Optimising computerised decision support to transform medication safety and reduce prescriber burden: study protocol for a mixed-methods evaluation of drug-drug interaction alerts.

Abstract:
INTRODUCTION
Drug-drug interaction (DDI) alerts in hospital electronic medication management (EMM) systems are generated at the point of prescribing to warn doctors about potential interactions in their patients' medication orders. This project aims to determine the impact of DDI alerts on DDI rates and on patient harm in the inpatient setting. It also aims to identify barriers and facilitators to optimal use of alerts, quantify the alert burden posed to prescribers with implementation of DDI alerts and to develop algorithms to improve the specificity of DDI alerting systems.

METHODS AND ANALYSIS
A controlled pre-post design will be used. Study sites include six major referral hospitals in two Australian states, New South Wales and Queensland. Three hospitals will act as control sites and will implement an EMM system without DDI alerts, and three as intervention sites with DDI alerts. The medical records of 280 patients admitted in the 6 months prior to and 6 months following implementation of the EMM system at each site (total 3360 patients) will be retrospectively reviewed by study pharmacists to identify potential DDIs, clinically relevant DDIs and associated patient harm. To identify barriers and facilitators to optimal use of alerts, 10-15 doctors working at each intervention hospital will take part in observations and interviews. Non-identifiable DDI alert data will be extracted from EMM systems 6-12 months after system implementation in order to quantify alert burden on prescribers. Finally, data collected from chart review and EMM systems will be linked with clinically relevant DDIs to inform the development of algorithms to trigger only clinically relevant DDI alerts in EMM systems.

ETHICS AND DISSEMINATION
This research was approved by the Hunter New England Human Research Ethics Committee (18/02/21/4.07). Study results will be published in peer-reviewed journals and presented at local and international conferences and workshops.

D020000:Decision Support Systems, Clinical

decision support
drug-drug interaction
alert
alert fatigue


Performance evaluation of the fully automated random-access multiparameter Sysmex CN-6000 hemostasis analyzer at a core laboratory with a high sample throughput.

Abstract:
INTRODUCTION
We aimed to evaluate the performance of the fully automated multiparameter CN-6000 hemostasis analyzer.

METHODS
Performance evaluation of the CN-6000 analyzer was conducted for 10 tests including prothrombin time (PT), activated partial prothrombin time (aPTT), fibrinogen level, anti-Xa activity, and antithrombin activity using a unique portfolio of liquid ready-to-use reagents. Precision, sample and reagent carryovers, throughput, and sample turnaround time (STAT) function were prospectively assessed. Results from 343 samples (normal subjects, critically ill patients, patients receiving anticoagulants, subjects with high or low fibrinogen levels, and patients with decreased levels of factor II, V, VII, and X) were compared to those obtained on the STA-R Max 2® analyzer using dedicated reagents.

RESULTS
Total precision (coefficient of variation) was below 7% for all parameters in both normal and pathological ranges. For all analyzed parameters, results obtained on the CN-6000 were strongly correlated with those obtained on the STA-R Max 2®analyzer. Agreement between both instruments was excellent for all assays. The CN-6000 demonstrated a 30% higher throughput compared to the STA-R Max 2® (258 vs 185 tests per hour for a panel of tests including PT, aPTT, fibrinogen, factor V, anti-Xa, and D-Dimer). STAT turnaround time for critical care samples testing was <7 minutes.

CONCLUSIONS
The CN-6000 analyzer performs equivalently or better than the STA-R Max 2® with a significantly improved throughput. This new hemostasis multiparameter analyzer appears to be particularly well suited for coagulation laboratories which require high sample throughput and manage high numbers of nonstandard and critical care samples.

throughput
coagulation
laboratory automation


Mapping the landscape of human dopamine D2/3 receptors with [11C]raclopride.

Abstract: The dopamine D2/3 system is fundamental for sensory, motor, emotional, and cognitive aspects of behavior. Small-scale human histopathological and animal studies show high density of D2/3 dopamine receptors (D2/3DR) in striatum, but also demonstrate the existence of such receptors across cortical and limbic regions. Assessment of D2/3DR BPND in the extrastriatal regions with [11C]raclopride has long been considered unreliable due to the relatively low density of D2/3DR outside the striatum. We describe the distribution and interregional links of D2/3DR availability measured with PET and [11C]raclopride across the human brain in a large sample (N = 176; age range 64-68 years). Structural equation modeling revealed that D2/3DR availability can be organized according to anatomical (nigrostriatal, mesolimbic, mesocortical) and functional (limbic, associative, sensorimotor) dopamine pathways. D2/3DR availability in corticolimbic functional subdivisions showed differential associations to corresponding striatal subdivisions, extending animal and pharmacological work. Our findings provide evidence on the dimensionality and organization of [11C]raclopride D2/3DR availability in the living human brain that conforms to known dopaminergic pathways.

Dopamine D2/3 receptors
[11C]raclopride
COBRA study
Inter-individual differences
Structural-equation modeling


Silicon-Induced UV Transparency in Phosphate Glasses and Its Application to the Enhancement of the UV Type B Emission of Gd3.

Abstract: The silicon route to improve the ultraviolet (UV) transparency in phosphate glasses is investigated and further exploited to enhance the UV type B (280-320 nm) emission of gadolinium(III) relevant for biomedical applications. The glasses were synthesized with a barium phosphate composition by melt-quenching in ambient atmosphere and the optical properties investigated by optical absorption and photoluminescence (PL) spectroscopy including emission decay kinetics. An improvement in the UV transparency was gradually developed for the glasses melted merely with increasing amounts of Si powder. A particular PL in the visible was also exhibited for such glasses under excitation at 275 nm, consistent with the presence of Si-induced defects. For Si-Gd codoped glasses, the UV transparency was likewise manifested, while the UV emission from Gd3+ around 312 nm was enhanced with the increase in Si concentration (up to ∼6.7 times). Moreover, along with the Gd3+ PL intensity enhancement, a linear correlation was revealed between the increase in decay times for the Gd3+6P7/2-emitting state and the amount of silicon. It is then suggested that the improved PL properties of gadolinium(III) originate from the increased UV transparency of the host and the consequent precluding of a nonradiative energy transfer from Gd3+ to the matrix. Accordingly, a role of Si as PL quenching inhibitor is supported. The demonstrated efficacy of the Si-Gd codoping concept realized by a facile glass synthesis procedure may appeal to the application of the UV-emitting glasses for phototherapy lamps.

UV transparency
glasses
phototherapy lamps
luminescence
optical materials


A Comparison of Buprenorphine + Naloxone to Buprenorphine and Methadone in the Treatment of Opioid Dependence during Pregnancy: Maternal and Neonatal Outcomes.

Abstract: Given that buprenorphine + naloxone is prescribed for opioid-dependent pregnant women, it is important to examine the extent to which it differs from buprenorphine alone, methadone, or methadone-assisted withdrawal on neonatal and maternal outcomes. Summary statistics on maternal and neonatal outcomes were collected from 7 previously published studies examining treatment for opioid-dependent pregnant women that represented a range of research methodologies. Outcomes from these studies were compared to the same outcomes for 10 women treated with the combined buprenorphine + naloxone product. There were no significant differences in maternal outcomes for buprenorphine + naloxone compared to buprenorphine, methadone, or methadone-assisted withdrawal. Preliminary findings suggest no significant adverse maternal or neonatal outcomes related to the use of buprenorphine + naloxone for the treatment of opioid dependence during pregnancy. However, further research should examine possible differences between buprenorphine + naloxone and buprenorphine alone or methadone in fetal physical development.

Lund|Ingunn O|IO|
Fischer|Gabriele|G|
Welle-Strand|Gabrielle K|GK|
O'Grady|Kevin E|KE|
Debelak|Kimber|K|
Morrone|William R|WR|
Jones|Hendrée E|HE|

buprenorphine
methadone
opioid dependence
pregnancy
neonates


mer-Tri-chlorido-tris-(tetra-hydro-thio-phene-κS)iridium(III): preparation and comparison with other mer-tri-chlorido-tris-(tetra-hydro-thio-phene-κS)metal complexes.

Abstract: The title complex, [IrCl3(C4H8S)3], was prepared according to a literature method. A suitable crystal was obtained by diffusion of pentane into a di-chloro-methane solution and analyzed by single-crystal X-ray diffraction at 100 K. The title complex is isotypic with mer-tri-chlorido-tris-(tetra-hydro-thio-phene-κS)rhodium(III). However, the orientation of the tetra-hydro-thio-phene rings is different from an earlier report of mer-tri-chlorido-tris-(tetra-hydro-thio-phene-κS)iridium(III) deposited in the Cambridge Structural Database. The IrS3Cl3 core shows a nearly octa-hedral structure with various bond angles within 1-2° of the perfect 90 or 180° expected for an octa-hedron. The structure of the title compound is compared with the previous iridium complex as well as the rhodium and other octa-hedral metal tris-tetra-hydro-thio-phene compounds previously structurally characterized. DFT calculations were performed, which indicate the mer isomer is significantly lower in energy than the fac isomer by 50.1 kJ mol-1, thereby accounting for all compounds in the CSD being of the mer geometry. Powder X-ray diffraction of the bulk material showed that the preparation method yielded only the isomorph reported in this communication.

Brown|Loren C|LC|
DuChane|Christine M|CM|
Merola|Joseph S|JS|

iridium
conformers
crystal structure
tetrahydrothiophene


Molecular dynamics simulations reveal how the reticulon-homology domain of the autophagy receptor RETREG1/FAM134B remodels membranes for efficient selective reticulophagy.

Abstract: The autophagy receptor for selective reticulophagy, RETREG1/FAM134B is essential for ER maintenance, and its dysfunction is associated with neuronal disorders, vascular dementia, or viral infections. The protein consists of the reticulon-homology domain (RHD) that is flanked at the N- and C-termini by an intrinsically disordered protein region (IDPR), where the C terminal IDPR carries the indispensable LC3-interacting region (LIR) motif for the interaction with LC3. The RHD of RETREG1 is presumed to play a role in membrane remodeling, but the absence of a known 3D structure of this domain so far prevented researchers from gaining mechanistic insights into how the RETREG1 RHD curves membranes, and thereby facilities reticulophagy. The recent study by Bhaskara et al., which is described in this editor's corner article, used molecular dynamics (MD) simulations to create a structural model of the RETREG1 RHD. MD simulations along with in vitro liposome remodeling experiments reveal how the RHD domain acts on the ER membrane and, in concert with the C terminal IDPR, executes the function of RETREG1 in selective reticulophagy.Abbreviations: ER, endoplasmic reticulum; IDPR, intrinsically disordered protein region; LIR, LC3-interacting region; MD, molecular dynamics; RHD, reticulon-homology domain; TM, transmembrane.

D047908:Intracellular Signaling Peptides and Proteins

receptor
Endoplasmic reticulum
lysosome
protein intrinsic disorder
selective autophagy
stress


New record of the rare genus Crinalium Crow (Oscillatoriales, Cyanobacteria) from sand dunes of the Baltic Sea, Germany: epitypification and emendation of Crinalium magnum Fritsch et John based on an integrative approach.

