ENZA) as first-line (L1).
Authors: Broyelle Antonin , Bimbai André-Michel , Carnot Aurelien , Pannier Diane , Makhloufi Samira , Ryckewaert Thomas , Penel Nicolas , Oudard Stephane
Published: February 2020

109

Background: The main treatments for mCRPC are 2 new ART (ABI, ENZA) and 2 taxanes [doctaxel (DOC) and Cabazitaxel]. The optimal sequence is currently not defined. An increasing number of pts are first treated with one of ART. In this population, data about efficacy of 2nd line (L2) are spare. We designed a retrospective study to evaluate activity of DOC vs ART in mCRPC pts treated with ART as L1 therapy. Methods: In this observational cohort study, we included all consecutive pts with ENZA or ABI as L1 for chemo-naïve mCRPC. We measured PFS and OS during both L1 & L2. To compare the efficacy of DOC versus ART as L2, we measured Growth Modulation Index (GMI=Time To progression with L2/TTP with L1) and we used Cox model to compare PFS/OS in both arm, in both univariate & multivariate analysis using propensity score. Results: We included 175 pts, including 75 treated ENZA and 100 with ABI as L1. 69 (39%) pts received DOC and 30 (17%) pts received ART as L2; 76 (43%) did not receive L2. Median follow-up was 36 months (CI95%: 30.4 - 40). From the starting of L1, PFS was 13.0 months (CI95% 11.0 – 15.0), OS was 34.5 months (CI95%: 28.7 – 38.6). There was no difference between ENZA and ABI in PFS and OS (p=0.684). From the start of L2, the median PFS was 6.0 months (CI95%: 5.0 – 6.6) and the median OS was 18.0 months (CI95%: 13.9 – 21.4). We found a significant benefit in PFS for DOC vs ART in L2 (6.7 months vs 4.0 months, HR 0.60 [CI95%: 0.31 – 0.96], p=0.03). This benefit did not reach the level of significance in OS (19.5 months vs 12.0 months, HR 0.60 [CI95%: 0.35 – 1.03], p=0.1). ECOG-PS and time of castration resistance were associated with OS in multivariable analysis and then used in propensity score. After adjustment to both parameters, we found no difference in PFS (p=0.2) and OS (p=0.1) in pts receiving DOC vs ART as L2. Only 56% of pts received L2. Probability for GMI being >1.33 was not significantly different between DOC (19%) and ART (13%), p=0.099. Conclusions: ABI and ENZA are similarly active in L1 mCRPC. In univariate analysis, L2 with DOC seemed more active than ART. However this benefit was not retained after adjustment to propensity score.
Systemic therapy for nonmetastatic castrate-resistant prostate cancer (M0 CRPC): A systematic review and network meta-analysis (NMA).
Authors: Cusano Ellen , Lee-Ying Richard M. , Boyne Devon J. , Brenner Darren , Vaska Marcus
Published: February 2020

