bluuebunny/crossref_metadata_2025_split huggingface dataset:
Opposing mechanisms underlying differential changes in brain oxygen and temperature induced by intravenous morphine
Authors: Solis Ernesto , Afzal Anum , Kiyatkin Eugene A. 
Published: September 2018

Morphine remains widely used in clinical settings due to its potent analgesic properties. However, one of the gravest risks of all opioids is their ability to induce respiratory depression and subsequent brain hypoxia that can lead to coma and death. Due to these life-threatening effects, our goal was to examine the effects of intravenous morphine at a wide range of doses (0.1–6.4 mg/kg) on changes in brain oxygen levels in freely moving rats. We used oxygen sensors coupled with high-speed amperometry and conducted measurements in the nucleus accumbens (NAc) and subcutaneous (SC) space, the latter serving as a proxy for blood oxygen levels that depend on respiratory activity. We also examined the effects of morphine on NAc, muscle, and skin temperature. Morphine induced dose-dependent decreases in SC oxygen levels, suggesting respiratory depression, but differential effects on NAc oxygen: increases at low and moderate doses (0.1–1.6 mg/kg) and decreases at the highest dose tested (6.4 mg/kg). Morphine also increased brain temperature at low and moderate doses but induced a biphasic, down-up change at high doses. The oxygen increases appear to result from a neurovascular coupling mechanism via local vasodilation and enhanced oxygen entry into brain tissue to compensate for blood oxygen drops caused by modest respiratory depression. At high morphine doses, this adaptive mechanism is unable to compensate for the enhanced respiratory depression, resulting in brain hypoxia. Hence, morphine appears to be safe when used as an analgesic at clinically relevant doses but poses great risks at high doses, likely to be abused by drug users. NEW & NOTEWORTHY With the use of oxygen sensors coupled with amperometry, we show that morphine induces differential effects on brain oxygen levels, slightly increasing them at low doses and strongly decreasing them at high doses. In contrast, morphine dose dependently decreases oxygen levels in the SC space. Therefore, morphine engages opposing mechanisms affecting brain oxygen levels, enhancing them through neurovascular coupling at low, clinically relevant doses and decreasing them due to dramatic respiratory depression at high doses, likely to be abused.
CDK8 Selectively Promotes the Growth of Colon Cancer Metastases in the Liver by Regulating Gene Expression of TIMP3 and Matrix Metalloproteinases
Authors: Liang Jiaxin , Chen Mengqian , Hughes Daniel , Chumanevich Alexander A. , Altilia Serena , Kaza Vimala , Lim Chang-Uk , Kiaris Hippokratis , Mythreye Karthikeyan , Pena Maria Marjorette , Broude Eugenia V. , Roninson Igor B. 
Published: September 2018

AbstractUnresectable hepatic metastases of colon cancer respond poorly to existing therapies and are a major cause of colon cancer lethality. In this study, we evaluated the therapeutic viability of targeting the mediator kinase CDK8, an early clinical stage drug target, as a means to suppress metastasis of colon cancer. CDK8 was amplified or overexpressed in many colon cancers and CDK8 expression correlated with shorter patient survival. Knockdown or inhibition of CDK8 had little effect on colon cancer cell growth but suppressed metastatic growth of mouse and human colon cancer cells in the liver. This effect was due in part to inhibition of already established hepatic metastases, indicating therapeutic potential of CDK8 inhibitors in the metastatic setting. In contrast, knockdown or inhibition of CDK8 had no significant effect on the growth of tumors implanted subcutaneously, intrasplenically, or orthotopically in the cecum. CDK8 mediated colon cancer growth in the liver through downregulation of matrix metalloproteinase (MMP) inhibitor TIMP3 via TGFβ/SMAD-driven expression of a TIMP3-targeting microRNA, miR-181b, along with induction of Mmp3 in murine or MMP9 in human colon cancer cells via Wnt/β-catenin-driven transcription. These findings reveal a new mechanism for negative regulation of gene expression by CDK8 and a site-specific role for CDK8 in colon cancer hepatic metastasis. Our results indicate the utility of CDK8 inhibitors for the treatment of colon cancer metastases in the liver and suggest that CDK8 inhibitors may be considered in other therapeutic settings involving TGFβ/SMAD or Wnt/β-catenin pathway activation.Significance:These findings demonstrate that inhibition of the transcription-regulating kinase CDK8 exerts a site-specific tumor-suppressive effect on colon cancer growth in the liver, representing a unique therapeutic opportunity for the treatment of advanced colon cancer.
Strategy for Tumor-Selective Disruption of Androgen Receptor Function in the Spectrum of Prostate Cancer
Authors: Rosati Rayna , Polin Lisa , Ducker Charles , Li Jing , Bao Xun , Selvakumar Dakshnamurthy , Kim Seongho , Xhabija Besa , Larsen Martha , McFall Thomas , Huang Yanfang , Kidder Benjamin L. , Fribley Andrew , Saxton Janice , Kakuta Hiroki , Shaw Peter , Ratnam Manohar 
Published: September 2018