Abstract: Representatives of the Gomontiellaceae (Oscillatoriales) are rare and hence unstudied cyanobacteria with unusual morphology, distributed in terrestrial and aquatic habitats all over the world. Investigation of the group based on an integrative approach is only beginning, and to understand the actual biodiversity and ecology, a greater number of cultivated strains is necessary. However, some ecological traits of these cyanobacteria (e.g. low population densities, the absence of conspicuous growth in nature) led to methodological difficulties during isolation in culture. One species in the family Gomontiellaceae, Crinalium magnum Fritsch et John, is characterized by prominent wide and flattened trichomes, and represented by the non-authentic strain SAG 34.87. Detailed previous investigation of this strain clearly showed its morphological discrepancy with the original description of C. magnum and the genus Crinalium in general. The new isolate from maritime sand dunes of the Baltic Sea coast (Germany), however, revealed morphological characters completely corresponding with the diagnosis of C. magnum. Phylogenetic analysis based on 16S rRNA sequences indicated a position of the new strain inside Gomontiellaceae. Both morphology and ultrastructure of the strain are congruous with characters of the family. Epitypification and emendation of C. magnum are proposed since the ecology and habitat of the original strain are congruent with the type locality of this rare species (sand, Irish Sea coast, North Wales, UK). We expanded the description of C. magnum by details of the filament development and specified dimensional ranges for trichomes and cells, as well as by new data about the transversely striated structure of mucilaginous sheath.

Mikhailyuk|Tatiana|T| Vinogradova|Oksana|O| Holzinger|Andreas|A| Glaser|Karin|K| Samolov|Elena|E| Karsten|Ulf|U|

epitypification
Crinalium magnum
integrative approach
Gomontiellaceae
16S rRNA
mucilaginous sheath
16S-23S ITS
TEM
phylogeny


Luminol-K3Fe(CN)6 chemiluminescence system for the determination of glipizide.

Abstract: A rapid and sensitive flow-injection chemiluminescence (CL) method for the determination of glipizide was developed on the basis of finding that glipizide can enhance the CL intensity of the luminol-K3Fe(CN)6 system. In optimum condition, the increased CL intensity was directly proportional to the concentration of glipizide in the range from 4.0×10-8 g/mL to 1.0×10-6 g/mL and the detection limit was 1.0×10-8 g/mL glipizide. The relative standard deviation (RSD) of the developed method was 2.1% with 11 repeated measurements of 1.0×10-7 g/mL glipizide. The developed method has been successfully applied to the analysis of glipizide in its pharmaceutical preparations.

Chen|Xin|X| Xing|Li-Li|LL| Tang|Yu-Hai|YH| Zhang|Guang-Bin|GB|

Chemiluminescence
Glipizide
Flow injection
Luminol–K3Fe(CN)6


Feasibility of super-selective neck dissection for indeterminate lateral neck nodes in papillary thyroid carcinoma.

Abstract:
BACKGROUND
Therapeutic lateral compartment neck dissection is recommended for cases of papillary thyroid carcinoma with biopsy-proven lymph node metastasis. The purpose of this study was to evaluate the efficacy and safety of super-selective neck dissection for patients with clinically suspicious lymph node metastasis not confirmed by biopsy.

METHODS
Among 620 patients treated for papillary thyroid carcinoma between 2008 and 2010, 34 had suspicious lymph node enlargement in the lateral neck and underwent total thyroidectomy with super-selective neck dissection.

RESULTS
Metastatic disease was confirmed in 38.2% patients (13 of 34) with indeterminate lymph nodes identified by preoperative CT and/or ultrasonography who underwent super-selective neck dissection. Most harvested lymph nodes were located at level IV. There was no recurrence during a mean follow-up period of 31.6 months.

CONCLUSION
Patients with clinically suspicious lateral neck nodes that are not confirmed by biopsy may be good candidates for super-selective neck dissection, which had minimal morbidity and did not compromise oncologic outcomes.

Kim|Heejin|H|
Jin|Young Ju|YJ|
Cha|Wonjae|W|
Jeong|Woo-Jin|WJ|
Ahn|Soon-Hyun|SH|

D000293:Adolescent
D000328:Adult
D000368:Aged
D000369:Aged, 80 and over
D044963:Biopsy, Fine-Needle
D002291:Carcinoma, Papillary
D018572:Disease-Free Survival
D005240:Feasibility Studies
D005260:Female
D005500:Follow-Up Studies
D006801:Humans
D008198:Lymph Nodes
D008207:Lymphatic Metastasis
D008297:Male
D008875:Middle Aged
D037981:Neck Dissection
D009364:Neoplasm Recurrence, Local
D012189:Retrospective Studies
D013964:Thyroid Neoplasms
D013965:Thyroidectomy
D055815:Young Adult

neck dissection
papillary thyroid carcinoma
thyroidectomy
locoregional neoplasm recurrences
lymphatic metastasis


Single-transcript multiplex in situ hybridisation reveals unique patterns of dystrophin isoform expression in the developing mammalian embryo.

Abstract: Background: The dystrophin gene has multiple isoforms: full-length dystrophin (dp427) is principally known for its expression in skeletal and cardiac muscle, but is also expressed in the brain, and several internal promoters give rise to shorter, N-terminally truncated isoforms with wider tissue expression patterns (dp260 in the retina, dp140 in the brain and dp71 in many tissues). These isoforms are believed to play unique cellular roles both during embryogenesis and in adulthood, but their shared sequence identity at both mRNA and protein levels makes study of distinct isoforms challenging by conventional methods. Methods: RNAscope is a novel in-situ hybridisation technique that offers single-transcript resolution and the ability to multiplex, with different target sequences assigned to distinct fluorophores. Using probes designed to different regions of the dystrophin transcript (targeting 5', central and 3' sequences of the long dp427 mRNA), we can simultaneously detect and distinguish multiple dystrophin mRNA isoforms at sub-cellular histological levels. We have used these probes in healthy and dystrophic canine embryos to gain unique insights into isoform expression and distribution in the developing mammal. Results: Dp427 is found in developing muscle as expected, apparently enriched at nascent myotendinous junctions. Endothelial and epithelial surfaces express dp71 only. Within the brain and spinal cord, all three isoforms are expressed in spatially distinct regions: dp71 predominates within proliferating germinal layer cells, dp140 within maturing, migrating cells and dp427 appears within more established cell populations. Dystrophin is also found within developing bones and teeth, something previously unreported, and our data suggests orchestrated involvement of multiple isoforms in formation of these tissues. Conclusions: Overall, shorter isoforms appear associated with proliferation and migration, and longer isoforms with terminal lineage commitment: we discuss the distinct structural contributions and transcriptional demands suggested by these findings.

Dystrophin
Expression
Development
Dp427
Muscle
Brain
Dp140
Dp71
Embryogenesis
RNAscope
In-situ hybridisation
DMD
DeltaE50-MD
Nerve


Changes in secretory pathway Ca(2+)-ATPase 2 following focal cerebral ischemia/reperfusion injury.

Abstract: This study aimed to investigate changes in secretory pathway Ca(2+)-ATPase 2 expression following cerebral ischemia/reperfusion injury, and to define the role of Ca(2+)-ATPases in oxidative stress. A rat model of cerebral ischemia/reperfusion injury was established using the unilateral middle cerebral artery occlusion method. Immunohistochemistry and reverse transcription-PCR assay results showed that compared with the control group, the expression of secretory pathway Ca(2+)-ATPase 2 protein and mRNA in the cerebral cortex and hippocampus of male rats did not significantly change during the ischemic period. However, secretory pathway Ca(2+)-ATPase 2 protein and mRNA expression reduced gradually at 1, 3, and 24 hours during the reperfusion period. Our experimental findings indicate that levels of secretory pathway Ca(2+)-ATPase 2 protein and mRNA expression in brain tissue change in response to cerebral ischemia/reperfusion injury.

Lu|Tonglin|T| Hu|Zhiping|Z| Zeng|Liuwang|L| Jiang|Zheng|Z|

focal cerebral ischemia
Ca2+ oscillations
Ca2+-ATPase
Golgi apparatus
brain injury
cerebral infarction
grants-supported paper
manganese
neural regeneration
neuroregeneration
oxidative damage
photographs-containing paper
secretory pathway Ca2+-ATPase 2


An NADH-Dependent Reductase from Eubacterium ramulus Catalyzes the Stereospecific Heteroring Cleavage of Flavanones and Flavanonols.

Abstract: The human intestinal anaerobe Eubacterium ramulus is known for its ability to degrade various dietary flavonoids. In the present study, we demonstrate the cleavage of the heterocyclic C-ring of flavanones and flavanonols by an oxygen-sensitive NADH-dependent reductase, previously described as enoate reductase, from E. ramulus This flavanone- and flavanonol-cleaving reductase (Fcr) was purified following its heterologous expression in Escherichia coli and further characterized. Fcr cleaved the flavanones naringenin, eriodictyol, liquiritigenin, and homoeriodictyol. Moreover, the flavanonols taxifolin and dihydrokaempferol served as substrates. The catalyzed reactions were stereospecific for the (2R)-enantiomers of the flavanone substrates and for the (2S,3S)-configured flavanonols. The enantioenrichment of the nonconverted stereoisomers allowed for the determination of hitherto unknown flavanone racemization rates. Fcr formed the corresponding dihydrochalcones and hydroxydihydrochalcones in the course of an unusual reductive cleavage of cyclic ether bonds. Fcr did not convert members of other flavonoid subclasses, including flavones, flavonols, and chalcones, the latter indicating that the reaction does not involve a chalcone intermediate. This view is strongly supported by the observed enantiospecificity of Fcr. Cinnamic acids, which are typical substrates of bacterial enoate reductases, were also not reduced by Fcr. Based on the presence of binding motifs for dinucleotide cofactors and a 4Fe-4S cluster in the amino acid sequence of Fcr, a cofactor-mediated hydride transfer from NADH onto C-2 of the respective substrate is proposed.IMPORTANCE Gut bacteria play a crucial role in the metabolism of dietary flavonoids, thereby contributing to their activation or inactivation after ingestion by the human host. Thus, bacterial activities in the intestine may influence the beneficial health effects of these polyphenolic plant compounds. While an increasing number of flavonoid-converting gut bacterial species have been identified, knowledge of the responsible enzymes is still limited. Here, we characterized Fcr as a key enzyme involved in the conversion of flavonoids of several subclasses by Eubacterium ramulus, a prevalent human gut bacterium. Sequence similarity of this enzyme to hypothetical proteins from other flavonoid-degrading intestinal bacteria in databases suggests a more widespread occurrence of this enzyme. Functional characterization of gene products of human intestinal microbiota enables the assignment of metagenomic sequences to specific bacteria and, more importantly, to certain activities, which is a prerequisite for targeted modulation of gut microbial functionality.

reductase
Eubacterium ramulus
flavanone
flavanonol
flavonoid
naringenin
enantiospecificity
intestinal bacteria


Telomerase abrogates aneuploidy-induced telomere replication stress, senescence and cell depletion.

Abstract: The causal role of aneuploidy in cancer initiation remains under debate since mutations of euploidy-controlling genes reduce cell fitness but aneuploidy strongly associates with human cancers. Telomerase activation allows immortal growth by stabilizing telomere length, but its role in aneuploidy survival has not been characterized. Here, we analyze the response of primary human cells and murine hematopoietic stem cells (HSCs) to aneuploidy induction and the role of telomeres and the telomerase in this process. The study shows that aneuploidy induces replication stress at telomeres leading to telomeric DNA damage and p53 activation. This results in p53/Rb-dependent, premature senescence of human fibroblast, and in the depletion of hematopoietic cells in telomerase-deficient mice. Endogenous telomerase expression in HSCs and enforced expression of telomerase in human fibroblasts are sufficient to abrogate aneuploidy-induced replication stress at telomeres and the consequent induction of premature senescence and hematopoietic cell depletion. Together, these results identify telomerase as an aneuploidy survival factor in mammalian cells based on its capacity to alleviate telomere replication stress in response to aneuploidy induction.

