bluuebunny/crossref_metadata_2025 huggingface dataset:
A Continuous‐Flow Process for Palladium‐Catalyzed Olefin Cleavage by using Oxygen within the Explosive Regime
Authors: Hone Christopher A. , O'Kearney‐McMullan Anne , Munday Rachel , Kappe C. Oliver
Published: May 2017

A continuous‐flow protocol for Pd‐catalyzed olefin cleavage by using molecular oxygen as the sole oxidant to give carbonyl compounds was explored. The developed flow protocol allowed the use of a low catalyst loading (0.1 mol %), and decomposition of the active catalyst was prevented through stabilization by poly(ethylene glycol)‐400 (PEG‐400), which was present as a cosolvent. Radical scavengers inhibited the reaction, which indicated the involvement of a free‐radical path in the reaction mechanism. The applicability of the continuous‐flow protocol was demonstrated on several olefin substrates. The continuous‐flow process enabled safe and scalable olefin cleavage.
Water‐Soluble Iridium N‐Heterocyclic Carbene Complexes for the Alkylation of Amines with Alcohols
Authors: Fernandes Ana , Royo Beatriz
Published: May 2017

A new series of water‐soluble Ir complexes with N‐heterocyclic carbene ligands that bear ester and amide groups has been obtained and fully characterized. The new complexes are highly reactive and selective for the alkylation of amines with alcohols with a 1:1 ratio of reactants in water and in the absence of base or other additives. The catalytic system has a broad substrate scope, which allows the synthesis of a variety of primary and secondary amines in excellent yields. A tolerance to a large range of functional groups was obtained.
A New Potent Inhibitor of Glycogen Phosphorylase Reveals the Basicity of the Catalytic Site
Authors: Mamais Michael , Degli Esposti Alessandra , Kouloumoundra Virginia , Gustavsson Thomas , Monti Filippo , Venturini Alessandro , Chrysina Evangelia D. , Markovitsi Dimitra , Gimisis Thanasis
Published: May 2017

The design and synthesis of a glucose‐based acridone derivative (GLAC), a potent inhibitor of glycogen phosphorylase (GP) are described. GLAC is the first inhibitor of glycogen phosphorylase, the electronic absorption properties of which are clearly distinguishable from those of the enzyme. This allows probing subtle interactions in the catalytic site. The GLAC absorption spectra, associated with X‐ray crystallography and quantum chemistry calculations, reveal that part of the catalytic site of GP behaves as a highly basic environment in which GLAC exists as a bis‐anion. This is explained by water‐bridged hydrogen‐bonding interactions with specific catalytic site residues.
Two‐Dimensional Metal‐Organic Layers as a Bright and Processable Phosphor for Fast White‐Light Communication
Authors: Hu Xuefu , Wang Zi , Lin Bangjiang , Zhang Cankun , Cao Lingyun , Wang Tingting , Zhang Jingzheng , Wang Cheng , Lin Wenbin
Published: May 2017

A metal–organic layer (MOL) is a new type of 2D material that is derived from metal–organic frameworks (MOFs) by reducing one dimension to a single layer or a few layers. Tetraphenylethylene‐based tetracarboxylate ligands (TCBPE), with aggregation‐induced emission properties, were assembled into the first luminescent MOL by linking with Zr6O4(OH)6(H2O)2(HCO2)6 clusters. The emissive MOL can replace the lanthanide phosphors in white light emitting diodes (WLEDs) with remarkable processability, color rendering, and brightness. Importantly, the MOL‐WLED exhibited a physical switching speed three times that of commercial WLEDs, which is crucial for visible‐light communication (VLC), an alternative wireless communication technology to Wi‐Fi and Bluetooth, by using room lighting to carry transmitted signals. The short fluorescence lifetime (2.6 ns) together with high quantum yield (50 %) of the MOL affords fast switching of the assembled WLEDs for efficient information encoding and transmission.
Formation of Tough Films by Evaporation of Water from Dispersions of Elastomer Microspheres Crosslinked with Rotaxane Supramolecules
Authors: Hiroshige Seina , Kureha Takuma , Aoki Daichi , Sawada Jun , Aoki Daisuke , Takata Toshikazu , Suzuki Daisuke
Published: May 2017