Abstract

Purpose:
Testosterone suppression in prostate cancer is limited by serious side effects and resistance via restoration of androgen receptor (AR) functionality. ELK1 is required for AR-dependent growth in various hormone-dependent and castration-resistant prostate cancer models. The amino-terminal domain of AR docks at two sites on ELK1 to coactivate essential growth genes. This study explores the ability of small molecules to disrupt the ELK1–AR interaction in the spectrum of prostate cancer, inhibiting AR activity in a manner that would predict functional tumor selectivity.

Experimental Design:
Small-molecule drug discovery and extensive biological characterization of a lead compound.

Results:
We have discovered a lead molecule (KCI807) that selectively disrupts ELK1-dependent promoter activation by wild-type and variant ARs without interfering with ELK1 activation by ERK. KCI807 has an obligatory flavone scaffold and functional hydroxyl groups on C5 and C3′. KCI807 binds to AR, blocking ELK1 binding, and selectively blocks recruitment of AR to chromatin by ELK1. KCI807 primarily affects a subset of AR target growth genes selectively suppressing AR-dependent growth of prostate cancer cell lines with a better inhibitory profile than enzalutamide. KCI807 also inhibits in vivo growth of castration/enzalutamide-resistant cell line–derived and patient-derived tumor xenografts. In the rodent model, KCI807 has a plasma half-life of 6 hours, and maintenance of its antitumor effect is limited by self-induced metabolism at its 3′-hydroxyl.

Conclusions:
The results offer a mechanism-based therapeutic paradigm for disrupting the AR growth-promoting axis in the spectrum of prostate tumors while reducing global suppression of testosterone actions. KCI807 offers a good lead molecule for drug development.
Effect of Combined Treatment with MLC601 (NeuroAiDTM) and Rehabilitation on Post-Stroke Recovery: The CHIMES and CHIMES-E Studies
Authors: Suwanwela Nijasri C. , Chen Christopher L.H. , Lee Chun Fan , Young Sherry H. , Tay San San , Umapathi Thirugnanam , Lao Annabelle Y. , Gan Herminigildo H. , Baroque II Alejandro C. , Navarro Jose C. , Chang Hui Meng , Advincula Joel M. , Muengtaweepongsa Sombat , Chan Bernard P.L. , Chua Carlos L. , Wijekoon Nirmala , de Silva H. Asita , Hiyadan John Harold B. , Wong Ka Sing Lawrence , Poungvarin Niphon , Eow Gaik Bee , Venketasubramanian Narayanaswamy ,   CHIMES-E Study Investigators
Published: September 2018