113

Background: The treatment landscape for M0 CRPC has changed following the demonstrated efficacy of new agents in recent randomized control trials (RCT). However, the comparative effectiveness of these novel agents is unknown. This NMA indirectly compared the efficacy and safety of available therapies for M0 CRPC. Methods: A literature search of MEDLINE (Ovid), EBM Reviews, HealthSTAR, PubMed, PubMed Central, CINAHL, and TRIP Database was performed. Studies were screened by two independent reviewers. Hazard ratios (HR) and confidence intervals were extracted for the primary outcome metastasis-free survival (MFS) and the secondary outcomes overall survival (OS) and grade 3 or higher adverse events (AE). Bone MFS was used as a surrogate for MFS when MFS was not reported. Risk of bias was assessed using the Cochrane Collaboration tool. A Bayesian NMA was performed using a fixed-effects model. Results: Four RCT were analyzed (n=5549). Each trial compared either apalutamide (APA), enzalutamide (ENZA), darolutamide (DARO), or denosumab (DENO) plus androgen deprivation therapy (ADT) to placebo plus ADT. Risk of bias was low. For MFS, APA and ENZA had similar efficacy (Table), and Surface Under the Cumulative Ranking Analysis demonstrated a 59% probability that APA was preferred for MFS, followed by ENZA (41%). There was a trend for improved OS for APA, DARO and ENZA, but no meaningful differences between these agents. APA, ENZA, and DARO had a similar risk of AEs and all had a greater risk of AEs compared to DENO. Conclusions: APA and ENZA appear to be the most efficacious treatments for MFS in M0 CRPC, though more data for OS is required. Compared to DARO, APA and ENZA’s demonstrated efficacy is not at the expense of added toxicity.[Table: see text]
Phase I study of pasotuxizumab (AMG 212/BAY 2010112), a PSMA-targeting BiTE (Bispecific T-cell Engager) immune therapy for metastatic castration-resistant prostate cancer (mCRPC).
Authors: Hummel Horst-Dieter , Kufer Peter , Grüllich Carsten , Deschler-Baier Barbara , Chatterjee Manik , Goebeler Maria-Elisabeth , Miller Kurt , De Santis Maria , Loidl Wolfgang C. , Buck Andreas , Wittemer-Rump Sabine , Koca Goekben , Boix Oliver , Doecke Wolf-Dietrich , Stienen Sabine , Sayehli Cyrus , Bargou Ralf C.
Published: February 2020

124

Background: mCRPC has a poor prognosis and immunotherapies are largely ineffective. PSMA is a promising therapeutic target in mCRPC. Pasotuxizumab is a PSMA x CD3 BiTE immune therapy that mediates killing of tumor cells by T cells. Methods: NCT01723475 was a first-in-human, multicenter, dose-escalation study in patients (pts) with mCRPC refractory to standard therapy. Pts received continuous IV infusion of pasotuxizumab in cohorts of 3–4 pts. Dose-escalation followed a continuous reassessment methodology. The primary objective was to determine safety and maximum tolerated dose (MTD); secondary objectives included pharmacokinetics, biomarkers, and tumor response. Results: 16 pts were enrolled into 5 dosing cohorts (5 µg/d, n=3; 10 µg/d, n=4; 20 µg/d, n=3; 40 µg/d, n=4; 80 µg/d, n=2). All pts had ≥1 AE of any grade; most common were fever (94%), chills (69%), and fatigue (50%). 13 pts (81%) had ≥1 AE of grade ≥3; most common were decreased lymphocytes and infections (both 44%). No grade 5 AE occurred. A serious drug-related AE was reported for 1 pt (fatigue, 20 µg/d). No antidrug antibodies were observed. Recruitment was stopped before MTD was reached to allow initiation of a new study sponsored by Amgen. Antitumor activity as indicated by PSA serum level decline was dose dependent, with a mean best PSA change per dosing cohort vs baseline of +0.74% (5 µg/d), −17.9% (10 µg/d), −37.4% (20 µg/d), −42.5% (40 µg/d) and −54.9% (80 µg/d). PSA decreases ≥50% occurred in 3 pts (n=1 each in 20 µg/d, 40 µg/d, 80 µg/d cohorts). One long-term PSA responder was treated for 14 months (40 µg/d) and one for 19.4 months (80 µg/d). The latter pt showed a complete regression of soft-tissue metastases and marked regression of bone metastases by PSMA-PET/CT, >90% reduction in PSA and alkaline phosphatase, and a significant and durable improvement in disease related symptoms. Conclusions: Pasotuxizumab had an acceptable safety profile and dose-dependent clinical activity in mCRPC pts. There were two long term responders in the dose escalation. This is the first clinical study showing that a BiTE immune therapy can be efficacious in solid tumors. Clinical trial information: NCT01723475.
Novel androgen receptor inhibitors in nonmetastatic castration-resistant prostate cancer: A network meta-analysis.
Authors: Hird Amanda Elizabeth , Magee Diana E. , Bhindi Bimal , Ye Xiang Y. , Chandrasekar Thenappan , Goldberg Hanan , Klotz Laurence , Fleshner Neil , Satkunasivam Raj , Klaassen Zachary William Abraham , Wallis Christopher J.D.
Published: February 2020

