bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dissecting primate early post-implantation development using long-term in vitro embryo culture
Authors: Niu Yuyu , Sun Nianqin , Li Chang , Lei Ying , Huang Zhihao , Wu Jun , Si Chenyang , Dai Xi , Liu Chuanyu , Wei Jingkuan , Liu Longqi , Feng Su , Kang Yu , Si Wei , Wang Hong , Zhang E. , Zhao Lu , Li Ziwei , Luo Xi , Cui Guizhong , Peng Guangdun , Izpisúa Belmonte Juan Carlos , Ji Weizhi , Tan Tao 
Published: October 2019

In vitro development of monkey embryosOwing to technical and ethical limitations, the molecular and cellular mechanisms underlying primate gastrulation are far from clear (see the Perspective by Tam). Two independent studies used an in vitro culture system to study cynomolgus monkey embryo postimplantation development up to and beyond gastrulation (day 9 to day 20). Niuet al.observed in vivo morphogenetic events and used single-cell RNA sequencing and single-cell chromatin accessibility to study the distinct cell lineages in developing embryos. Maet al.also observed that key events of in vivo early development were recapitulated in their system, and single-cell RNA-sequencing analysis revealed molecular signatures of postimplantation cell types. These systems will help elucidate the dynamics and regulation of gastrulation in primates, including possible relevance to human development.Science, this issue p.eaaw5754, p.eaax7890; see also p.798
Optimised transcranial direct current stimulation (tDCS) for fibromyalgia—targeting the endogenous pain control system: a randomised, double-blind, factorial clinical trial protocol
Authors: Castelo-Branco Luis , Uygur Kucukseymen Elif , Duarte Dante , El-Hagrassy Mirret M , Bonin Pinto Camila , Gunduz Muhammed Enes , Cardenas-Rojas Alejandra , Pacheco-Barrios Kevin , Yang Yiling , Gonzalez-Mego Paola , Estudillo-Guerra Anayali , Candido-Santos Ludmilla , Mesia-Toledo Ines , Rafferty Haley , Caumo Wolnei , Fregni Felipe 
Published: October 2019

IntroductionFibromyalgia (FM) is a common debilitating condition with limited therapeutic options. Medications have low efficacy and are often associated with adverse effects. Given that FM is associated with a defective endogenous pain control system and central sensitisation, combining interventions such as transcranial direct current stimulation (tDCS) and aerobic exercise (AE) to modulate pain-processing circuits may enhance pain control.Methods and analysisA prospective, randomised (1:1:1:1), placebo-controlled, double-blind, factorial clinical trial will test the hypothesis that optimised tDCS (16 anodal tDCS sessions combined with AE) can restore of the pain endogenous control system. Participants with FM (n=148) will undergo a conditioning exercise period and be randomly allocated to one of four groups: (1) active tDCS and AE, (2) sham tDCS and AE, (3) active tDCS and non-aerobic exercise (nAE) or (4) sham tDCS and nAE. Pain inhibitory activity will be assessed using conditioned pain modulation (CPM) and temporal slow pain summation (TSPS)—primary outcomes. Secondary outcomes will include the following assessments: Transcranial magnetic stimulation and electroencephalography as cortical markers of pain inhibitory control and thalamocortical circuits; secondary clinical outcomes on pain, FM, quality of life, sleep and depression. Finally, the relationship between the two main mechanistic targets in this study—CPM and TSPS—and changes in secondary clinical outcomes will be tested. The change in the primary efficacy endpoint, CPM and TSPS, from baseline to week 4 of stimulation will be tested with a mixed linear model and adjusted for important demographic variables.Ethics and disseminationThis study obeys the Declaration of Helsinki and was approved by the Institutional Review Board (IRB) of Partners Healthcare under the protocol number 2017P002524. Informed consent will be obtained from participants. Study findings will be reported in conferences and peer-reviewed journal publications.Trial registration numberNCT03371225.
Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium
Authors: Goggins Michael , Overbeek Kasper Alexander , Brand Randall , Syngal Sapna , Del Chiaro Marco , Bartsch Detlef K , Bassi Claudio , Carrato Alfredo , Farrell James , Fishman Elliot K , Fockens Paul , Gress Thomas M , van Hooft Jeanin E , Hruban R H , Kastrinos Fay , Klein Allison , Lennon Anne Marie , Lucas Aimee , Park Walter , Rustgi Anil , Simeone Diane , Stoffel Elena , Vasen Hans F A , Cahen Djuna L , Canto Marcia Irene , Bruno Marco 
Published: October 2019