<b><i>Background and Purpose:</i></b> MLC601 has been shown in preclinical studies to enhance neurorestorative mechanisms after stroke. The aim of this post hoc analysis was to assess whether combining MLC601 and rehabilitation has an effect on improving functional outcomes after stroke. <b><i>Methods:</i></b> Data from the CHInese Medicine NeuroAiD Efficacy on Stroke (CHIMES) and CHIMES-Extension (CHIMES-E) studies were analyzed. CHIMES-E was a 24-month follow-up study of subjects included in CHIMES, a multi-centre, double-blind placebo-controlled trial which randomized subjects with acute ischemic stroke, to either MLC601 or placebo for 3 months in addition to standard stroke treatment and rehabilitation. Subjects were stratified according to whether they received or did not receive persistent rehabilitation up to month (M)3 (non- randomized allocation) and by treatment group. The modified Rankin Scale (mRS) and Barthel Index were assessed at month (M) 3, M6, M12, M18, and M24. <b><i>Results:</i></b> Of 880 subjects in CHIMES-E, data on rehabilitation at M3 were available in 807 (91.7%, mean age 61.8 ± 11.3 years, 36% female). After adjusting for prognostic factors of poor outcome (age, sex, pre-stroke mRS, baseline National Institute of Health Stroke Scale, and stroke onset-to-study-treatment time), subjects who received persistent rehabilitation showed consistently higher treatment effect in favor of MLC601 for all time points on mRS 0–1 dichotomy analysis (ORs 1.85 at M3, 2.18 at M6, 2.42 at M12, 1.94 at M18, 1.87 at M24), mRS ordinal analysis (ORs 1.37 at M3, 1.40 at M6, 1.53 at M12, 1.50 at M18, 1.38 at M24), and BI ≥95 dichotomy analysis (ORs 1.39 at M3, 1.95 at M6, 1.56 at M12, 1.56 at M18, 1.46 at M24) compared to those who did not receive persistent rehabilitation. <b><i>Conclusions:</i></b> More subjects on MLC601 improved to functional independence compared to placebo among subjects receiving persistent rehabilitation up to M3. The larger treatment effect of MLC601 was sustained over 2 years which supports the hypothesis that MLC601 combined with rehabilitation might have beneficial and sustained effects on neuro-repair processes after stroke. There is a need for more data on the effect of combining rehabilitation programs with stroke recovery treatments.
Sunitinib or Sorafenib as Neoadjuvant Therapy May not Improve the Survival Outcomes of Renal Cell Carcinoma with Tumor Thrombus
Authors: Cai Wen , Huang Jiwei , Yuan Yichu , Hu Xiaoyi , Li Mingyang , Kong Wen , Zhang Jin , Guo Jianming , Chen Yonghui , Huang Yiran 
Published: September 2018

<b><i>Objectives:</i></b> The purpose of this work was to investigate the effect of sorafenib or sunitinib as neoadjuvant therapy on the survival outcomes of renal cell carcinoma (RCC) with tumor thrombus. <b><i>Methods:</i></b> A total of 92 RCC patients with tumor thrombus were included in this 2-center retrospective research from January 2007 to December 2014. Sorafenib and sunitinib were administered as neoadjuvant therapy in 9 patients and 14 patients, respectively, and 69 patients constituted non-neoadjuvant therapy groups. The Kaplan-Meier method was used to estimate the recurrence-free survival (RFS) and overall survival (OS). Log-rank test was used to compare the survival outcomes of patients with or without neoadjuvant therapy. <b><i>Results:</i></b> The overall median RFS and OS time for all 92 patients were 28 months (95% CI 17–39 months) and 42 months (95% CI 30–54 months). Patients with neoadjuvant therapy had no significantly longer median RFS (30 vs. 28 months, <i>p</i> = 0.376) and OS (45 vs. 42 months, <i>p</i> = 0.702) than those without neoadjuvant therapy. <b><i>Conclusions:</i></b> Neoadjuvant therapy of sorafenib or sunitinib might not improve survival outcomes for high risk RCC patients with tumor thrombus. Thus, neoadjuvant therapy for RCC with tumor thrombus should be considered cautiously.
Diplomats' Mystery Illness and Pulsed Radiofrequency/Microwave Radiation
Authors: Golomb Beatrice Alexandra 
Published: September 2018

AbstractImportance: A mystery illness striking U.S. and Canadian diplomats to Cuba (and now China) “has confounded the FBI, the State Department and US intelligence agencies” (Lederman, Weissenstein, & Lee, 2017). Sonic explanations for the so-called health attacks have long dominated media reports, propelled by peculiar sounds heard and auditory symptoms experienced. Sonic mediation was justly rejected by experts. We assessed whether pulsed radiofrequency/microwave radiation (RF/MW) exposure can accommodate reported facts in diplomats, including unusual ones.Observations: (1) Noises: Many diplomats heard chirping, ringing or grinding noises at night during episodes reportedly triggering health problems. Some reported that noises were localized with laser-like precision or said the sounds seemed to follow them (within the territory in which they were perceived). Pulsed RF/MW engenders just these apparent “sounds” via the Frey effect. Perceived “sounds” differ by head dimensions and pulse characteristics and can be perceived as located behind in or above the head. Ability to hear the “sounds” depends on high-frequency hearing and low ambient noise. (2) Signs/symptoms: Hearing loss and tinnitus are prominent in affected diplomats and in RF/MW-affected individuals. Each of the protean symptoms that diplomats report also affect persons reporting symptoms from RF/MW: sleep problems, headaches, and cognitive problems dominate in both groups. Sensations of pressure or vibration figure in each. Both encompass vision, balance, and speech problems and nosebleeds. Brain injury and brain swelling are reported in both. (3) Mechanisms: Oxidative stress provides a documented mechanism of RF/MW injury compatible with reported signs and symptoms; sequelae of endothelial dysfunction (yielding blood flow compromise), membrane damage, blood-brain barrier disruption, mitochondrial injury, apoptosis, and autoimmune triggering afford downstream mechanisms, of varying persistence, that merit investigation. (4) Of note, microwaving of the U.S. embassy in Moscow is historically documented.Conclusions and relevance: Reported facts appear consistent with pulsed RF/MW as the source of injury in affected diplomats. Nondiplomats citing symptoms from RF/MW, often with an inciting pulsed-RF/MW exposure, report compatible health conditions. Under the RF/MW hypothesis, lessons learned for diplomats and for RF/MW-affected civilians may each aid the other.
Rediscovery of the bopyrid isopod Parabopyrella thomasi (Nierstrasz & Brender à Brandis, 1929), parasite of the arrow shrimp Tozeuma carolinense Kingsley, 1878 (Decapoda, Caridea) in the Caribbean region
Authors: Romero-Rodríguez Jesús , Martínez-Mayén Mario 
Published: September 2018