Meena|Jitendra K|JK|
Cerutti|Aurora|A|
Beichler|Christine|C|
Morita|Yohei|Y|
Bruhn|Christopher|C|
Kumar|Mukesh|M|
Kraus|Johann M|JM|
Speicher|Michael R|MR|
Wang|Zhao-Qi|ZQ|
Kestler|Hans A|HA|
d'Adda di Fagagna|Fabrizio|F|
Günes|Cagatay|C|
Rudolph|Karl Lenhard|KL|

telomerase
telomere
replication stress
senescence
aneuploidy


Salting-in counter-current chromatography separation of tanshinones based on room temperature ionic liquids.

Abstract: Ionic liquids have been widely used for the extraction and separation of bioactive natural and synthetic mixtures. In this study, we provided an updated example by using an ionic liquid-based salting-in counter-current chromatography (CCC) strategy for the separation of hydrophobic tanshinones without subsequent column chromatography purification. Several ionic liquids such as 1-allyl-3-methylimidazolium chloride ([AMIM]Cl), 1-methallyl-3-methylimidazolium chloride ([MAMIM]Cl) and 1-butyl-3-ethylimidazolium chloride [BMIM]Cl could significantly decrease the partition coefficients (K) of tanshinones in the selected two-phase solvent composed of hexane-ethyl acetate-methanol-ionic liquid aqueous solution (5:5:6:4, v/v). Typically, K values of three target tanshinones including tanshinone I, 1,2-dihydrotanshinquione and tanshinone IIA were reduced from 3.57, 4.57 and 5.50 to 1.62, 2.33 and 3.08, respectively, by the inclusion of 10% [AMIM]Cl in the solvent system. After salting-in CCC separation, the purified tanshinones were obtained only by simple ethyl acetate extraction. In general, the current results demonstrated that the ionic liquid-based salting-in CCC may be as an alternative strategy for the optimization of CCC solvent systems and separation of lipophilic natural products.

Wang|Yanyan|Y| Zhang|Lihong|L| Guo|Xiuyun|X| Wu|Shihua|S|

D002851:Chromatography, High Pressure Liquid

Salting-in
Tanshinone
Room temperature ionic liquids
Natural product isolation
Salting-out
Traditional Chinese medicine


Ultra high-frequency ultrasound with seventy-MHz transducer in hair disorders: Development of a novel noninvasive diagnostic methodology.

Abstract:
BACKGROUND
Ultra high-frequency ultrasound (uHFUS) is a recently developed diagnostic technology. Despite its potential usefulness, no study has assessed its advantage in diagnosis and evaluation of hair disorders in comparison with other diagnostic methods.

OBJECTIVES
To assess the practicability of uHFUS in diagnosing hair disorders and propose a diagnostic methodology.

METHODS
Ultrasonographic images of scalp and forehead from patients with hair disorders (n = 103) and healthy controls (n = 40) were obtained by uHFUS and analyzed by both descriptive and numerical parameters. Furthermore, the data were compared with trichoscopic and histopathological findings.

RESULTS
The pattern of inflammation and fibrosis, hair cycle abnormality, and the findings in subcutis were detected by uHFUS. Significant differences were noted in the numerical parameters associated with the number of hair shafts and follicles, hair diameters and their diversity, and dermal echogenicity in both cicatricial and non-cicatricial hair disorders. Findings in uHFUS were associated with those observed in trichoscopy and scalp biopsy but uHFUS was able to detect pathological findings associated with hair cycle, inflammation, fibrosis, and subcutaneous abnormalities, which are hardly assessable by trichoscopy.

CONCLUSION
The findings of this study highlighted usefulness of uHFUS in diagnosing hair disorders, while overcoming the weaknesses and limitations of other diagnostic tools.

Kinoshita-Ise|Misaki|M|
Ohyama|Manabu|M|
Ramjist|Joel M|JM|
Foster|F Stuart|FS|
Yang|Victor X D|VXD|
Sachdeva|Muskaan|M|
Sade|Shachar|S|
Shear|Neil H|NH|

High-frequency ultrasound
Hair disorders
Trichoscopy
Scalp biopsy
Dermoscopy


Comparison of interactive voice response (IVR) with paper administration of instruments to assess functional status, sexual function, and quality of life in elderly men.

Abstract:
PURPOSE
Patient-reported outcome (PRO) measures are essential for assessing subjective patient experiences. Interactive voice response (IVR) data collection provides advantages for clinical trial design by standardizing and centralizing the assessment. Prior to adoption of IVR as a mode of PRO administration in the Testosterone Trials (TTrials), we compared IVR to paper versions of the instruments to be used.

METHODS
IVR versions of the FACIT-Fatigue scale and Psychosexual Daily Questionnaire, Question 4, were developed. In one pilot study, IVR versions of these scales were compared to paper versions in 25 men ≥ 65 years at each of two clinical sites. In another study, IVR versions of the SF-36 Vitality Scale (SF-36), Positive and Negative Affect Scale, and Patient Health Questionnaire were evaluated in comparison with previously validated paper versions in 25 men at two clinical sites. Both paper and IVR versions of each instrument were administered in counterbalanced order, and test-retest reliability was evaluated by repeated administration of the test. Bland-Altman plots were used to assess the degree of agreement. Test-retest correlations for each measure were also determined.

RESULTS
Satisfactory agreement was observed between IVR and paper versions of each study measure. Specifically, linear and highly positive associations were observed consistently across the study for IVR and paper versions of all study measures. These ranged from r = 0.91-0.99. Test-retest reliability for all measures was acceptable or better (r = 0.70-0.90).

CONCLUSIONS
The IVR versions of TTrials endpoints in these two studies performed consistently well in comparison with paper versions.

Rosen|Raymond C|RC|
Stephens-Shields|Alisa J|AJ|
Cunningham|Glenn R|GR|
Cifelli|Denise|D|
Cella|David|D|
Farrar|John T|JT|
Barrett-Connor|Elizabeth|E|
Lewis|Cora E|CE|
Pahor|Marco|M|
Hou|Xiaoling|X|
Snyder|Peter J|PJ|

Interactive voice response
Sexual function
Quality of life
Vitality
Fatigue


Validation of a wrist-type home nocturnal blood pressure monitor in the sitting and supine position according to the ANSI/AAMI/ISO81060-2:2013 guidelines: Omron HEM-9601T.

Abstract: This study aimed to validate the accuracy of the Omron HEM-9601T, an automatic wrist-type device for self-blood pressure (BP) measurement with a timer function for automatic measurement of nocturnal BP, in the sitting position according to the American National Standards Institute/Association for the Advancement of Medical Instrumentation/International Organization for Standardization (ANSI/AAMI/ISO) 81060-2:2013 guidelines, and to assess its performance in the supine position by applying the same protocol as conducted in the sitting position. The mean differences between the reference BPs and HEM-9601T readings were 1.2 ± 6.9/1.1 ± 5.5 mmHg, 2.2 ± 6.5/1.8 ± 5.7 mmHg, 0.1 ± 6.6/1.5 ± 6.2 mmHg, and -0.8 ± 7.2/0.5 ± 6.4 mmHg for systolic BP/diastolic BP for criterion 1 in the sitting position, supine with sideways palm position, supine with upward palm position, and supine with downward palm position, respectively. In addition, the mean differences and their standard deviations for systolic BP and diastolic BP calculated according to criterion 2 in the ANSI/AAMI/ISO 81060-2:2013 guidelines were acceptable in all four positions. In conclusion, the Omron HEM-9601T fulfilled the validation criteria of the ANSI/AAMI/ISO81060-2:2013 guidelines when used in the sitting position with the wrist at heart level, and its accuracy in the supine position was acceptable and roughly equivalent to that in the sitting position. The wrist-type home BP monitor could be a more suitable tool for repeated nocturnal BP measurements at home than upper-arm devices, and could improve the reliability of diagnosis and management of nocturnal hypertension.

validation
home nocturnal blood pressure
blood pressure
ANSI/AAMI/ISO81060-2:2013
self-measurement
wrist-type blood pressure monitor


Capitalizing on Synthetic Lethality of MYC to Treat Cancer in the Digital Age.

Abstract: Deregulation of MYC is among the most frequent oncogenic drivers of cancer. Developing targeted therapies against MYC is, therefore, one of the most critical unmet needs of cancer therapy. Unfortunately, MYC has been labelled as undruggable due to the lack of success in developing clinically relevant MYC-targeted therapies. Synthetic lethality is a promising approach that targets MYC-dependent vulnerabilities in cancer. However, translating the synthetic lethality targets to the clinics is still challenging due to the complex nature of cancers. This review highlights the most promising mechanisms of MYC synthetic lethality and how these discoveries are currently translated into the clinic. Finally, we discuss how in silico computational platforms can improve clinical success of synthetic lethality-based therapy.

Thng|Dexter Kai Hao|DKH|
Toh|Tan Boon|TB|
Chow|Edward Kai-Hua|EK|

synthetic lethality
MYC
cancer
computational
drug targets


Occurrence of nocturia is not mediated by nocturnal hypoxia length and severity in patients with sleep-disordered breathing.

Abstract:
BACKGROUND
Nocturia is highly prevalent in subjects with respiratory sleep disturbances (ie obstructive sleep apnea). The aim of our study is to evaluate whether nocturia is associated with intermittent desaturations or hypoxia length and severity in people undergoing polysomnography.

METHODS
We recruited 275 consecutive subjects attending the outpatient clinic for respiratory diseases at Campus Bio-Medico Teaching Hospital. Nocturia was defined as a self-reported voiding frequency ≥ two per night. The groups with and without nocturia were compared with parametric and non-parametric tests, as appropriated. Multivariable logistic regression analysis was used to assess the association of nocturia with patients' characteristics, including oxygen desaturation index (ODI), respiratory efforts (RE) and oxygen saturation below 90% (TST90).

RESULTS
Sixty-six (24%) subjects reported nocturia, the median ODI was 15 (8-31), the median RE was 22 (12-38) and the median TST90 was 4.7 (0.3-20.6). ODI and RE were significantly higher in subjects with nocturia as compared with controls. In the multivariable model, ODI was associated with an increased probability of nocturia (OR = 1.03; 95% CI = 1.01-1.06), and the higher the ODI score, the higher the probability to have nocturia (P for trend = 0.038). No significant association was found between TST90 and the occurrence of nocturia.

CONCLUSIONS
Intermittent desaturations and not hypoxia length and severity, expressed by TST90, are associated with the occurrence of nocturia in subjects complaining sleep disturbances.

Finamore|P|P|
Scarlata|S|S|
Laudisio|A|A|
Galdi|F|F|
Pipita|M E|ME|
Chiarella|I|I|
Giua|R|R|
Cortese|L|L|
Rivera|C|C|
Antonelli Incalzi|R|R|

Nocturia
Hypoxia
Polysomnography
Oxygen desaturation index
Total sleep time with SpO(2)<90%


In-Depth Study of Cyclodextrin Complexation with Carotenoids toward the Formation of Enhanced Delivery Systems.

Abstract: The goal of this study was molecular modeling of cyclodextrin (CD) and carotenoid complex formation. Distinction was made between complexes resulting from interactions between carotenoids and either molecularly dispersed CDs or solid crystalline CDs, considering that both cases can occur depending on the complex formation process pathways. First, the formation of complexes from dispersed CD molecules was investigated considering five different CDs (αCD, βCD, methyl-βCD, hydroxypropyl-βCD, and γCD) and lutein, as a model carotenoid molecule. The interactions involved and the stability of the different complexes formed were evaluated according to the CD size and steric hindrance. Second, the formation of complexes between four different crystalline CDs (βCD with three different water contents and methyl-βCD) and three carotenoid molecules (lutein, lycopene, and β-carotene) was studied. The docking/adsorption of the carotenoid molecules was modeled on the different faces of the CD crystals. The findings highlight that all the CD faces, and thus their growth rates, were equally impacted by the adsorption of the carotenoids. This is due to the fact that all the CD faces are exhibiting similar chemical compositions, the three studied carotenoid molecules are rather chemically similar, and last, the water-carotenoid interactions appear to be weak compared to the CD-carotenoid interactions.

cyclodextrin
complexation
delivery systems
molecular modeling
adsorption


Effect of Zuoguiwan on osteoporosis in ovariectomized rats through RANKL/OPG pathway mediated by β2AR.