Compared to rigid microspheres that consist, for example, of polystyrene or silica, soft and deformable elastomer microspheres can be used to generate colorless transparent films upon evaporating the solvent from microsphere‐containing dispersions. To obtain tough films, a post‐polymerization reaction to crosslink the microspheres is usually necessary, which requires extra additives during the drying process. This restriction renders this film‐formation technology complex and rather unsuitable for applications in which impurities are undesirable. In the present study, it is demonstrated that tough elastomer microspheres that are crosslinked with rotaxanes can form tough bulk films upon evaporation of water from microsphere dispersions, so that post‐polymerization reactions are not required. The results of this study should thus lead to new applications including coatings for biomaterials that need complete removal of all impurities from the materials prior to use.
Synthesis, Photophysical Characterization, and Self‐Assembly of Hexa‐peri‐hexabenzocoronene/Benzothiadiazole Donor–Acceptor Structure
Authors: Hu Yunbin , Dössel Lukas F. , Wang Xiao‐Ye , Mahesh Sankarapillai , Pisula Wojciech , De Feyter Steven , Feng Xinliang , Müllen Klaus , Narita Akimitsu
Published: May 2017

Hexa‐peri‐hexabenzocoronene (HBC) substituted by six benzothiadiazole (BTZ) units with ethynylene bridges is synthesized as a new donor–acceptor (D–A) motif. The C≡C bridges significantly reduce the dihedral angles between HBC and BTZ, and thus, lead to a planar molecular conformation as predicted by density functional theory calculations. The optoelectronic properties are investigated by UV/Vis absorption and emission spectroscopies with absorption and emission maxima at 424 and 650 nm, respectively, demonstrating the tunable electronic structures of HBC through the attachment of electron‐withdrawing BTZ units. Two‐dimensional wide‐angle X‐ray scattering analysis shows that the molecules self‐assemble into liquid‐crystalline columns with high stability over a wide temperature range. Scanning tunneling microscopy reveals the formation of ordered bilayers of the D–A molecules with star‐shaped structures.
Improved panels for clinical immune phenotyping: Utilization of the violet laser
Authors: Ryherd Mark , Plassmeyer Matthew , Alexander Connor , Eugenio Ines , Kleschenko Yuliya , Badger Ariel , Gupta Raavi , Alpan Oral , Sønder Søren Ulrik
Published: May 2017

Background

Clinical diagnostic laboratories are subject to numerous regulations imposed by government agencies. Laboratory developed tests for flow cytometry panels are essentially restricted to the use of analyte‐specific reagents (ASR) antibodies. With the advances in clinical flow cytometry systems, there is a trend toward the utilization of blue/red/violet laser flow systems and 8 to 10‐color panels. Currently, the selection of commercially available ASR antibodies for the violet laser is very limited. The market is dominated by Brilliant Violet 421 (BV421) manufactured by BD Biosciences and Pacific Blue (PB) manufactured by Beckman Coulter. In this study, we compare BV421 and PB conjugated ASR antibodies.

Methods

Whole blood was stained and acquired on a Gallios flow cytometer system. For single color staining, the stain index (SI) was calculated. For the two panels, the compensation matrix was calculated and the performance of the antibody cocktails analyzed in FCS Express.

Results

The results show that five out of six tested BV421 conjugated antibodies have significantly higher SI than their PB counterparts. Furthermore, BV421 antibodies require less compensation for spillover than PB. Finally, BV421 conjugated antibodies give better separation between negative and positive populations in the context of an 8 and 10 color panel without affecting the intensity of the other dyes.

Conclusions

Overall, using BV421 conjugated antibodies results in better separation between populations compared to PB conjugated antibodies without negatively affecting other fluorochromes in our panels. We conclude that the BV421 conjugated ASR antibodies are currently the better available option for clinical flow panels. © 2017 International Clinical Cytometry Society
Neonatal myeloid derived suppressor cells show reduced apoptosis and immunosuppressive activity upon infection with Escherichia coli
Authors: Leiber Anja , Schwarz Julian , Köstlin Natascha , Spring Bärbel , Fehrenbach Birgit , Katava Nenad , Poets Christian F. , Gille Christian
Published: May 2017