Background and aimThe International Cancer of the Pancreas Screening Consortium met in 2018 to update its consensus recommendations for the management of individuals with increased risk of pancreatic cancer based on family history or germline mutation status (high-risk individuals).MethodsA modified Delphi approach was employed to reach consensus among a multidisciplinary group of experts who voted on consensus statements. Consensus was considered reached if ≥75% agreed or disagreed.ResultsConsensus was reached on 55 statements. The main goals of surveillance (to identify high-grade dysplastic precursor lesions and T1N0M0 pancreatic cancer) remained unchanged. Experts agreed that for those with familial risk, surveillance should start no earlier than age 50 or 10 years earlier than the youngest relative with pancreatic cancer, but were split on whether to start at age 50 or 55. Germline ATM mutation carriers with one affected first-degree relative are now considered eligible for surveillance. Experts agreed that preferred surveillance tests are endoscopic ultrasound and MRI/magnetic retrograde cholangiopancreatography, but no consensus was reached on how to alternate these modalities. Annual surveillance is recommended in the absence of concerning lesions. Main areas of disagreement included if and how surveillance should be performed for hereditary pancreatitis, and the management of indeterminate lesions.ConclusionsPancreatic surveillance is recommended for selected high-risk individuals to detect early pancreatic cancer and its high-grade precursors, but should be performed in a research setting by multidisciplinary teams in centres with appropriate expertise. Until more evidence supporting these recommendations is available, the benefits, risks and costs of surveillance of pancreatic surveillance need additional evaluation.
Nationwide trends in acute coronary syndrome by subtype in New Zealand 2006–2016
Authors: Wang Tom Kai Ming , Grey Corina , Jiang Yannan , Jackson Rodney T , Kerr Andrew J 
Published: October 2019

ObjectivesRecent studies in acute coronary syndrome (ACS) have reported mixed results for trends in ACS subtypes. The All New Zealand Acute Coronary Syndrome Quality Improvement (ANZACS-QI) 31 study evaluated trends in ACS event rates, invasive management and mortality of ST-elevation myocardial infarction (STEMI), non-STEMI (NSTEMI) and unstable angina (UA) in New Zealand.MethodsAll ACS hospitalisations between 2006 and 2016 were identified from routinely collected national data and categorised into STEMI, NSTEMI, UA and MI unspecified (MIU). Annual hospitalisation, coronary procedure, 28-day and 1-year mortality rates were calculated and trends tested using Poisson regression adjusting for age and sex.ResultsOver the 11-year study period, there were 188 264 ACS admissions, of which 16.0% were STEMI, 54.5% NSTEMI, 25.7% UA and 3.8% MIU. Event rates of all ACS subtypes fell: STEMI by 3.4%/year, NSTEMI by 5.9%/year and UA by 8.5%/year, while the proportion of patients with ACS receiving angiography and revascularisation increased by 5.6% per year. Rates of percutaneous coronary intervention rose for STEMI, NSTEMI and UA, but coronary artery bypass grafting increased only for NSTEMI and UA. Mortality at 28 days and 1 year was higher for STEMI than NSTEMI and lowest for UA. There was a relative 1.6%/year decline in 1 year mortality for NSTEMI (p<0.001), but no significant change for STEMI and UA.ConclusionsWe observed declines in the event rates of all ACS subtypes and increases in revascularisation rates. The finding that mortality declined in patients with NSTEMI, but not in patients with STEMI and UA, despite increases in invasive procedures, requires further investigation.
Expression of the checkpoint receptors LAG-3, TIM-3 and VISTA in peripheral T cell lymphomas
Authors: Murga-Zamalloa Carlos A , Brown Noah A. , Wilcox Ryan A. 
Published: October 2019