Abstract:
ETHNOPHARMACOLOGICAL RELEVANCE
The deficiency of kidney Yin is the main pathogenesis of postmenopausal osteoporosis (PMOP) according to traditional Chinese medicine (TCM). Zuoguiwan (ZGW) is among the classical prescriptions in TCM and has been applied to various diseases that are due to deficiency of kidney Yin, including osteoporosis, fractures, menopausal syndromes. However, the underlying mechanism of ZGW in treating PMOP remains poorly understood.

AIM OF THE STUDY
ZGW, a traditional Chinese prescription, has been used to nourish Yin and reinforce the kidney since ancient times. The investigation aimed to explore the mechanism of ZGW via the receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) signaling pathway as mediated by the β2-adrenergic receptor (β2AR) in an osteoporosis rat model.

MATERIALS AND METHODS
An osteoporosis model induced by ovariectomy was established in rats. A total of 40 female Sprague-Dawley rats were randomly assigned into bilateral ovariectomy group (OVX), sham operated group (Sham), 17β-estradiol-treated positive group (E2, 25 μg/kg/d), ZGW low-dose group (ZGW-L, 2.3 g/kg/d lyophilized powder) and ZGW high-dose group (ZGW-H, 4.6 g/kg/d lyophilized powder). The serum markers of bone turnover were measured using enzyme-linked immunosorbent assay (ELISA). The morphological structure changes in bones were detected through H&E staining. Local bone mineral density (BMD) and trabecular bone microarchitecture of the right distal femur were measured and evaluated by using micro-CT. Furthermore, the mRNA and protein expressions levels of β2AR, OPG and RANKL were measured by qPCR and Western blot analysis.

RESULTS
Compared with the OVX group, ZGW groups showed significantly reduced levels of serum tartrate-resistant acid phosphatase 5b (TRACP-5b) and β-cross-linked c-telopeptide of type I collagen (β-CTX) (P ＜ 0.01), increased levels of serum bone-specific alkaline phosphatase (BALP) (P ＜ 0.01) and OPG (P ＜ 0.05), prevention of OVX-induced bone loss, and improved microarchitecture of the trabecular bone of distal femur. Moreover, ZGW mediated the osteoporosis syndrome by reducing the empty bone lacunae, promoting the ordered arrangement of trabeculae structure, and increasing the trabeculae structure thickness. Furthermore, in ZGW groups, the protein expression of OPG in the tibia was notably up-regulated (P ＜ 0.01), whereas the mRNA and protein expression of β2AR in the hippocampus (P ＜ 0.01), and the protein expressions levels of β2AR (P ＜ 0.01) and RANKL (P ＜ 0.05) in the tibia were down-regulated compared with OVX group.

CONCLUSIONS
ZGW through its protective effects, stimulates bone formation and suppresses bone resorption. The underlying mechanism of ZGW in improving perimenopausal syndrome and increasing bone mass might be attributed to the regulation of RANKL/OPG, as mediated by β2AR. Therefore, ZGW may be used as an alternative treatment for PMOP.

Liu|Feixiang|F| Tan|Feng|F| Tong|Weiwei|W| Fan|Qiaoling|Q| Ye|Sumin|S| Lu|Shengfeng|S| Teng|Zhanli|Z| Han|Miaomiao|M| Zhang|Mingyue|M| Chai|Yi|Y|

Zuoguiwan
Postmenopausal osteoporosis
β2-adrenergic receptor
RANKL/OPG signaling pathway


Nanophosphor-Based Contrast Agents for Spectral X-ray Imaging.

Abstract: Lanthanide-based nanophosphors (NPhs) are herein developed as contrast agents for spectral X-ray imaging, highlighting the chemical, macromolecular and structural differences derived from ligand exchange on computed tomography (CT) and solvent dispersibility. Taking advantage of the ability of spectral X-ray imaging with photon-counting detectors to perform image acquisition, analysis, and processing at different energy windows (bins), enhanced signal of our K-edge materials was derived, improving sensitivity of CT imaging, and differentiation between water, tumor-mimic phantoms, and contrast materials. Our results indicate that the most effective of our oleic acid-stabilized K-edge nanoparticles can achieve 2-4x higher contrast than the examined iodinated molecules, making them suitable for deep tissue imaging of tissues or tumors. On the other hand, ligand exchange yielding poly(acrylic acid)-stabilized K-edge nanoparticles allows for high dispersibility and homogeneity in water, but with a lower contrast due to the high density of the polymer grafted, unless further engineering is probed. This is the first well-defined study that manages to correlate NPh grafting density with CT numbers and water dispersibility, laying the groundwork for the development of the next generation CT-guided diagnostic and/or theranostic materials.

Smith|Kevin|K|
Getzin|Matthew|M|
Garfield|Josephine J|JJ|
Suvarnapathaki|Sanika|S|
Camci-Unal|Gulden|G|
Wang|Ge|G|0000-0002-2656-7705
Gkikas|Manos|M|

nanophosphors
computed tomography
CT imaging
X-ray contrast agents
lanthanide nanoparticles
rare earth metals
spectral CT


Role of karyopherin nuclear transport receptors in nuclear transport by nuclear trafficking peptide.

Abstract: Nuclear trafficking peptide (NTP), a cell-penetrating peptide (CPP) composed of 10 amino acids (aa) (RIFIHFRIGC), has potent nuclear trafficking activity. Recently, we established a protein-based cell engineering system by using NTP, but it remained elusive how NTP functions as a CPP with nuclear orientation. In the present study, we identified importin subunit β1 (IMB1) and transportin 1 (TNPO1) as cellular proteins underlying the activity of NTP. These karyopherin nuclear transport receptors were identified as candidate molecules by liquid chromatography/mass spectrometry analysis, and downregulation of each protein by small interfering RNA significantly reduced NTP activity (P < 0.01). Biochemical analyses revealed that NTP bound directly to both molecules, and the forced expression of an IMB1 fragment (296-516 aa) or TNPO1 fragment (1-297 aa), which both contain binding sites to NTP, reduced nuclear NTP-green fluorescent protein (GFP) levels when it was added to cell culture medium. NTP is derived from viral protein R (Vpr) of human immunodeficiency virus-1, and Vpr enters the nucleus and exerts pleiotropic functions. Notably, Vpr bound directly to IMB1 and TNPO1, and its function was significantly impaired by the forced expression of the 296-516-aa fragment of IMB1 and 1-297-aa fragment of TNPO1. Interestingly, NTP completely blocked the physical association of Vpr with IMB1 and TNPO1. Although the nuclear localization mechanism of Vpr remains unknown, our data suggest that NTP functions as a novel nuclear localization signal of Vpr.

Nuclear trafficking peptide
Transportin 1
Vpr
HIV-1
Importin b1
Nuclear cargo


Transcriptomic landscape of skin lesions in cutaneous leishmaniasis reveals a strong CD8+ T cell immunosenescence signature linked to immunopathology.

Abstract: The severity of lesions that develop in patients infected by Leishmania braziliensis is mainly associated with a highly cytotoxic and inflammatory cutaneous environment. Recently, we demonstrated that senescent T and NK cells play a role in the establishment and maintenance of this tissue inflammation. Here, we extended those findings using transcriptomic analyses that demonstrate a strong co-induction of senescence and pro-inflammatory gene signatures in cutaneous leishmaniasis (CL) lesions. The senescence-associated signature was characterized by marked expression of key genes such as ATM, Sestrin 2, p16, p21 and p38. The cell type identification from deconvolution of bulk sequencing data showed that the senescence signature was linked with CD8+ effector memory and TEMRA subsets and also senescent NK cells. A key observation was that the senescence markers in the skin lesions are age-independent of patients and were correlated with lesion size. Moreover, a striking expression of the senescence-associated secretory phenotype (SASP), pro-inflammatory cytokine and chemokines genes was found within lesions that were most strongly associated with the senescent CD8 TEMRA subset. Collectively, our results confirm that there is a senescence transcriptomic signature in CL lesions and supports the hypothesis that lesional senescent cells have a major role in mediating immunopathology of the disease.


Identification of conformationally sensitive residues essential for inhibition of vesicular monoamine transport by the noncompetitive inhibitor tetrabenazine.

Abstract: Vesicular monoamine transporter 2 (VMAT2) transports monoamines into storage vesicles in a process that involves exchange of the charged monoamine with two protons. VMAT2 is a member of the DHA12 family of multidrug transporters that belongs to the major facilitator superfamily of secondary transporters. Tetrabenazine (TBZ) is a non-competitive inhibitor of VMAT2 that is used in the treatment of hyperkinetic disorders associated with Huntington disease and Tourette syndrome. Previous biochemical studies suggested that the recognition site for TBZ and monoamines is different. However, the precise mechanism of TBZ interaction with VMAT2 remains unknown. Here we used a random mutagenesis approach and selected TBZ-resistant mutants. The mutations clustered around the lumenal opening of the transporter and mapped to either conserved proline or glycine, or to residues immediately adjacent to conserved proline and glycine. Directed mutagenesis provides further support for the essential role of the latter residues. Our data strongly suggest that the conserved α-helix breaking residues identified in this work play an important role in conformational rearrangements required for TBZ binding and substrate transport. Our results provide a novel insight into the mechanism of transport and TBZ binding by VMAT2.

Ugolev|Yelena|Y| Segal|Tali|T| Yaffe|Dana|D| Gros|Yael|Y| Schuldiner|Shimon|S|

D050493:Vesicular Monoamine Transport Proteins

Multidrug Transporters
Directed Evolution
Ion-coupled Transporters
MFS Superfamily
Membrane Proteins
Neurotransmitter Transport
Neurotransmitters
PXXP Motifs


Two cases of response to pembrolizumab in epidermal growth factor receptor mutated lung adenocarcinoma patients with programmed death-ligand 1 overexpression.

Abstract: Recently, the immune checkpoint inhibitor (ICI) pembrolizumab was demonstrated to be superior to platinum doublet chemotherapy in the first-line setting in patients with tumor programmed death-ligand 1 (PD-L1) expression of at least 50%. However, because patients with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements were not included in that study, the efficacy of pembrolizumab in lung cancers carrying EGFR mutations could not be determined. Here we describe two cases of response to pembrolizumab in EGFR mutated lung adenocarcinoma patients with PD-L1 overexpression. These cases indicate that ICI is an effective treatment for EGFR mutated lung adenocarcinoma patients with PD-L1 overexpression.

Uenami|Takeshi|T| Ishijima|Mikako|M| Kanazu|Masaki|M| Kurebe|Hiroyuki|H| Edahiro|Ryuya|R| Nishida|Kohei|K| Akazawa|Yuki|Y| Yano|Yukihiro|Y| Yamaguchi|Toshihiko|T| Mori|Masahide|M|

pembrolizumab
programmed death-ligand 1 (PD-L1)
epidermal growth factor receptor (EGFR)
Non-small cell lung cancer (NSCLC)


Quality of life for chronic psychiatric illnesses and home care.