Susceptibility to infection during the neonatal period and reduced control of inflammation in neonates are attributed to immunosuppression persisting from fetal life. Myeloid‐derived suppressor cells (MDSCs) are immature myeloid progenitors with suppressive activity and increased numbers in cord blood. We hypothesized that MDSCs contribute to innate host defence in neonates, paralleled by anti‐inflammatory signalling.Phagocytic activity, infection induced apoptosis, expression of B‐cell lymphoma (Bcl)‐2 family proteins, production of reactive oxygen species (ROS), cytokine production and T‐cell suppression of neonatal granulocytic‐MDSCs (G‐MDSCs) after infection with Escherichia coli (E. coli) were compared to neonatal autologous mature polymorphonuclear leukocytes (PMNs). Phagocytic activity of G‐MDSCs upon infection with E. coli was equal to that of mature PMNs, however, apoptosis of G‐MDSCs was decreased. G‐MDSCs showed enhanced Bcl‐2‐expression and lower ROS production compared to PMNs. Inhibition of Bcl‐2 reduced apoptosis rates of G‐MDSCs to that of mature PMNs. Induction of anti‐inflammatory transforming growth factor beta (TGF‐β) was enhanced, while pro‐inflammatory IL‐8 decreased in G‐MDSCs compared to PMNs. Infected G‐MDSCs strongly suppressed proliferation of T cells. We show a direct role of G‐MDSCs for anti‐bacterial host defence. Prolonged survival and anti‐inflammatory capacity suggest that G‐MDSCs are important for immune‐regulation after bacterial infection.
Preparation of Crystalline Phases of 3D Coordination Polymers Based on Tetracarbonatodiruthenium Units and Lanthanide(III) Ions – Magnetic Characterization
Authors: Delgado‐Martínez Patricia , González‐Prieto Rodrigo , Herrero Santiago , Jiménez‐Aparicio Reyes , Perles Josefina , Priego José L. , Torres M. Rosario , Sufrate Berta
Published: May 2017

Attempts to obtain pure crystalline phases of heteropolynuclear diruthenium–lanthanide complexes were made through four different experimental procedures: a conventional method, solvothermal synthesis, solvothermal synthesis assisted by microwave irradiation and layering synthesis. The complexes [Ln(H2O)4][Ru2(CO3)4(H2O)]·xH2O [Ln = Gd, x = 2.5 (1); Ln = Nd, x = 4 (2); Ln = Eu, x = 2.25 (3); Ln = Yb, x = 2.5 (4)] were obtained in good yields through the different procedures, but the layering method was the best to yield single crystals of 1, 3 and 4. In the solvothermal synthesis of 1, the minor product K3[Gd(H2O)4]2[Ru2(CO3)4]3·3.5H2O (5) was also obtained in a very low yield. The crystal structures of the three‐dimensional compounds 1 and 3–5 were determined by single‐crystal X‐ray diffraction, and two different structural types were found for the Gd derivatives. The magnetic properties of 1, 2 and 4 were fitted with an equation including the sum of the molar susceptibilities of the diruthenium unit and the lanthanide ion. However, the fit of the magnetic properties of 3 requires the consideration of the existence of the splitting of the 7F ground‐state term by spin–orbit coupling. This study shows that the magnetic behaviours of 1, 2 and 4 are governed by weak antiferromagnetic interactions between the diruthenium units and the lanthanide ions.
Neurotransmitters behind pain relief with transcranial magnetic stimulation – positron emission tomography evidence for release of endogenous opioids
Authors: Lamusuo S. , Hirvonen J. , Lindholm P. , Martikainen I. K. , Hagelberg N. , Parkkola R. , Taiminen T. , Hietala J. , Helin S. , Virtanen A. , Pertovaara A. , Jääskeläinen S.K.
Published: May 2017

Background

Repetitive transcranial magnetic stimulation (rTMS) at M1/S1 cortex has been shown to alleviate neuropathic pain.

Objectives

To investigate the possible neurobiological correlates of cortical neurostimulation for the pain relief.

Methods

We studied the effects of M1/S1 rTMS on nociception, brain dopamine D2 and μ‐opioid receptors using a randomized, sham‐controlled, double‐blinded crossover study design and 3D‐positron emission tomography (PET). Ten healthy subjects underwent active and sham rTMS treatments to the right M1/S1 cortex with E‐field navigated device. Dopamine D2 and μ‐receptor availabilities were assessed with PET radiotracers [11C]raclopride and [11C]carfentanil after each rTMS treatment. Thermal quantitative sensory testing (QST), contact heat evoked potential (CHEP) and blink reflex (BR) recordings were performed between the PET scans.