AimsPeripheral T cell lymphomas represent approximately 10%–15% of non-Hodgkin lymphomas and are characterised by an aggressive clinical courses and poor outcomes. Ligands provided by constituents of the tumour microenvironment engage receptors expressed by malignant T cells, promoting tumour growth and chemotherapy resistance. In addition to stimulatory receptors that promote the growth and survival of malignant T cells, recent studies suggest that homologous inhibitory receptors may have an opposing effect and function as tumour suppressors. For example, recent data suggest that programmed cell death 1 blockade may lead to increased lymphoma growth. Therefore, the identification of alternative checkpoint receptors in T cell lymphoproliferative neoplasms is an important and clinically relevant question.MethodsThe checkpoint receptors T cell immunoglobulin-3 (TIM-3), V-domain Ig-containing suppressor of T cell activation (VISTA) and lymphocyte-activation gene 3 (LAG-3) play fundamental roles in peripheral tolerance, and their ligands are exploited by many solid tumours to evade host immunity. However, their expression in T cell lymphoproliferative neoplasms has not been evaluated. In this study, we evaluated the expression of TIM-3, VISTA and LAG-3 in a cohort of peripheral T cell lymphomas cases by immunohistochemistry and flow cytometric analysis.ResultsOur results demonstrate that TIM-3, VISTA and LAG-3 expression is rarely identified within a large cohort of T cell lymphomas and its tumour microenvironment.ConclusionsOur data suggest that immune-regulatory roles for TIM-3, VISTA and LAG-3 may be predominant in lymphomas subsets different than the ones analysed in the current study. However, a potential role for these checkpoint receptors as tumour suppressors in T cell lymphomas remains to be elucidated.
New model of dielectric strength of Debye relaxation in monohydroxy alcohols
Authors: Wang Li-Na , Zhao Xing-Yu , Huang Yi-Neng 
Published: October 2019

The Debye relaxation of dielectric spectroscopy exists extensively in monohydroxy alcohols, and the existing theory of the dielectric strength is obviously inconsistent with the experimental results. In this paper, we propose an Ising model of infinite free-rotating pseudospin chains and get the exact solution of the dielectric strength versus temperature. The model predictions are qualitatively consistent with the experimental results, especially the crossover from the low to the high-temperature Curie–Weiss law. The quantitative comparisons indicate that the model predictions can agree well with the experimental data below 250 K.
A Highly Extended High-Efficiency Range Class-F–C Doherty Power Amplifier
Authors: Ahmadi Kayvan , Dousti Massoud , Asadi Shahrooz 
Published: October 2019

This paper presents a new extended high-efficiency-range Doherty power amplifier (DPA) with a main and only a single auxiliary amplifier. In order to extend the output high-efficiency range with a high-efficiency level, asymmetrical cells are employed as the main and auxiliary amplifiers in class-F and class-C complex combining load (CCL) methodology, respectively. To verify the proposed methodology, a DPA with 12-dB output back-off (OBO) is designed and fabricated for wideband code division multiple access (WCDMA) applications. Large-signal continuous-wave measurement results show the power gain of about 11[Formula: see text]dB with a drain efficiency of 59.9% at 12[Formula: see text]dB of OBO. A two-tone test exhibits a third-order intermodulation distortion (IMD) of lower than [Formula: see text][Formula: see text]dBc. Modulated wave measurements show over 55% of average drain efficiency and an adjacent channel leakage power ratio (ACLR) of lower than [Formula: see text][Formula: see text]dBc at an output power level of 31.5[Formula: see text]dBm.
Age-related responses to a bout of mechanotherapy in skeletal muscle of rats
Authors: Van Pelt Douglas W. , Confides Amy L. , Abshire Sarah M. , Hunt Emily R. , Dupont-Versteegden Esther E. , Butterfield Timothy A. 
Published: October 2019

Cyclic compressive loading (CCL) is a massage mimetic that improves muscle regrowth from atrophy in adult rats. Therefore, we tested if a single bout of CCL increases anabolic signaling and protein synthesis in muscle during normal, weight-bearing conditions in gastrocnemius muscle from adult and aged rats. Male Brown Norway/F344 rats at 10 (adult) and 30 (aged) months of age were assigned control or CCL (receiving a single bout of CCL). Twenty-four hours following a single bout of CCL there was no change in protein synthesis, Akt, or GSK3β signaling at either age, despite adult rats having higher abundance and activation of mechanosensitive pathways (integrins and integrin-linked kinase). Murf1 was elevated in response to CCL in both age groups, potentially indicating muscle remodeling. Muscle from aged rats exhibited an increase in heat shock protein (HSP) 25 and HSP70 and in the cold shock protein RNA-binding motif 3 (RBM3), demonstrating a unique stress response to CCL in aged muscle only. Finally, muscle from aged rats exhibited higher basal protein synthesis that was corroborated by elevated eIF2Bε and rpS6 signaling, without an additional effect of CCL. In summary, a single bout of CCL does not have anabolic effects on skeletal muscle during normal, weight-bearing conditions, even though it has previously been shown to improve regrowth from atrophy. These data demonstrate that interventions that may help recover from atrophy do not necessarily induce muscle hypertrophy in unperturbed conditions. NEW & NOTEWORTHY Massage has been demonstrated to be an effective mechanotherapy to improve recovery from atrophy in adult skeletal muscle; however, this study shows that a single bout of massage fails to increase protein synthesis or anabolic signaling in adult or aged skeletal muscle during normal, weight-bearing conditions. Altogether, our data suggest massage is a useful mechanotherapy for preserving skeletal muscle when combined with other interventions but is not an anabolic stimulus on its own.
Application of a Promising Bone Graft Substitute in Bone Tissue Regeneration: Characterization, Biocompatibility, and In Vivo Animal Study
Authors: Wahyuningtyas Endang , Hsu Ling-Chuan , Lan Wen-Chien , Wen Shih-Cheng , Ou Keng-Liang , Chou Hsin-Hua , Huang Mao-Suan , Sugiatno Erwan 
Published: October 2019