Abstract:
UNLABELLED
Nowadays, mental illnesses are gradually increasing and so does chronic psychiatric patients. As a result of this increase, chronic psychiatric disorders lead the burden of patients and their families. To reduce the burden of mental illnesses on individuals and their families, treatment and care are given including psychosocial, physiological and medical support and social services. To begin with, home care enables both the patient and his or her family to stay at their own houses and not to be bothered with residents or long-term, institutional-based nursing homes. In addition, the home care providers deliver services to the patient's at their own house. The other advantages of taking care at home is that it eases financial issues in terms of reducing the cost, reduces the patient's symptoms and improve the individual's quality of life (QoL). In addition to these, home care also minimizes the burden on outpatient services and provides help for the patient and the family in order to solve their problems and give support. Home care services help patients to get their freedom back and enhance the quality of their lives. Thus, it is necessary to procure and implement these services and supply both the patient and his or her family a high-quality life.

SOURCES OF DATA/ STUDY SELECTION
Literature review was done by using the keywords "home care, patient with chronic mental illness, quality of life, home care nursing" from the sources including PsychINFO, PsychARTICLES, MEDLINE, PubMED, EBSCOHOST and The COCHRANE LIBRARY in the time period of 2005- 2015.

Molu|Nesibe Gunay|NG|
Ozkan|Birgul|B|
Icel|Sema|S|

Quality of life
Home care
Psychiatric patients


Free-radical scavenging activity and antibacterial impact of Greek oregano isolates obtained by SFE.

Abstract: The antioxidant and antibacterial properties of Greek oregano extracts obtained by fractional supercritical fluid extraction (SFE) with carbon dioxide were investigated and compared with the properties of essential oil obtained by hydrodistillation. According to DPPH, hydroxyl radical and superoxide anion radical scavenging activity assays, the supercritical extracts expressed stronger antioxidant activity comparing to the essential oil. The most effective was the supercritical extract obtained by fractional extraction at 30 MPa and 100°C after the volatile fraction had been extracted at lower pressure. At the same time this extract showed strong antibacterial activity against staphylococci, including MRSA strain, but did not affect Escherichia coli of normal intestinal flora. The essential oil obtained by hydrodistillation showed stronger antibacterial activity against E. coli, Salmonella and Klebsiella pneumoniae, comparing to the supercritical extracts but at the same affected the normal gut flora.

Stamenic|Marko|M| Vulic|Jelena|J| Djilas|Sonja|S| Misic|Dusan|D| Tadic|Vanja|V| Petrovic|Slobodan|S| Zizovic|Irena|I|

Greek oregano
Supercritical extraction
Antibacterial activity
MRSA
Intestinal flora
Natural antioxidants


Reconstructed evolutionary history of the yeast septins Cdc11 and Shs1.

Abstract: Septins are GTP-binding proteins conserved across metazoans. They can polymerize into extended filaments and, hence, are considered a component of the cytoskeleton. The number of individual septins varies across the tree of life-yeast (Saccharomyces cerevisiae) has seven distinct subunits, a nematode (Caenorhabditis elegans) has two, and humans have 13. However, the overall geometric unit (an apolar hetero-octameric protomer and filaments assembled there from) has been conserved. To understand septin evolutionary variation, we focused on a related pair of yeast subunits (Cdc11 and Shs1) that appear to have arisen from gene duplication within the fungal clade. Either Cdc11 or Shs1 occupies the terminal position within a hetero-octamer, yet Cdc11 is essential for septin function and cell viability, whereas Shs1 is not. To discern the molecular basis of this divergence, we utilized ancestral gene reconstruction to predict, synthesize, and experimentally examine the most recent common ancestor ("Anc.11-S") of Cdc11 and Shs1. Anc.11-S was able to occupy the terminal position within an octamer, just like the modern subunits. Although Anc.11-S supplied many of the known functions of Cdc11, it was unable to replace the distinct function(s) of Shs1. To further evaluate the history of Shs1, additional intermediates along a proposed trajectory from Anc.11-S to yeast Shs1 were generated and tested. We demonstrate that multiple events contributed to the current properties of Shs1: (1) loss of Shs1-Shs1 self-association early after duplication, (2) co-evolution of heterotypic Cdc11-Shs1 interaction between neighboring hetero-octamers, and (3) eventual repurposing and acquisition of novel function(s) for its C-terminal extension domain. Thus, a pair of duplicated proteins, despite constraints imposed by assembly into a highly conserved multi-subunit structure, could evolve new functionality via a complex evolutionary pathway.

Takagi|Julie|J|
Cho|Christina|C|
Duvalyan|Angela|A|
Yan|Yao|Y|
Halloran|Megan|M|
Hanson-Smith|Victor|V|
Thorner|Jeremy|J|
Finnigan|Gregory C|GC|

yeast
septins
cytoskeleton
ancestral gene reconstruction
molecular evolution


Cancer Biomarkers in the era of precision oncology: Addressing the needs of patients and health systems.

Abstract: Cancer Biomarkers are the key to unlocking the promise of precision oncology, selecting which patients will respond to a more personalised treatment while sparing non-responders the therapy-related toxicity. In this paper, we highlight the primacy of cancer biomarkers, but focus on their importance to patients and to health systems. We also highlight how cancer biomarkers represent value for money. We emphasise the need for cancer biomarkers infrastructure to be embedded into European health systems. We also highlight the need to deploy multiple biomarker testing to deliver the optimal benefit for patients and health systems and consider cancer biomarkers from the perspective of cost, value and regulation. Cancer biomarkers must also be situated in the context of the upcoming In Vitro Diagnostics Regulation, which may pose certain challenges (e.g. non-compliance of laboratory developed tests, leading to cancer biomarker shortages and increased costs) that need to be overcome. Cancer biomarkers must be embedded in the real world of oncology delivery and testing must be implemented across Europe, with the intended aim of narrowing, not widening the inequity gap for patients. Cancer patients must be placed firmly at the centre of a cancer biomarker informed precision oncology care agenda.

Normanno|Nicola|N|
Apostolides|Kathi|K|
de Lorenzo|Francesco|F|
Beer|Philip A|PA|
Henderson|Raymond|R|
Sullivan|Richard|R|
Biankin|Andrew V|AV|
Horgan|Denis|D|
Lawler|Mark|M|

Cancer biomarkers
Precision oncology
Patient-centred care
Personalised care


Prediction of neo-adjuvant chemotherapy response in bladder cancer: the impact of clinical parameters and routine biomarkers.

Abstract:
PURPOSE
To investigate the role of clinical parameters and immunohistochemical (IHC) biomarkers in their feasibility to predict the effect of neo-adjuvant chemotherapy (NAC) in patients with muscle-invasive urothelial bladder cancer (MIBC).

MATERIALS AND METHODS
The first 76 consecutive patients with MIBC treated with NAC and radical cystectomy in two University hospitals in Finland between 2008 and 2013 were chosen for this study. After excluding patients with non-urothelial cancer, less than two cycles of chemotherapy, no tissue material for IHC analysis or non-muscle-invasive bladder cancer in re-review, 59 patients were included in the final analysis. A tissue microarray block was constructed from the transurethral resection samples and IHC stainings of Ki-67, p53, Her-2 and EGFR were made. The correlations between histological features in transurethral resection samples and immune-histochemical stainings were calculated. The associations of clinicopathological parameters and IHC stainings with NAC response were evaluated. Factors affecting survival were estimated.

RESULTS
The complete response rate after NAC was 44%. A higher number of chemotherapy cycles was associated with better response to neo-adjuvant chemotherapy. No response to neo-adjuvant chemotherapy and female gender was associated with decreased cancer-specific survival. The IHC stainings used failed to show an association with neo-adjuvant chemotherapy response and overall or cancer specific survival.

CONCLUSIONS
Patients who do not respond to neo-adjuvant chemotherapy do significantly worse than responders. This study could not find clinical tools to distinguish responders from non-responders. Further studies preferably with larger cohorts addressing this issue are warranted to improve the selection of patients for neo-adjuvant chemotherapy.

Koskinen|I|I|
Boström|P J|PJ|
Taimen|P|P|
Salminen|A|A|
Tervahartiala|M|M|
Sairanen|J|J|
Erickson|A|A|
Mirtti|T|T|0000-0003-0455-9891

neo-adjuvant chemotherapy
cystectomy
Muscle-invasive bladder cancer
immunohistochemistry


The Road to Reproducibility in Animal Research.

Abstract: Reproducibility of research findings is the hallmark of scientific advance. However, the recently noted lack of reproducibility and transparency of published research using animal models of human biology and disease has alarmed funders, scientists, and the public. Improved reporting of methodology and better use of statistical tools are needed to enhance the quality and utility of published research. Reporting guidelines like Animal Research: Reporting In Vivo Experiments (ARRIVE) have been devised to achieve these goals, but most biomedical research journals, including the JBMR, have not been able to obtain high compliance. Cooperative efforts among authors, reviewers and editors-empowered by increased awareness of their responsibilities, and enabled by user-friendly guidelines-are needed to solve this problem. © 2016 American Society for Bone and Mineral Research.

D000818:Animals
D035843:Biomedical Research
D004195:Disease Models, Animal
D017408:Guidelines as Topic
D015203:Reproducibility of Results

ANIMAL MODELS
PRACTICE/POLICY-RELATED ISSUES
PRECLINICAL STUDIES


Multiple Myeloma: Clinical Updates From the American Society of Hematology Annual Meeting 2018.

Abstract: Herein, we summarize the novel clinical data for multiple myeloma (MM) that were presented in the 2019 Annual Meeting of the American Society of Hematology. Triplet regimens including lenalidomide-dexamethasone for high-risk smoldering MM are effective but longer follow-up data are needed. Among transplant-eligible, newly diagnosed MM (NDMM) patients, carfilzomib- and daratumumab-based combinations are promising as effective and safe induction regimens and do not impair stem cell collection. Maintenance with ixazomib results in prolonged progression-free survival (PFS) compared with placebo. Regarding transplant-ineligible NDMM patients, large phase III studies showed that the additional use of daratumumab in backbone first-line regimens provides deep responses and PFS prolongation, whereas dose-/schedule-adjusted lenalidomide-dexamethasone has similar efficacy and is more tolerable than continuous lenalidomide-dexamethasone. In the relapsed/refractory setting carfilzomib- and daratumumab-based regimens remain highly effective and safe treatments, whereas the introduction of venetoclax, isatuximab, atezolizumab, and oprozomib broadens the therapeutic options. Among heavily pretreated MM patients, selinexor and melflufen showed particularly encouraging results. Novel immunotherapeutic approaches including chimeric antigen receptor T cells against B-cell maturation antigen and bispecific antibodies constitute a promising alternative that remains to be evaluated in later-phase studies.

D000066491:Clinical Decision-Making
D002986:Clinical Trials as Topic
D003131:Combined Modality Therapy
D019468:Disease Management
D019008:Drug Resistance, Neoplasm
D006801:Humans
D009101:Multiple Myeloma
D011379:Prognosis
D012008:Recurrence
D019233:Retreatment
D000075122:Smoldering Multiple Myeloma
D016896:Treatment Outcome

Daratumumab
B-cell maturation antigen
CAR-T cells
Carfilzomib
Lenalidomide


Molecular diagnosis of invasive mycoses of the central nervous system.