Results

μ‐Opioid receptor availability was lower after active than sham rTMS (P ≤ 0.0001) suggested release of endogenous opioids in the right ventral striatum, medial orbitofrontal, prefrontal and anterior cingulate cortices, and left insula, superior temporal gyrus, dorsolateral prefrontal cortex and precentral gyrus. There were no differences in striatal dopamine D2 receptor availability between active and sham rTMS, consistent with lack of long‐lasting measurable dopamine release. Active rTMS potentiated the dopamine‐regulated habituation of the BR compared to sham (P = 0.02). Thermal QST and CHEP remained unchanged after active rTMS.

Conclusions

rTMS given to M1/S1 activates the endogenous opioid system in a wide brain network associated with processing of pain and other salient stimuli. Direct enhancement of top‐down opioid‐mediated inhibition may partly explain the clinical analgesic effects of rTMS.

Significance

Neurobiological correlates of rTMS for the pain relief are unclear. rTMS on M1/S1 with 11C‐carfentanyl‐PET activates endogenous opioids. Thermal and heat pain thresholds remain unchanged. rTMS induces top‐down opioid‐mediated inhibition but not change the sensory discrimination of painful stimuli.
Resilience in ecotoxicology: Toward a multiple equilibrium concept
Authors: Bundschuh Mirco , Schulz Ralf , Schäfer Ralf B. , Allen Craig R. , Angeler David G.
Published: May 2017

The term resilience describes stress–response patterns across scientific disciplines. In ecology, advances have been made to clearly define resilience based on underlying mechanistic assumptions. Engineering resilience (rebound) is used to describe the ability of organisms to recover from adverse conditions (disturbances), which is termed the rate of recovery. By contrast, the ecological resilience definition considers a systemic change, that is, when ecosystems reorganize into a new regime following disturbance. Under this new regime, structural and functional aspects change considerably relative to the previous regime, without recovery. In this context, resilience is an emergent property of complex systems. In the present study, we argue that both definitions and uses are appropriate in ecotoxicology, and although the differences are subtle, the implications and uses are profoundly different. We discuss resilience concepts in ecotoxicology, where the prevailing view of resilience is engineering resilience from chemical stress. Ecological resilience may also be useful for describing systemic ecological changes because of chemical stress. We present quantitative methods that allow ecotoxicologists and risk managers to assess whether an ecosystem faces an impending regime shift or whether it has already undergone such a shift. We contend that engineering and ecological resilience help to distinguish ecotoxicological responses to chemical stressors mechanistically and thus have implications for theory, policy, and application. Environ Toxicol Chem 2017;36:2574–2580. © 2017 SETAC
Comprehensive characterization of the acute and chronic toxicity of the neonicotinoid insecticide thiamethoxam to a suite of aquatic primary producers, invertebrates, and fish
Authors: Finnegan Meaghean C. , Baxter Leilan R. , Maul Jonathan D. , Hanson Mark L. , Hoekstra Paul F.
Published: May 2017

Thiamethoxam is a neonicotinoid insecticide used widely in agriculture to control a broad spectrum of chewing and sucking insect pests. Recent detection of thiamethoxam in surface waters has raised interest in characterizing the potential impacts of this insecticide to aquatic organisms. We report the results of toxicity testing (acute and chronic) conducted under good laboratory practices for more than 30 freshwater species (insects, molluscs, crustaceans, algae, macrophytes, and fish) and 4 marine species (an alga, a mollusc, a crustacean, and a fish). As would be anticipated for a neonicotinoid, aquatic primary producers and fish were the least sensitive organisms tested, with acute median lethal and effect concentrations (LC50/EC50) observed to be ≥80 mg/L in all cases, which far exceeds surface water exposure concentrations. Tested molluscs, worms, and rotifers were similarly insensitive (EC50 ≥ 100 mg/L), except for Lumbriculus sp., with an EC50 of 7.7 mg/L. In general, insects were the most sensitive group in the study, with most acute EC50 values < 1 mg/L. However, the crustaceans Asellus aquaticus and Ostracoda exhibited a sensitivity similar to that of insects (acute EC50 < 1 mg/L), and the midge larvae Chaoborus sp. were relatively insensitive compared with other insects (EC50 > 5.5 mg/L). The most sensitive chronic response was for Chironomus riparius, with a 30-d no-observed-effect concentration (NOEC; emergence) of 0.01 mg/L. Observed toxicity to the tested marine organisms was comparable to that of freshwater species. We used the reported data to construct species sensitivity distributions for thiamethoxam, to calculate 5% hazard concentrations (HC5s) for acute data (freshwater invertebrates), and compared these with measured concentrations from relevant North American surface waters. Overall, based on acute toxicity endpoints, the potential acute risk to freshwater organisms was found to be minimal (likelihood of exceeding HC5s < 1%). Environ Toxicol Chem 2017;36:2838–2848. © 2017 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals, Inc. on behalf of SETAC.
A nonrandom subset of olfactory genes is associated with host preference in the fruit flyDrosophila orena
Authors: Comeault Aaron A. , Serrato-Capuchina Antonio , Turissini David A. , McLaughlin Patrick J. , David Jean R. , Matute Daniel R.
Published: May 2017