AbstractThis is only the second report of the bopyrid isopodParabopyrella thomasi(Nierstrasz & Brender à Brandis, 1929) since it was described. The species infests the arrow shrimpTozeuma carolinenseKingsley, 1878, and this report of new material extends its known geographic distribution to the Caribbean coasts of Mexico. We provide data on some morphological variations in both sexes of this species as well as on the fecundity of this ectoparasite.
Abundance of Boeckella gracilis (Daday, 1902) (Copepoda, Calanoida) in seasonal coastal pools in the Araucania region (38°S, Chile)
Authors: De los Ríos Patricio 
Published: September 2018

Abstract
The presence of the calanoid copepod Boeckella gracilis (Daday, 1902) in Chilean seasonal pools has been only poorly studied as yet. The aim of the present study thus is to investigate the role of conductivity and temperature on the relative and absolute abundance of B. gracilis in seasonal coastal pools in the Araucania region (38°S, Chile). The results of correlation analysis revealed the presence of a significant inverse correlation between conductivity and relative abundance, whereas no significant correlations were found between conductivity and absolute abundance, between temperature and absolute abundance, and between temperature and relative abundance. These results agree partially with similar observations for mountain pools in the same region, but they would not agree with observations for calanoids of saline and subsaline inland waters in the northern and southern extremes of Chile. Considering this scenario, the species would show different populational responses to environmental stress in different situations, which phenomenon deserves to be studied more extensively and in more detail.
Claw regeneration, waving display and burrow characteristics of Austruca perplexa (H. Milne Edwards, 1852) (Brachyura, Ocypodidae) from southern Thailand
Authors: Tina Fahmida Wazed , Jaroensutasinee Mullica , Jaroensutasinee Krisanadej 
Published: September 2018

Abstract
We studied the effects of claw regeneration on male waving rate and burrow characteristics (i.e., important mate choice criteria) by examining the waving rates and burrow characteristics (diameter, total and horizontal lengths, depth, volume, maximum width, entry and burrow angles, and presence and location of chambers) of large-sized original-clawed males (OCMs) and regenerated-clawed males (RCMs) of Austruca perplexa (H. Milne Edwards, 1852). Female burrows were also examined. The results showed that female burrows were smaller than male burrows, with no chamber and, thus, female burrows are not used for breeding; however, 80% of RCM burrows, and 65% of OCM burrows, had chambers. Other characteristics were not different between RCM and OCM burrows, except for maximum width, which was larger in RCM burrows. The waving rates of OCMs and RCMs were not different. Our results indicate that claw regeneration do not have detrimental effects on male waving rate and burrow characteristics.
Effects of the Number of Muscle-Nerve-Muscle Grafts on Rat Facial Nerve Functional Recovery
Authors: Foecking Eileen M. , Burgess Bridget D. , Fridrici Zachary C. , Bialek Samantha E. , Low Christopher , Charous Steven J. 
Published: September 2018