Abstract: In September 2012, the Centers for Disease Control and Prevention (CDC) began investigating an outbreak of fungal meningitis among patients who had received contaminated preservative-free methyl prednisolone acetate injections from the New England Compounding Center in Framingham, Massachusetts. Thousands of patients were potentially exposed to tainted corticosteroids, but establishing the diagnosis of fungal meningitis during the nationwide outbreak was difficult because little was known about the natural history of the disease. Areas covered: The challenges associated with this outbreak highlighted the need for rapid and reliable methodologies to assist in the diagnosis of invasive mycoses of the central nervous system (IMCNS), which may be devastating and difficult to treat. In this paper, we review the causative agents of these potentially-lethal infections, which include cryptococcal meningitis, cerebral aspergillosis, and hematogenous Candida meningoencephalitis. Expert commentary: While microscopy, culture, and histopathologic identification of fungal pathogens remain the gold standard for diagnosis, new platforms and species-specific assays have recently emerged, including lateral flow immunoassays (LFA), matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS), and multiplex PCR in conjunction with magnetic resonance (MR) to potentially aid in the diagnosis of IMCNS.

McCarthy|Matthew William|MW|
Walsh|Thomas J|TJ|

invasive mycoses
MALDI-TOF
PCR
magnetic resonance
Exserohilum rostratum
dematiaceous mold


Ceramic based electronic component as retrospective radiation dosimeter.

Abstract: Surface mount electronic devices (like resistors, capacitors, and inductors) extracted from the portable electronic devices (mobile phones, USB drives, etc.) have been studied for dose reconstruction using luminescence techniques for radiological or nuclear emergencies. In this work, carbon coated ceramic resistors removed from the electronic instruments are analyzed using thermo luminescence (TL) technique for the retrospective dose reconstruction. TL measurements on beta irradiated ceramic resistors exhibited one major dosimetric peak at around 540 K in addition to three other low temperature peaks. A linear beta dose response has been observed from 1 Gy to 125 Gy with Minimum Detectable Dose (MDD) of 0.1 Gy. The dose response is found to be supralinear below 1 Gy. The fading studies have been carried out and investigated up to 30 days. The important kinetic parameters for the material like TL trap depth, frequency factor and order of kinetics are evaluated by deconvolution method.

Jakathamani|S|S|
Annalakshmi|O|O|
Jose|M T|MT|
Mathiyarasu|R|R|
Venkatraman|B|B|

Ceramic resistor
Kinetic parameter
Retrospective dosimetry
SAR protocol
Thermoluminescence


New Octadecanoid Enantiomers from the Whole Plants of Plantago depressa.

Abstract: In this study, 19 octadecanoid derivatives-four pairs of enantiomers (1⁻8), two racemic/scalemic mixtures (9⁻10), and nine biosynthetically related analogues-were obtained from the ethanolic extract of a Chinese medicinal plant, Plantago depressa Willd. Their structures were elucidated on the basis of detailed spectroscopic analyses, with the absolute configurations of the new compounds assigned by time-dependent density functional theory (TD-DFT)-based electronic circular dichroism (ECD) calculations. Six of them (1, 3⁻6, and 9) were reported for the first time, while 2, 7, and 8 have been previously described as derivatives and are currently obtained as natural products. Our bioassays have established that selective compounds show in vitro anti-inflammatory activity by inhibiting lipopolysaccharide-induced nitric oxide (NO) production in mouse macrophage RAW 264.7 cells.

Song|Xiu-Qing|XQ| Zhu|Kongkai|K| Yu|Jin-Hai|JH| Zhang|Qianqian|Q| Zhang|Yuying|Y| He|Fei|F| Cheng|Zhi-Qiang|ZQ| Jiang|Cheng-Shi|CS|0000-0002-2760-7596 Bao|Jie|J| Zhang|Hua|H|

octadecanoid
Plantago depressa
anti-inflammation
fatty acid
natural enantiomer


Computed Tomography as a Predictor of Sinonasal Inverted Papilloma Origin, Skull Base Involvement, and Stage.

Abstract: Objective  To investigate the diagnostic performance of computed tomography (CT) to determine the origin, skull base involvement, and stage of sinonasal inverted papilloma (IP). Design  This is a retrospective cohort study. Setting  This is set at a tertiary care medical center. Participants  Patients with preoperative CT imaging who underwent extirpative surgery for histologically confirmed sinonasal IP between January 2005 and October 2019. Main Outcome Measures  The likely sites of tumor origin, skull base involvement, and radiographic tumor stage were determined by two board-certified neuroradiologists after re-reviewing preoperative CT imaging. These radiologic findings were then compared with intraoperative and pathologic findings. Results  Of 86 patients, 74% (64/86) had IP lesions with correctly classified sites of origin on CT. CT was not sensitive for diagnosing ethmoid sinus origin (48%, 52%), frontal sinus origin (80%, 40%), and skull base origin (17%, 17%). CT was not sensitive (62%, 57%) but specific (86%, 98%) for identifying any skull base involvement. There was substantial-to-near perfect agreement between radiographic and pathologic Cannady stages (weighted κ = 0.61 for rater 1; weighted κ = 0.81 for rater 2). Interrater agreement was substantial for identifying tumor origin (κ = 0.75) and stage (weighted κ = 0.62) and moderate for identifying skull base involvement (κ = 0.43). Conclusion  Interrater agreement on CT findings was substantial except on skull base involvement. CT correctly predicted site of tumor origin in up to 74% of subjects. CT was not sensitive for diagnosing skull base involvement but had substantial-to-near perfect agreement with pathologic tumor staging. CT is a useful but albeit limited adjunct for tumor localization and surgical planning for sinonasal IP.

Lee|Jake J|JJ|
Orlowski|Hilary L P|HLP|
Schneider|John S|JS|
Roland|Lauren T|LT|
Eldaya|Rami|R|
Jiramongkolchai|Pawina|P|
Kallogjeri|Dorina|D|
Chernock|Rebecca D|RD|
Klatt-Cromwell|Cristine N|CN|

computed tomography
inverted papilloma
origin
skull base
stage
paranasal sinus


Effects of Afforestation Restoration on Soil Potential N2O Emission and Denitrifying Bacteria After Farmland Abandonment in the Chinese Loess Plateau.

Abstract: Denitrification is a critical component of soil nitrogen (N) cycling, including its role in the production and loss of nitrous oxide (N2O) from the soil system. However, restoration effects on the contribution of denitrification to soil N2O emissions, the abundance and diversity of denitrifying bacteria, and relationships among N2O emissions, soil properties, and denitrifying bacterial community composition remains poorly known. This is particularly true for fragile semiarid ecosystems. In order to address this knowledge gap, we utilized 42-year chronosequence of Robinia pseudoacacia plantations in the Chinese hilly gullied Loess Plateau. Soil potential N2O emission rates were measured using anaerobic incubation experiments. Quantitative polymerase chain reaction (Q-PCR) and Illumina MiSeq high-throughput sequencing were used to reveal the abundance and community composition of denitrifying bacteria. In this study, the afforestation practices following farmland abandonment had a strong negative effect on soil potential N2O emission rates during the first 33 years. However, potential N2O emission rates steadily increased in 42 years of restoration, leading to enhanced potential risk of greenhouse gas emissions. Furthermore, active afforestation increased the abundance of denitrifying functional genes, and enhanced microbial biomass. Actinobacteria and Proteobacteria were the dominant denitrifying bacterial phyla in the 0 to 33-years old sites, while the 42-years sites were dominated by Planctomycetes and Actinobacteria, implying that the restoration performed at these sites promoted soil microbial succession. Finally, correlation analyses revealed that soil organic carbon concentrations had the strongest relationship with potential N2O emission rates, followed by the abundance of the nosZ functional gene, bulk density, and the abundance of Bradyrhizobium and Variovorax across restoration stages. Taken together, our data suggest above-ground restoration of plant communities results in microbial community succession, improved soil quality, and significantly altered N2O emissions.

Deng|Na|N| Wang|Honglei|H| Hu|Shu|S| Jiao|Juying|J|

afforestation restoration
denitrifying bacteria
farmland abandonment
Loess Plateau
denitrification
nitrous oxide
high-throughput sequencing


A pharmacokinetic study of morphine-6-O-sulfate in rat plasma and brain.

Abstract: Morphine-6-O-sulfate (M6S), a polar, zwitterionic sulfate ester of morphine, is a powerful and safe analgesic in several rat models of pain. A sensitive liquid chromatography-tandem mass spectrometry bioanalytical method was developed and validated for the simultaneous determination of M6S and morphine (MOR) in rat plasma and brain after M6S administration. Morphine-d6 was used as internal standard. Multiple reaction monitoring was used for detection and quantitation of M6S, MOR, and morphine-d6 in the turbo ion spray positive mode. The chromatographic separation was carried out on an Alltech Altima C18 column. The analytical method was validated for linearity, precision, accuracy, specificity, and stability over a concentration range of 3-8000 ng/ml in rat plasma and 10-10,000 ng/ml in brain samples for both M6S and MOR. The validated method was applied to determine the PK profile of M6S in plasma after i.v., i.p., and oral dosing in male Sprague-Dawley rats. Rats were administered M6S by i.p. administration (5.6 and 10.0 mg/kg) or orally (10 and 30 mg/kg) and bioavailability compared to an i.v. injection (1 mg/kg) of M6S. The in vivo results indicate that M6S is not a prodrug of morphine, since M6S is not biotransformed into MOR in plasma after either i.p. or oral administration, and MOR was not detected in brain. The bioavailability of M6S was >93% and about 5% after i.p. and oral dosing, respectively. The low oral bioavailability of M6S may be due to poor permeation of the intestinal epithelial membrane. After i.p.-administration, M6S appears to reach brain tissues in low, but significant, concentrations.

pharmacokinetics
morphine-6-O-sulfate
Sprague-Dawley rats
bioavailability
analgesic agent


Pubic stress fracture presenting as a strain of adductor longus in a 16-year-old elite soccer player with Crohn's disease: a case report.

Abstract:
Background
Adductor strains are the most commonly reported muscle injuries in adolescent soccer players and the second most common muscle injuries in adult players. Health practitioners should be aware of possible differential diagnoses, such as a pubic stress fracture or pubic apophysitis when athletes present with chronic groin pain.

Purpose
To present a rare case of a unilateral pelvic stress fracture of a 16-year old elite soccer player with a history of Crohn's disease.

Study design
Retrospective case report (n=1).

Methods
Case notes of two sports-based practitioners were reviewed and compiled retrospectively.

Results
Following activity restriction, a period of rest, conservative care, and progressive rehabilitation, this athlete was able to achieve a pain-free state with near equal iso-kinetic strength bilaterally as measured by Cybex 6000 (Cybex International Inc., Medway, MA, USA) muscle testing. Full activity was resumed 10 months after initial presentation and the athlete was able to return to playing professional soccer.

Summary
This case report presents a rare diagnosis of a unilateral pubic stress fracture presenting as a strain of adductor longus. Although quite rare, differential diagnoses such as a potential underlying stress fracture should be considered when presented with chronic or recurrent groin pain.

stress fracture
groin pain
chiropractic
pubic bone
soccer injury


Establishment of a neonatal rhesus macaque model to study Mycobacterium tuberculosis infection.

Abstract: Mycobacterium tuberculosis (Mtb) is the causative agent of human tuberculosis (TB) with an estimated 8.8 million new TB cases and 1.4 million deaths annually. Tuberculosis is the leading cause of death in AIDS patients worldwide but very little is known about early TB infection or TB/HIV co-infection in infants. A clinically relevant newborn animal model to study TB infection is urgently needed. We have successfully established an aerosol newborn/infant model in neonatal nonhuman primates (NHPs) that mimics clinical and bacteriological characteristics of Mtb infection as seen in human newborns/infants. Further, this model will allow the establishment of a TB coinfection model of pediatric AIDS. Aerosol versus intra broncho-alveolar Mtb infection was studied. Interestingly, 42 days post infection specific lesions were detected suggestive of the classic Ghon focus in human children. Concurrently, specific cellular immune responses developed 4-6 weeks after Mtb infection. Using the enzyme-linked immunospot (ELISPOT) assays, we found that IL-12 production correlated with early Mtb infection lesions seen by routine thoracic radiographs. Overall, this work represents the first example of early Mtb infection of newborn macaques. This study gives us a unique opportunity to further characterize immunopathogenesis and establish a TB/SIV co-infection model for pediatric AIDS.