Specialization onto different host plants has been hypothesized to be a major driver of diversification in insects, and traits controlling olfaction have been shown to play a fundamental role in host preferences. A diverse set of olfactory genes control olfactory traits in insects, and it remains unclear whether specialization onto different hosts is likely to involve a nonrandom subset of these genes. Here, we test the role of olfactory genes in a novel case of specialization in Drosophila orena. We report the first population-level sample of D. orena on the West African island of Bioko, since its initial collection in Cameroon in 1975, and use field experiments and behavioral assays to show that D. orena has evolved a strong preference for waterberry (Syzygium staudtii). We then show that a nonrandom subset of genes controlling olfaction-–those controlling odorant-binding and chemosensory proteins–-have an enriched signature of positive selection relative to the rest of the D. orena genome. By comparing signatures of positive selection on olfactory genes between D. orena and its sister species, D. erecta we show that odorant-binding and chemosensory have evidence of positive selection in both species; however, overlap in the specific genes with evidence of selection in these two classes is not greater than expected by chance. Finally, we use quantitative complementation tests to confirm a role for seven olfactory loci in D. orena’s preference for waterberry fruit. Together, our results suggest that D. orena and D. erecta have specialized onto different host plants through convergent evolution at the level of olfactory gene family, but not at specific olfactory genes.
Functional hypergraph uncovers novel covariant structures over neurodevelopment
Authors: Gu Shi , Yang Muzhi , Medaglia John D. , Gur Ruben C. , Gur Raquel E. , Satterthwaite Theodore D. , Bassett Danielle S.
Published: May 2017

Brain development during adolescence is marked by substantial changes in brain structure and function, leading to a stable network topology in adulthood. However, most prior work has examined the data through the lens of brain areas connected to one another in large‐scale functional networks. Here, we apply a recently developed hypergraph approach that treats network connections (edges) rather than brain regions as the unit of interest, allowing us to describe functional network topology from a fundamentally different perspective. Capitalizing on a sample of 780 youth imaged as part of the Philadelphia Neurodevelopmental Cohort, this hypergraph representation of resting‐state functional MRI data reveals three distinct classes of subnetworks (hyperedges): clusters, bridges, and stars, which respectively represent homogeneously connected, bipartite, and focal architectures. Cluster hyperedges show a strong resemblance to previously‐described functional modules of the brain including somatomotor, visual, default mode, and salience systems. In contrast, star hyperedges represent highly localized subnetworks centered on a small set of regions, and are distributed across the entire cortex. Finally, bridge hyperedges link clusters and stars in a core–periphery organization. Notably, developmental changes within hyperedges are ordered in a similar core–periphery fashion, with the greatest developmental effects occurring in networked hyperedges within the functional core. Taken together, these results reveal a novel decomposition of the network organization of human brain, and further provide a new perspective on the role of local structures that emerge across neurodevelopment. Hum Brain Mapp 38:3823–3835, 2017. © 2017 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.
Superior parathyroid gland approach to the recurrent laryngeal nerve
Authors: Elsheikh Ezzeddin
Published: May 2017

Background

The superior parathyroid gland is known to be almost constant in its location under the false thyroid capsule. Could it be a landmark to point to the site of incision of the false thyroid capsule and find the plane of the recurrent laryngeal nerve (RLN) during thyroidectomy?

Methods

The study included 48 patients with benign goiter scheduled for hemithyroidectomy or total thyroidectomy; there were 16 cases of solitary thyroid nodules, 27 cases of multinodular goiter, and 5 cases of toxic goiter.

Results

This study included 80 lobectomies. All patients showed no evidence of postoperative RLN palsy, bleeding, or hypoparathyroidism. The superior parathyroid gland was consistently found within the false capsule in all cases, whereas the inferior parathyroid was found within the same layer in 64 sides (80%).