Introduction: Facial nerve denervation can be devastating for patients. Primary neurorrhaphy and interposition (IP) nerve grafting are common reinnervation techniques. Muscle-nerve-muscle (MNM) grafting is a lesser known alternative. After previously demonstrating significant return of function using MNM grafting in a rat facial nerve model, the authors compare the use of multiple MNM nerve grafts with that of single MNM and IP nerve grafts. Methods: Thirty-six male rats were randomized into 4 groups: (1) repair with IP grafts, (2) 1 MNM graft, (3) 3 MNM grafts, and (4) control with no intervention. All groups had the lower zygomatic, buccal, and marginal mandibular branches of the right facial nerve removed. Return of movement and snout symmetry was measured over 16 weeks. Axonal regeneration and muscle atrophy were assessed and quantified. Results: All intervention groups had significantly improved movement and snout symmetry compared with control. Rats in the IP group had significantly increased axon density compared with those in the MNM groups but with smaller axonal diameter than control rats. No difference in axon density or diameter was observed between MNM groups. Use of 3 MNM grafts and IP grafts resulted in preservation of similar muscle mass compared with the control and 1-MNM groups. Conclusion: MNM grafting may be an alternative when other reanimation techniques are not possible. Level of Evidence: NA
A Viscoelastic-Plastic Behaviour Analysis of Expanded Polystyrene under Compressive Loading: Experiments and Modelling
Authors: Imad Abdellatif 
Published: September 2018

Generally, when soil has poor properties (unstable or compressible soils) it is possible to use EPS foam in road construction, because this material has low density. In this case, it is necessary to investigate the mechanical properties of EPS. In this work, an experimental study and modelling investigation were performed in order to determine the EPS mechanical behaviour under compressive loading.The experimental results show that the global compression behaviour of EPS is characterised by three stages. The linear elastic stage is defined by an initial tangent modulus E* followed by a non-linear elastic part. The second stage, which is described by a plateau, is characterised by a stress threshold σs*. Finally, the densification stage corresponds to large compressive strains when the material of the cell walls is entirely compressed.Globally, the apparent density of EPS plays an important role. In fact, when the density increases Young's modulus and threshold stress increase, but the densification strain decreases.A phenomenological mechanical model is verified in order to simulate the EPS viscoelastic-plastic behaviour under compressive loading. This model, which is based on a super-position of viscoelastic and elastic-plastic behaviour, introduces six parameters determined by an identification technique. The results obtained in terms of the stress-strain curves are in a good agreement with the experimental data.Using “Castem 2000” finite element software, the numerical simulations were achieved in order to describe the mechanical behaviour of the EPS material. This shows that it is possible to use numerical simulation in order to compute EPS structure used in road laying.
Supercritical Fluids in Thermoplastics Foaming: Facts or Fallacies?
Authors: Gendron Richard , Champagne Michel F. , Reigniër Joël 
Published: September 2018

The past two decades have seen extensive interests and efforts for developing processes based on supercritical fluids (SCF). Microcellular foaming is one of these processes that take advantage of the unique properties of supercritical fluids when they are used as physical foaming agents (PFA). In this technology, the emphasis has been mostly focused on inert gases such as carbon dioxide and nitrogen that both inherently provides very high cell densities and very small cell sizes. Incidentally the benign carbon dioxide is frequently considered as the panacea of PFA, in response notably to the environmental pressures related to the destruction of the ozone layer. Hydrofluorocarbons (HFCs) have also been identified as potential alternative agents for extruded polystyrene foam. Unfortunately, HFCs remain difficult to process at the high concentrations required to yield low-density foams. Surprisingly, the processing difficulties occur when the pressures required for dissolving high HFCs concentrations reach the range located immediately above the critical pressure of the PFA used. PS/HFC systems have been well documented in terms of abnormal behaviors occurring as the foaming agent gets into the supercritical conditions, and similar observations have also been made for other SCF used for thermoplastic foaming. These observations are reported here, and attempts are made to link the supercritical nature of the fluid to the PFA heterogeneities suspected under these conditions.
Microwave Enhanced Foaming of Carbon Black Filled Polypropylene
Authors: Prociak Aleksander , Sterzynski Tomasz , Michalowski Slawomir , Andrzejewski Jacek 
Published: September 2018

Microwave heating has a number of advantages in comparison to the conventional method due to the ability to heat a part of composite material directly through specific interaction of electromagnetic radiation with selected types of materials. Most thermoplastics are relatively transparent for microwave irradiation and they do not absorb microwaves to a sufficient extent to be heated. Enhanced microwave heating can result from the use of fillers such as carbon black. Different types of carbon black were used to increase the susceptibility of polypropylene (PP) for microwave processing. Measurements were carried out on PP filled with carbon black of different grades. Relative temperature rises and heat efficiency versus the content of carbon black in PP were analyzed. The temperature changes of different mass samples of these materials under microwave irradiation with various power were also investigated. Moreover, polypropylene composites with additive of chemical blowing agents were blown under microwave irradiation and the influence of foaming conditions on cell structure and selected properties of porous products were estimated.