bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

AbstractSpinal 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

Abstract
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

AbstractThis 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

AbstractBy 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 methodIn 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.ResultsThe 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 implicationsMental 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

Summary
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.