Conclusion

The described approach can accurately guide dissection between true and false capsules of the thyroid to reach and preserve both the RLN and the superior parathyroid gland. © 2017 Wiley Periodicals, Inc. Head Neck 39: 1287–1290, 2017
An international survey on the awareness, use, preference, and health perception of novel psychoactive substances (NPS)
Authors: Deligianni Elena , Corkery John M. , Schifano Fabrizio , Lione Lisa A.
Published: May 2017

Objective

This survey investigated the level of public awareness, preference, and motivation of novel psychoactive substances (NPS) use as well as knowledge of potential associated health risks.

Methods

A Bristol Online Survey was advertised through social media and a drug forum “Bluelight” between January 7 and February 7, 2015.

Results

Responses were received from 17 countries, mainly from Europe. Most responses (83%) came from university educated students. Two‐thirds (65%) of the 168 respondents were aware of NPS. Awareness was significantly increased in those with bisexual or homosexual orientation (p < .05) and those in employment (p < .05). Fourteen percent of the 168 respondents were users of NPS, and use was significantly affected by age and employment (p < .01) but unaffected by level of education (p > .05). Nearly half of the NPS users perceived NPS to carry either a low risk to health (20%) or did not know whether or not they posed a health risk (29%).

Conclusions

These survey data indicate that awareness of NPS and, importantly, perception of the potential health risks associated with NPS use is lacking. NPS awareness and use is higher in those in employment but is unaffected by level of education. This highlights the need for targeted drugs education intervention by policy‐makers in schools and universities.
Genomic analysis of inherited breast cancer among Palestinian women: Genetic heterogeneity and a founder mutation in TP53
Authors: Lolas Hamameh Suhair , Renbaum Paul , Kamal Lara , Dweik Dima , Salahat Mohammad , Jaraysa Tamara , Abu Rayyan Amal , Casadei Silvia , Mandell Jessica B. , Gulsuner Suleyman , Lee Ming K. , Walsh Tom , King Mary‐Claire , Levy‐Lahad Ephrat , Kanaan Moein
Published: May 2017

Breast cancer among Palestinian women has lower incidence than in Europe or North America, yet is very frequently familial. We studied genetic causes of this familial clustering in a consecutive hospital‐based series of 875 Palestinian patients with invasive breast cancer, including 453 women with diagnosis by age 40, or with breast or ovarian cancer in a mother, sister, grandmother or aunt (“discovery series”); and 422 women diagnosed after age 40 and with negative family history (“older‐onset sporadic patient series”). Genomic DNA from women in the discovery series was sequenced for all known breast cancer genes, revealing a pathogenic mutation in 13% (61/453) of patients. These mutations were screened in all patients and in 300 Palestinian female controls, revealing 1.0% (4/422) carriers among older, nonfamilial patients and two carriers among controls. The mutational spectrum was highly heterogeneous, including pathogenic mutations in 11 different genes: BRCA1, BRCA2, TP53, ATM, CHEK2, BARD1, BRIP1, PALB2, MRE11A, PTEN and XRCC2. BRCA1 carriers were significantly more likely than other patients to have triple negative tumors (p = 0.03). The single most frequent mutation was TP53 p.R181C, which was significantly enriched in the discovery series compared to controls (p = 0.01) and was responsible for 15% of breast cancers among young onset or familial patients. TP53 p.R181C predisposed specifically to breast cancer with incomplete penetrance, and not to other Li‐Fraumeni cancers. Palestinian women with young onset or familial breast cancer and their families would benefit from genetic analysis and counseling.
Quantitative proteomics to study a small molecule targeting the loss of von Hippel–Lindau in renal cell carcinomas
Authors: Bouhamdani Nadia , Joy Andrew , Barnett David , Cormier Kevin , Léger Daniel , Chute Ian C. , Lamarre Simon , Ouellette Rodney , Turcotte Sandra
Published: May 2017