The purpose of thehttp://mts.hindawi.com/update/) in our Manuscript Tracking System and after you have logged in click on the ORCID link at the top of the page. This link will take you to the ORCID website where you will be able to create an account for yourself. Once you have done so, your new ORCID will be saved in our Manuscript Tracking System automatically."?> present study was to investigate the effect of local hydroxyapatite (HA) combined with extracted sea cucumber (Stichopus hermanni) collagen as a promising bone graft substitute on bone remodeling. Fourier-transform infrared spectroscopy, X-ray diffractometry, transmission electron microscopy, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, and Sprague-Dawley rat model were used to characterize the microstructure, in vitro cytotoxicity, and in vivo bone-healing properties of the investigated biocomposite material. Analytical results found that the hydrothermal reaction-synthesized local HA had a hexagonal close-packed structure. The addition of extracted S. hermanni collagen did not influence the microstructure and functional groups of the local HA. Moreover, the MTT assay indicated that the investigated biocomposite material possessed a good in vitro biocompatibility. The in vivo animal study also revealed that the investigated biocomposite material exhibited the highest number of osteoblasts after 14 days of healing. Therefore, the results demonstrate that the local HA combined with extracted S. hermanni collagen could potentially enhance osteoblast formation in promoting bone healing and regeneration.
Parallel Signaling through IRE1α and PERK Regulates Pancreatic Neuroendocrine Tumor Growth and Survival
Authors: Moore Paul C. , Qi Jenny Y. , Thamsen Maike , Ghosh Rajarshi , Peng Justin , Gliedt Micah J. , Meza-Acevedo Rosa , Warren Rachel E. , Hiniker Annie , Kim Grace E. , Maly Dustin J. , Backes Bradley J. , Papa Feroz R. , Oakes Scott A. 
Published: October 2019

Abstract

Master regulators of the unfolded protein response (UPR), IRE1α and PERK, promote adaptation or apoptosis depending on the level of endoplasmic reticulum (ER) stress. Although the UPR is activated in many cancers, its effects on tumor growth remain unclear. Derived from endocrine cells, pancreatic neuroendocrine tumors (PanNET) universally hypersecrete one or more peptide hormones, likely sensitizing these cells to high ER protein-folding stress. To assess whether targeting the UPR is a viable therapeutic strategy, we analyzed human PanNET samples and found evidence of elevated ER stress and UPR activation. Genetic and pharmacologic modulation of IRE1α and PERK in cultured cells, xenograft, and spontaneous genetic (RIP-Tag2) mouse models of PanNETs revealed that UPR signaling was optimized for adaptation and that inhibiting either IRE1α or PERK led to hyperactivation and apoptotic signaling through the reciprocal arm, thereby halting tumor growth and survival. These results provide a strong rationale for therapeutically targeting the UPR in PanNETs and other cancers with elevated ER stress.