Cepeda|Magdalena|M|
Salas|Mary|M|
Folwarczny|Jessica|J|
Leandro|Ana C|AC|
Hodara|Vida L|VL|
de la Garza|Melissa A|MA|
Dick|Edward J|EJ|
Owston|Michael|M|
Armitige|Lisa Y|LY|
Gauduin|Marie-Claire|MC|

D016097:Simian Acquired Immunodeficiency Syndrome

rhesus macaque
TB
newborn
Ghon focus
ELISPOT IL-12


Long-Term Results of an Imperforate Hymen Procedure that Leaves the Hymen Intact.

Abstract:
Purpose of the Study
The aim of this study was to show the clinical results of postoperative evaluation of cases of imperforate hymen that presented at our center during a 21-year period.

Methods
A Foley's catheter was inserted in 74 patients of imperforate hymen who reported to the Department of Obstetrics and Gynecology, Meram Faculty of Medicine, Necmettin Erbakan University, between January 1, 1996, and December 31, 2016 with history of pelvic pain. In each case, the hymen was opened via a circular incision from the central of the distended. A Foley's catheter was inserted, and estrogen cream was prescribed for application on the hymenal structure for 14 days. The catheter was removed after 14 days.

Results
The mean age of the patients at the time of this study was 28.3 ± 2.6 years, and the mean age at diagnosis was 13.2 ± 2.5 years. Twenty-nine (96.6%) patients had experienced vaginal bleeding during their first sexual intercourse experience, and one patient (3.4%) had not. Fourteen out of the 30 married women had become pregnant, of whom nine had delivered vaginally and five had delivered via a cesarean section. After undergoing renal ultrasound, none of the patients had any apparent anomalies. Only one patient had a uterine anomaly, which was a bicornuate uterus.

Conclusion
A circular incision with insertion of Foley's catheter prevents many social problems by preserving the hymen's architecture and allowing vaginal bleeding to occur during the first sexual intercourse experience.

Acar|Ali|A|
Ercan|Fedi|F|0000-0003-2175-5405
Balci|Osman|O|
Elçi Atılgan|Adeviye|A|
Alan|Cemre|C|
Niftiyev|Kemal|K|

Imperforate hymen
Foley catheter
Virginity sparing procedure


Effect of the specific proteasome inhibitor bortezomib on cancer-related muscle wasting.

Abstract:
BACKGROUND
Muscle wasting, a prominent feature of cancer cachexia, is mainly caused by sustained protein hypercatabolism. The enhanced muscle protein degradation rates rely on the activity of different proteolytic systems, although the Adenosine triphosphate (ATP)-ubiquitin-proteasome-dependent pathway and autophagy have been shown to play a pivotal role. Bortezomib is a potent reversible and selective proteasome and NF-κB inhibitor approved for the clinical use, which has been shown to be effective in preventing muscle wasting in different catabolic conditions. The aim of the present study has been to investigate whether pharmacological inhibition of proteasome by bortezomib may prevent skeletal muscle wasting in experimental cancer cachexia.

METHODS
Cancer cachexia was induced in rats by intraperitoneal injection of Yoshida AH-130 ascites hepatoma cells and in mice by subcutaneous inoculation of C26 carcinoma cells. Animals were then further randomized to receive bortezomib. The AH-130 hosts were weighted and sacrificed under anaesthesia, on Days 3, 4, 5, and 7 after tumour inoculation, while C26-bearing mice were weighted and sacrificed under anaesthesia 12 days after tumour transplantation. NF-κB and proteasome activation, MuRF1 and atrogin-1 mRNA expression and beclin-1 protein levels were evaluated in the gastrocnemius of controls and AH-130 hosts.

RESULTS
Bortezomib administration in the AH-130 hosts, although able to reduce proteasome and NF-κB DNA-binding activity in the skeletal muscle on Day 7 after tumour transplantation, did not prevent body weight loss and muscle wasting. In addition, bortezomib exerted a transient toxicity, as evidenced by the reduced food intake and by the increase in NF-κB DNA-binding activity in the AH-130 hosts 3 days after tumour transplantation. Beclin-1 protein levels were increased by bortezomib treatment in Day 3 controls but were unchanged on both Days 3 and 7 in the AH-130 hosts, suggesting that an early compensatory induction of autophagy may exist in healthy but not in tumour-bearing animals. Regarding C26-bearing mice, bortezomib did not prevent as well body and muscle weight loss 12 days after tumour implantation.

CONCLUSIONS
The results obtained suggest that proteasome inhibition by bortezomib is not able to prevent muscle wasting in experimental cancer cachexia. Further studies are needed to address the issue whether a different dosage of bortezomib alone or in combination with other drugs modulating different molecular pathways may effectively prevent muscle wasting during cancer cachexia.

Penna|Fabio|F|
Bonetto|Andrea|A|
Aversa|Zaira|Z|
Minero|Valerio Giacomo|VG|
Rossi Fanelli|Filippo|F|
Costelli|Paola|P|
Muscaritoli|Maurizio|M|

Proteasome
Bortezomib
Muscle wasting
Cancer cachexia


Extra-Large Gα Protein (XLαs) Deficiency Causes Severe Adenine-Induced Renal Injury with Massive FGF23 Elevation.

Abstract: Fibroblast growth factor-23 (FGF23) is critical for phosphate and vitamin D homeostasis. Cellular and molecular mechanisms underlying FGF23 production remain poorly defined. The extra-large Gα subunit (XLαs) is a variant of the stimulatory G protein alpha-subunit (Gsα), which mediates the stimulatory action of parathyroid hormone in skeletal FGF23 production. XLαs ablation causes diminished FGF23 levels in early postnatal mice. Herein we found that plasma FGF23 levels were comparable in adult XLαs knockout (XLKO) and wild-type littermates. Upon adenine-rich diet-induced renal injury, a model of chronic kidney disease, both mice showed increased levels of plasma FGF23. Unexpectedly, XLKO mice had markedly higher FGF23 levels than WT mice, with higher blood urea nitrogen and more severe tubulopathy. FGF23 mRNA levels increased substantially in bone and bone marrow in both genotypes; however, the levels in bone were markedly higher than in bone marrow. In XLKO mice, a positive linear correlation was observed between plasma FGF23 and bone, but not bone marrow, FGF23 mRNA levels, suggesting that bone, rather than bone marrow, is an important contributor to severely elevated FGF23 levels in this model. Upon folic acid injection, a model of acute kidney injury, XLKO and WT mice exhibited similar degrees of tubulopathy; however, plasma phosphate and FGF23 elevations were modestly blunted in XLKO males, but not in females, compared to WT counterparts. Our findings suggest that XLαs ablation does not substantially alter FGF23 production in adult mice but increases susceptibility to adenine-induced kidney injury, causing severe FGF23 elevations in plasma and bone.

Matthias|Julia|J|
Cui|Qiuxia|Q|
Shumate|Lauren T|LT|
Plagge|Antonius|A|
He|Qing|Q|
Bastepe|Murat|M|

D019205:GTP-Binding Protein alpha Subunits, Gs

fibroblast growth factor-23
stimulatory G protein
chronic kidney disease
acute kidney injury
heterotrimeric G protein


Structural validity and reliability of the Spanish Central Sensitization Inventory in breast cancer survivors.

Abstract:
INTRODUCTION
One of the most widely used instruments to identify symptoms that may be related to central sensitization is the Central Sensitization Inventory (CSI). Although this instrument has been translated and validated in Spanish patients with chronic musculoskeletal pain, no psychometric analysis has been carried out in breast cancer survivors. The aim of this study was to perform a psychometric analysis of the Spanish version of the Central Sensitization Inventory (CSI-Sp) in Spanish breast cancer survivors.

MATERIALS AND METHODS
A validation study was carried out in 183 breast cancer survivors. A psychometric analysis of internal consistency, factor structure, and test-retest reliability of the CSI-Sp was performed. Internal consistency was determined using Cronbach's alpha. Test-retest reliability was evaluated using the Intraclass Correlation Coefficient (ICC) Type 2.1. Exploratory factor analysis was used to determine the internal structure of the questionnaire.

RESULTS
The internal consistency was high (α = 0.91). The test-retest reliability was satisfactory with excellent values (ICC 2.1 = 0.95). The exploratory factor analysis yielded a one factor structure explaining the 33.88% of total variance.

CONCLUSIONS
The CSI-Sp has demonstrated to be a psychometrically strong measure for assessing central sensitization symptoms in breast cancer survivors based on internal consistency, test-retest reliability, and structural validity. Further studies that analyze other measurement properties in different Spanish clinical populations are needed.

D059333:Central Nervous System Sensitization

central sensitization
breast cancer
Central Sensitization Inventory (CSI)
validation studies
chronic pain
psychometric properties


Neurofibromin Regulates Seizure Attacks in the Rat Pilocarpine-Induced Model of Epilepsy.

Abstract: Studies have shown that neurofibromin (NF1) restricts GABA release at inhibitory synapses and regulates dendritic spine formation, which may play an important role in temporal lobe epilepsy (TLE). NF1 expression was detected by double-label immunofluorescence, immunohistochemistry, and western blot analysis in the brains of pilocarpine-induced epilepsy model rats at 6 h, 24 h, 72 h, 7 days, 14 days, 30 days, and 60 days after kindling. NF1 was localized primarily in the nucleus and cytoplasm of neurons. NF1 protein levels significantly increased in the chronic phase (from 7 days until 60 days) in this epileptic rat model. After NF1 expression was knocked down by specific siRNA, the effects of kindling with pilocarpine were evaluated on the 7th day after kindling. The onset latencies of pilocarpine-induced seizures were elevated, and the seizure frequency and duration were reduced in these rats. Our study demonstrates that NF1 promoted seizure attacks in rats with pilocarpine-induced epilepsy.

Ren|Min|M| Li|Kunyi|K| Wang|Dan|D| Guo|Jiamei|J| Li|Jing|J| Yang|Guang|G| Long|Xianghua|X| Shen|Wenjing|W| Hu|Rong|R| Wang|Xuefeng|X| Zeng|Kebin|K|

Neurofibromin
Seizure
Rat
siRNA
RNA interference


Epigenetic modifiers in normal and malignant hematopoiesis.

Abstract: Genome scale sequencing in patients with cancer has revealed a lower frequency of genetic aberrations in hematologic disorders compared with most other malignancies, suggesting a prominent role for epigenetic mechanisms. In parallel, epigenetic modifiers that are altered in cancer play critical roles in normal hematopoietic development, influencing both self-renewal of hematopoietic stem cells and differentiation into the different lineages. In this review, we aim to compare the role of several key DNA or histone modifying enzymes and complexes in normal development and hematopoietic malignancies, including DNMT3A, TET2, IDH1, IDH2, MLL1, MLL4, DOT1L, PRC1/2 and WSHC1/NSD2/MMSET. Insights into their biological mechanisms led to the development of therapies designed to target mutant IDH1 and IDH2, DOT1L in MLL-rearranged leukemias and EZH2 in several cancer types including lymphomas. Inhibitors for these enzymes are currently in clinical trials.

Haladyna|Jessica N|JN|
Yamauchi|Taylor|T|
Neff|Tobias|T|
Bernt|Kathrin M|KM|


Prevalence of Campylobacter jejuni and Campylobacter coli in captive wildlife species of India.