Inactivation of the tumor suppressor gene, von Hippel–Lindau (VHL), is known to play an important role in the development of sporadic clear cell renal cell carcinomas (ccRCCs). Even if available targeted therapies for metastatic RCCs (mRCCs) have helped to improve progression‐free survival rates, they have no durable clinical response. We have previously shown the feasibility of specifically targeting the loss of VHL with the identification of a small molecule, STF‐62247. Understanding its functionality is crucial for developing durable personalized therapeutic agents differing from those available targeting hypoxia inducible factor (HIF‐) pathways. By using SILAC proteomics, we identified 755 deregulated proteins in response to STF‐62247 that were further analyzed by ingenuity pathway analysis (IPA). Bioinformatics analyses predicted alterations in 37 signaling pathways in VHL‐null cells in response to treatment. Validation of some altered pathways shows that STF‐62247's selectivity is linked to an important inhibition of mTORC1 activation in VHL‐null cells leading to protein synthesis arrest, a mechanism differing from two allosteric inhibitors Rapamycin and Everolimus. Altogether, our study identified signaling cascades driving STF‐62247 response and brings further knowledge for this molecule that shows selectivity for the loss of VHL. The use of a global SILAC approach was successful in identifying novel affected signaling pathways that could be exploited for the development of new personalized therapeutic strategies to target VHL‐inactivated RCCs.
Genome‐wide analysis of somatic copy number alterations and chromosomal breakages in osteosarcoma
Authors: Smida Jan , Xu Hongen , Zhang Yanping , Baumhoer Daniel , Ribi Sebastian , Kovac Michal , von Luettichau Irene , Bielack Stefan , O'Leary Valerie B. , Leib‐Mösch Christine , Frishman Dmitrij , Nathrath Michaela
Published: May 2017

Osteosarcoma (OS) is the most common primary malignant bone tumor in children and adolescents. It is characterized by highly complex karyotypes with structural and numerical chromosomal alterations. The observed OS‐specific characteristics in localization and frequencies of chromosomal breakages strongly implicate a specific set of responsible driver genes or a specific mechanism of fragility induction. In this study, a comprehensive assessment of somatic copy number alterations (SCNAs) was performed in 160 OS samples using whole‐genome CytoScan High Density arrays (Affymetrix, Santa Clara, CA). Genes or regions frequently targeted by SCNAs were identified. Breakage analysis revealed OS specific unstable regions in which well‐known OS tumor suppressor genes, including TP53, RB1, WWOX, DLG2 and LSAMP are located. Certain genomic features, such as transposable elements and non‐B DNA‐forming motifs were found to be significantly enriched in the vicinity of chromosomal breakage sites. A complex breakage pattern—chromothripsis—has been suggested as a widespread phenomenon in OS. It was further demonstrated that hyperploidy and in particular chromothripsis were strongly correlated with OS patient clinical outcome. The revealed OS‐specific fragility pattern provides novel clues for understanding the biology of OS.
Involvement and comfort of gynecologic oncologists in the treatment of pediatric, adolescent, and young adult patients with gynecologic malignancies
Authors: Winer Ira , Patel Divya , Dalton Vanessa , Johnston Carolyn , Quint Elisabeth H. , Zochowski Melissa , Munkarah Adnan , Morris Robert , Haefner Hope
Published: May 2017

Objective

To investigate the provision of care for pediatric and adolescent patients by gynecologic oncologists.

Methods

The present prospective cross‐sectional study enrolled attending physicians and fellows specializing in gynecologic oncology from the USA during December 2012 and January 2013. A 33‐question survey collecting demographic data and details of participant opinions on existing practices was distributed to potential respondents. Survey responses were aggregated and descriptive analyses were performed.

Results

The survey was distributed to 1252 physicians and 178 (14.2%) surveys were returned; 105 (59.0%) participants thought that the care of patients aged younger than 21 years should be included in their practice. Only 7 (3.9%) participants had received formal training in caring for pediatric patients and young adults; however, 85 (47.8%) felt this should be incorporated into formal fellowship training. Multidisciplinary teams were reported to be the best method for caring pediatric patients by 160 (88.9%) participants but only 42 (23.6%) participants reported that multidisciplinary teams were involved in pediatric gynecologic oncology care at their institutions.

Conclusion

Gynecologic oncologists wanted to be involved in pediatric care and open dialogue between specialists could help in the provision of optimal, longitudinal care to these patients. Furthermore, the incorporation of formal pediatric patient‐focused training into gynecologic oncology fellowship programs should be considered.
Prevalence of gestational diabetes mellitus evaluated by universal screening with a 75‐g, 2‐hour oral glucose tolerance test and IADPSG criteria
Authors: Karcaaltincaba Deniz , Calis Pinar , Ocal Nagehan , Ozek Aykut , Altug Inan Melis , Bayram Merih
Published: May 2017

Objective

To determine the prevalence of gestational diabetes mellitus (GDM) and its association with maternal age among Turkish women diagnosed by International Association of Diabetes and Pregnancy Study Group (IADPSG) criteria.