Significance:
The UPR is upregulated in pancreatic neuroendocrine tumors and its inhibition significantly reduces tumor growth in preclinical models, providing strong rationale for targeting the UPR in these cancers.
Targeting Novel Sodium Iodide Symporter Interactors ADP-Ribosylation Factor 4 and Valosin-Containing Protein Enhances Radioiodine Uptake
Authors: Fletcher Alice , Read Martin L. , Thornton Caitlin E.M. , Larner Dean P. , Poole Vikki L. , Brookes Katie , Nieto Hannah R. , Alshahrani Mohammed , Thompson Rebecca J. , Lavery Gareth G. , Landa Iñigo , Fagin James A. , Campbell Moray J. , Boelaert Kristien , Turnell Andrew S. , Smith Vicki E. , McCabe Christopher J. 
Published: October 2019

AbstractThe sodium iodide symporter (NIS) is required for iodide uptake, which facilitates thyroid hormone biosynthesis. NIS has been exploited for over 75 years in ablative radioiodine (RAI) treatment of thyroid cancer, where its ability to transport radioisotopes depends on its localization to the plasma membrane. The advent of NIS-based in vivo imaging and theranostic strategies in other malignancies and disease modalities has recently increased the clinical importance of NIS. However, NIS trafficking remains ill-defined. Here, we used tandem mass spectrometry followed by coimmunoprecipitation and proximity ligation assays to identify and validate two key nodes—ADP-ribosylation factor 4 (ARF4) and valosin-containing protein (VCP)—controlling NIS trafficking. Using cell-surface biotinylation assays and highly inclined and laminated optical sheet microscopy, we demonstrated that ARF4 enhanced NIS vesicular trafficking from the Golgi to the plasma membrane, whereas VCP—a principal component of endoplasmic reticulum (ER)–associated degradation—governed NIS proteolysis. Gene expression analysis indicated VCP expression was particularly induced in aggressive thyroid cancers and in patients who had poorer outcomes following RAI treatment. Two repurposed FDA-approved VCP inhibitors abrogated VCP-mediated repression of NIS function, resulting in significantly increased NIS at the cell-surface and markedly increased RAI uptake in mouse and human thyroid models. Collectively, these discoveries delineate NIS trafficking and highlight the new possibility of systemically enhancing RAI therapy in patients using FDA-approved drugs.Significance:These findings show that ARF4 and VCP are involved in NIS trafficking to the plasma membrane and highlight the possible therapeutic role of VCP inhibitors in enhancing radioiodine effectiveness in radioiodine-refractory thyroid cancer.
A Phase Ib/II Trial of the First-in-Class Anti-CXCR4 Antibody Ulocuplumab in Combination with Lenalidomide or Bortezomib Plus Dexamethasone in Relapsed Multiple Myeloma
Authors: Ghobrial Irene M. , Liu Chia-Jen , Redd Robert A. , Perez Raymond P. , Baz Rachid , Zavidij Oksana , Sklavenitis-Pistofidis Romanos , Richardson Paul G. , Anderson Kenneth C. , Laubach Jacob , Henrick Patrick , Savell Alexandra , Reyes Kaitlen , Hornburg Kalvis , Chuma Stacey , Sabbatini Peter , Robbins Michael D. , Becker Pamela S. 
Published: October 2019

Abstract

Purpose:
Ulocuplumab (BMS-936564) is a first-in-class fully human IgG4 monoclonal anti-CXCR4 antibody that inhibits the binding of CXCR4 to CXCL12.

Patients and Methods:
This phase Ib/II study aimed to determine the safety and tolerability of ulocuplumab alone and in combination with lenalidomide and dexamethasone (Arm A), or bortezomib and dexamethasone (Arm B), in patients with relapsed/refractory multiple myeloma.

Results:
Forty-six patients were evaluated (median age, 60 years; range, 53–67). The median number of prior therapies was 3 (range, 1–11), with 70% of subjects having received ≥3. This trial had a dose-escalation and a dose-expansion part. Using a 3+3 design on both arms of the trial, ulocuplumab's dose was escalated to a maximum of 10 mg/kg without reaching MTD. The most common treatment-related adverse events (AE) were neutropenia (13 patients, 43.3%) in Arm A and thrombocytopenia (6 patients, 37.5%) in Arm B. No deaths related to study drugs occurred. The combination of ulocuplumab with lenalidomide and dexamethasone showed a high response rate (PR or better) of 55.2% and a clinical benefit rate of 72.4%, even in patients who had been previously treated with immunomodulatory agents (IMiD).

Conclusions:
This study showed that blockade of the CXCR4–CXCL12 axis by ulocuplumab is safe with acceptable AEs and leads to a high response rate in combination with lenalidomide and dexamethasone in patients with relapsed/refractory myeloma, making CXCR4 inhibitors a promising class of antimyeloma drugs that should be further explored in clinical trials.