131

Background: Novel non-steroidal anti-androgens (NSAAs) including enzalutamide, apalutamide, and darolutamide with androgen deprivation therapy (ADT) have proven efficacy in men with high-risk non-metastatic castrate resistant prostate cancer (nmCRPC). However, in the absence of direct comparative trials, there is little evidence to guide therapeutic choice. Our objective was to perform a network meta-analysis to compare agents and perform a class-level meta-analysis of NSAAs with androgen deprivation therapy (ADT) versus ADT-alone. Methods: We performed a systematic review of phase III parallel-group RCTs in men ≥18 years of age with nmCRPC using EMBASE and MEDLINE, indexed as of March 8, 2019. Our primary outcome was metastasis free survival (MFS). Secondary outcomes included OS, PSA progression free survival (PFS), and rates of grade 3-4 adverse events (AEs). Three RCTs were identified. We performed a random effects meta-analysis of NSAA versus ADT-alone using the inverse variance technique for meta-analysis for efficacy outcomes and the Mantel-Haenszel method for meta-analysis of dichotomous data for AEs. We then performed a network meta-analysis to compare outcomes between NSAAs using fixed-effect models in a Bayesian framework. We estimated the relative ranking of the different treatments for each outcome. Results: Pooled MFS, PSA-PFS, and OS were significantly greater with NSAA versus placebo (HR:0.32,95%CI:0.25-0.41, HR:0.08,95%CI:0.05-0.13, and HR:0.74,95%CI:0.61-0.90, respectively). Apalutamide and enzalutamide had a 56% and 44% likelihood of maximizing MFS, respectively. There was a 44%, 41%, and 15% likelihood that apalutamide, darolutamide and enzalutamide offered the greatest OS benefit, respectively. There was a 61% chance that darolutamide was preferred with respect to AEs. Conclusions: NSAAs improve survival outcomes in patients with high-risk nmCRPC. Apalutamide and enzalutamide may offer improved oncological outcomes. Darolutamide may result in fewer adverse events. These differences, if confirmed, would be meaningful to patients and practitioners when selecting treatment.
Contribution of extragonadal steroids to the androgen receptor activity and to the castration-resistance development in recurrent prostate cancers after primary therapy.
Authors: Pouliot Frederic , Rouleau Mélanie , Neveu Bertrand , Toren Paul , Morin Fannie , Vélot Lauriane , Ding Keyue , Caron Patrick , Lacombe Louis , Levesque Eric , Klotz Laurence , Guillemette Chantal
Published: February 2020

148

Background: Beyond testosterone, several steroids contribute to the activation of the androgen receptor (AR) pathway, but their relative contributions in castrated prostate cancer (PCa) patients remain unknown. Methods: Serum levels of nine steroids were measured by mass spectrometry from continuously castrated patients of the PR.7 study (n=219) and from the PCA24 cohort (n=116). For each steroid, standard curves for dose-dependent prostate-specific antigen promoter activation were built in castration-sensitive (LAPC4) and resistant (VCaP) PCa models. Standard curves were used to determine the AR activation potency for each steroid measurement from patients. Results: In LAPC4 and VCaP cells, testosterone, dihydrotestosterone and androstenedione induced AR transcriptional activity, while dehydroepiandrosterone, 5alpha-androstan-3beta,17beta-diol, androstenediol, androsterone stimulated AR only in VCaP cells. Extragonadal steroids were responsible for 34% (LAPC4) and 88% (VCaP) of the serum total AR transcriptional activity found in castrated patients. The total AR transcriptional activity secondary to testosterone, dihydrotestosterone and androstenedione was associated with time to castration resistance in patients from the PR.7 study (HR=2.17; 95% CI: 1.12-4.23; p=0.02) in multivariate analysis using the castration-sensitive model (LAPC4). AR transcriptional activity of extragonadal androstenedione was the only steroid statistically associated with time to castration resistance in univariate analysis (HR=1.89; 95% CI: 1.04-3.44; p=0.036). Conclusions: Extragonadal steroids contribute significantly to the AR axis activation at testosterone castration levels in recurrent non-metastatic PCa and these sustain the development of castration resistance after primary local treatment.