Abstract: Campylobacteriosis is an important zoonotic disease and the prevalence of Campylobacter is largely unknown in the wildlife of India. A total of 370 samples, comprising of 314 fresh faecal samples from apparently healthy captive wild animals and birds, 30 stool swabs from animal care takers and 26 samples of the animals' food and water were collected from G. B. Pant High Altitude Zoo, Nainital, Kanpur Zoo, Wildlife Park, IVRI and the Post Graduate Research Institute in Animal Sciences (PGRIAS), Chennai, Tamilnadu from August 2014 to May 2015. Samples were processed for cultural isolation, direct PCR and multiplex PCR for species confirmation. To decipher the genetic diversity, the 16S rRNA gene was amplified, sequenced and analyzed. Based on isolation, the overall occurrence rate of Campylobacter spp. was 0.8% (3/370), being 2.94% (3/102) for captive wild birds. Three Campylobacter jejuni were isolated from silver pheasants, lady amherest pheasants and saras cranes. Direct PCR assay showed the overall occurrence rate of Campylobacter spp. to be 4.77% (15/315), being 1.58% (2/126) for captive wild ruminants, 5.81% (5/86) for non-ruminants and 7.84% (8/102) for birds. All the isolates were identified as C. jejuni.

Prince Milton|A A|AA|
Agarwal|R K|RK|
Priya|G B|GB|
Saminathan|M|M|
Aravind|M|M|
Reddy|A|A|
Athira|C K|CK|
Anjay|||
Ramees|T P|TP|
Dhama|K|K|
Sharma|A K|AK|
Kumar|A|A|

Campylobacter jejuni
Campylobacter coli
Captive wildlife
India
Zoo


The role of JNK in prostate cancer progression and therapeutic strategies.

Abstract: Prostate cancer (PC), which has high morbidity and mortality among elderly men, is becoming the most common malignancy in men. The progression of PC is associated with several aspects including apoptosis, proliferation and metastasis. C-Jun N-terminal kinase (JNK) is a member of mitogen-activated protein kinases (MAPKs), which play vital roles in regulating diverse cell processes. JNK has been shown to activate multiple substrates to modulate apoptosis, proliferation, tumorigenesis and inflammation in response to various stimuli including cytokines, pathogens, growth factors, oxidative stress, ultraviolet radiation, toxins and drugs. In addition, emerging evidence has indicated the significant roles of androgen receptor in prostate cancer development. In this review, we will summarize our current knowledge on the roles of JNK in the apoptosis, proliferation, migration and DNA repair as well as dissect the relationships between JNK and androgen receptor in prostate cancer. Chemotherapeutic drugs targeting JNK will also be discussed, possibly providing an overview on the development of therapeutic strategies.

D048031:JNK Mitogen-Activated Protein Kinases

JNK
Prostate cancer
Apoptosis
Proliferation
Androgen receptor
Migration


Wnt inhibition is dysregulated in gliomas and its re-establishment inhibits proliferation and tumor sphere formation.

Abstract: Evidence indicates that the growth of glioblastoma (GBM), the most common and malignant primary brain cancer, is driven by glioma stem cells (GSCs) resistant to current treatment. As Wnt-signaling is pivotal in stem cell maintenance, we wanted to explore its role in GSCs with the objective of finding distinct signaling mechanisms that could serve as potential therapeutic targets. We compared gene expression in GSCs (n=9) and neural stem cells from the adult human brain (ahNSC; n=3) to identify dysregulated genes in the Wnt signaling pathway. This identified a six-gene Wnt signature present in all nine primary GSC cultures, and the combined expression of three of these genes (SFRP1, SFRP4 and FZD7) reduced median survival of glioma patients from 38 to 17 months. Treatment with recombinant SFRP1 protein in primary cell cultures downregulated nuclear β-catenin and decreased in vitro proliferation and sphere formation in a dose-dependent manner. Furthermore, expressional and functional analysis of SFRP1-treated GSCs revealed that SFRP1 halts cell cycling and induces apoptosis. These observations demonstrate that Wnt signaling is dysregulated in GSC, and that inhibition of the Wnt pathway could serve as a therapeutic strategy in the treatment of GBM.

Kierulf-Vieira|Kirsten Strømme|KS|
Sandberg|Cecilie J|CJ|
Grieg|Zanina|Z|
Günther|Clara-Cecilie|CC|
Langmoen|Iver A|IA|
Vik-Mo|Einar O|EO|

D036341:Intercellular Signaling Peptides and Proteins

Secreted Frizzled-related protein 1 (SFRP1)


HE4 levels in uncomplicated pregnancies: are there any differences?

Abstract: Objective: The aim of our study was to evaluate HE4 serum concentrations throughout uncomplicated pregnancies in the absence of adnexal masses.Methods: In a retrospectively designed, monocentric study (Department of Gynecology and Obstetrics, General Hospital Celje, Celje, Slovenia, EU), 229 women with uncomplicated pregnancies were included. HE4 levels were obtained and analyzed with regard to gestational age of pregnancy.Results: While having all HE4 levels within reference range, differences in mean concentrations between study groups were found be statistically significant (Group I, n = 22, <20 weeks of pregnancy, mean = 42.2 pmol/L; Group II, n = 40, pregnancies between 20-34 weeks of pregnancy, mean = 43.6 pmol/L; Group III, n = 167, ≥34 weeks of pregnancy, mean = 57.5 pmol/L, p < .001).Conclusion: Our findings confirmed that HE4 levels in uncomplicated pregnancies are within reference range provided by manufacturer, however its serum concentration rises significantly in third trimester. The HE4 cutoff value (<140 pmol/L) used for nonpregnant women can be helpful in the evaluation of adnexal masses in pregnancy.

Delić|Ratko|R| Štefanović|Mario|M| Krivec|Štefka|Š| Weber|Vladimir|V| Koren|Jakob|J|

HE4
uncomplicated pregnancy
third trimester


microRNA-31 regulates skeletogenesis by direct suppression of Eve and Wnt1.

Abstract: microRNAs (miRNAs) play a critical role in a variety of biological processes, including embryogenesis and the physiological functions of cells. Evolutionarily conserved microRNA-31 (miR-31) has been found to be involved in cancer, bone formation, and lymphatic development. We previously discovered that, in the sea urchin, miR-31 knockdown (KD) embryos have shortened dorsoventral connecting rods, mispatterned skeletogenic primary mesenchyme cells (PMCs) and shifted and expanded Vegf3 expression domain. Vegf3 itself does not contain miR-31 binding sites; however, we identified its upstream regulators Eve and Wnt1 to be directly suppressed by miR-31. Removal of miR-31's suppression of Eve and Wnt1 resulted in skeletal and PMC patterning defects, similar to miR-31 KD phenotypes. Additionally, removal of miR-31's suppression of Eve and Wnt1 results in an expansion and anterior shift in expression of Veg1 ectodermal genes, including Vegf3 in the blastulae. This indicates that miR-31 indirectly regulates Vegf3 expression through directly suppressing Eve and Wnt1. Furthermore, removing miR-31 suppression of Eve is sufficient to cause skeletogenic defects, revealing a novel regulatory role of Eve in skeletogenesis and PMC patterning. Overall, this study provides a proposed molecular mechanism of miR-31's regulation of skeletogenesis and PMC patterning through its cross-regulation of a Wnt signaling ligand and a transcription factor of the endodermal and ectodermal gene regulatory network.

Sampilo|Nina Faye|NF|
Stepicheva|Nadezda A|NA|
Song|Jia L|JL|

D018507:Gene Expression Regulation, Developmental

MicroRNA-31
Sea urchin
Primary mesenchyme cells
Wnt
Even-skipped
Post-transcriptional regulation
Vegf signaling
miRNA target protector


Overcoming Challenges in Recruitment of South Asians for Health Disparities Research in the USA.

Abstract: South Asians-individuals with origins in the countries of Bangladesh, Bhutan, India, Maldives, Nepal, Pakistan, Sri Lanka, and other regions of the subcontinent-are an understudied and at-risk racial/ethnic minority population for disproportionate burden of preventable diseases in the USA. Notwithstanding lack of research disaggregating Asian American subgroups, a key factor in this paucity of data is the lack of participation and engagement of community members in studies which examine distribution and determinants of adverse health outcomes. The purpose of this case study series is to elucidate distinct barriers in recruitment of South Asians in health disparities research within four diverse study designs. These illustrations are followed by a discussion of effective strategies and promising practices to increase and enhance the participation of community members in health-related studies in order to ultimately understand and address disparities among this rapidly growing cultural group in the US systematic collection of data which not only is representative of this understudied population but also elucidates contextual influences on community health and well-being and is pivotal to the reduction and elimination of preventable disparities among South Asians in the USA.

Mukherjea|Arnab|A|
Ivey|Susan L|SL|
Shariff-Marco|Salma|S|
Kapoor|Nilesh|N|
Allen|Laura|L|

D044466:Asians
D003256:Community Participation
D006302:Health Services Research
D054624:Health Status Disparities
D006801:Humans
D014481:United States

Recruitment
South Asians
Health disparities
Diversity
Community engagement


Epidemiology of burns in the United Arab Emirates: lessons for prevention.

Abstract:
PURPOSE
To study mechanism, risk factors and outcome of hospitalized burns so as to give recommendations for prevention.

METHODS
Burn patients admitted to Al Ain hospital for more than 24h or who died after arrival were studied over 4 years. Demographics, burn type, location and time of injury, total body burned surface area (TBSA), body region, hospital and ICU stay and outcome were analyzed.

RESULTS
203 patients were studied, 69% were males and 25% were children under 5 years old. The most common location for burn was home. Women were burned more at home (p<0.0001). 28% of patients were injured at work with more men (p<0.0001) and non-UAE nationals (p<0.01). Scalds from water, tea were the major hazard at home, while majority of burns at work were from gas and flame. Burns caused by gas and flame had larger TBSA and longer ICU stay. Six (3%) patients died and nine (4%) were transferred to the specialized burn center.

CONCLUSIONS
Safety education for caregivers and close supervision of young children is important to reduce pediatric burns. Occupational safety education of young men could prevent burns caused by gas and flame.

Grivna|Michal|M|
Eid|Hani O|HO|
Abu-Zidan|Fikri M|FM|

Burn
United Arab Emirates
Prevention
Scalds
Flame


Avian oncogenesis induced by lymphoproliferative disease virus: a neglected or emerging retroviral pathogen?

Abstract: Lymphoproliferative disease virus (LPDV) is an exogenous oncogenic retrovirus that induces lymphoid tumors in some galliform species of birds. Historically, outbreaks of LPDV have been reported from Europe and Israel. Although the virus has previously never been detected in North America, herein we describe the widespread distribution, genetic diversity, pathogenesis, and evolution of LPDV in the United States. Characterization of the provirus genome of the index LPDV case from North America demonstrated an 88% nucleotide identity to the Israeli prototype strain. Although phylogenetic analysis indicated that the majority of viruses fell into a single North American lineage, a small subset of viruses from South Carolina were most closely related to the Israeli prototype. These results suggest that LPDV was transferred between continents to initiate outbreaks of disease. However, the direction (New World to Old World or vice versa), mechanism, and time frame of the transcontinental spread currently remain unknown.

Allison|Andrew B|AB|
Kevin Keel|M|M|
Philips|Jamie E|JE|
Cartoceti|Andrew N|AN|
Munk|Brandon A|BA|
Nemeth|Nicole M|NM|
Welsh|Trista I|TI|
Thomas|Jesse M|JM|
Crum|James M|JM|
Lichtenwalner|Anne B|AB|
Fadly|Aly M|AM|
Zavala|Guillermo|G|
Holmes|Edward C|EC|
Brown|Justin D|JD|