Methods

A cross‐sectional study was conducted in 2013–2015 among non‐diabetic pregnant women aged 18–49 years who were universally screened for GDM by IADPSG criteria. The percentage of women meeting each diagnostic threshold and the prevalence of GDM by age group were calculated. Linear trends were evaluated by logistic regression.

Results

Among 1434 women screened, 159 (11.1%, 95% confidence interval 9.5%–12.7%) were diagnosed with GDM; eleven of these women had been diagnosed according to a fasting glucose level in the first trimester. The prevalence of GDM was 6.6% (10/151), 7.3% (37/507), 8.8% (42/479), 16.7% (45/270), and 35.2% (25/71) among women aged younger than 25, 25–29, 30–34, 35–39, and 40 years or older, respectively. GDM prevalence increased with age (P<0.001). The numbers of women diagnosed with GDM in the second trimester who exceeded one, two, and three thresholds of the 2‐hour oral glucose tolerance test were 66 (44.6%), 52 (35.1%), and 30 (20.3%), respectively.

Conclusion

Prevalence of GDM was correlated with maternal age. Most women diagnosed in the second trimester exceeded the threshold at only one of the three timepoints.
Examining the emerging entrepreneurial mindset in adolescence: A study in Nigeria
Authors: Salami Samuel O.
Published: May 2017

This study investigated the relationship of family environment, network, parental socio‐economic status, self‐efficacy and proactive personality on entrepreneurial intention of secondary school adolescents and the mediating role of self‐efficacy. The participants were 250 secondary school SS2 adolescents randomly selected from six secondary schools in Ibadan Metropolis, Ibadan, Oyo State, Nigeria. Structural Equation Modelling was used to analyse the data obtained from the participants. The results showed that all the contextual and individual factors had significant relationship with entrepreneurial intention and self‐efficacy partially mediated the relationship. It was suggested that counselling psychologists should consider the contextual and individual variables while assisting students in building their entrepreneurial intention.
Using Every Word and Image: Framing Graphic Novel Instruction in the Expanded Four Resources Model
Authors: Meyer Carla K. , Jiménez Laura M.
Published: May 2017

In many classrooms, teachers have started to incorporate graphic novels in classroom instruction. However, research has suggested that some readers may have limited understanding of how to read graphic novels, which can create challenges for teachers using the medium. Drawing from a larger study, this article highlights two cases, an expert graphic novel and an expert traditional print text reader, to illustrate how the expanded four resources model may be used as a framework to guide novice graphic novel readers as they engage with graphic text. The article provides next steps for educators as they begin their journey with graphic novels.
Optomechanical measurement of the role of lamins in whole cell deformability
Authors: Kolb Thorsten , Kraxner Julia , Skodzek Kai , Haug Michael , Crawford Dean , Maaß Kendra K. , Aifantis Katerina E. , Whyte Graeme
Published: May 2017

There is mounting evidence that the nuclear envelope, and particularly the lamina, plays a critical role in the mechanical and regulation properties of the cell and changes to the lamina can have implications for the physical properties of the whole cell. In this study we demonstrate that the optical stretcher can measure changes in the time‐dependent mechanical properties of living cells with different levels of A‐type lamin expression. Results from the optical stretcher shows a decrease in the deformability of cells as the levels of lamin A increases, for cells which grow both adherently and in suspension. Further detail can be probed by combining the optical stretcher with fluorescence microscopy to investigate the nuclear mechanical properties which show a larger decrease in deformability than for the whole cell.
Autofluorescence imaging identifies tumor cell‐cycle status on a single‐cell level
Authors: Heaster Tiffany M. , Walsh Alex J. , Zhao Yue , Hiebert Scott W. , Skala Melissa C.
Published: May 2017

The goal of this study is to validate fluorescence intensity and lifetime imaging of metabolic co‐enzymes NAD(P)H and FAD (optical metabolic imaging, or OMI) as a method to quantify cell‐cycle status of tumor cells. Heterogeneity in tumor cell‐cycle status (e. g. proliferation, quiescence, apoptosis) increases drug resistance and tumor recurrence. Cell‐cycle status is closely linked to cellular metabolism. Thus, this study applies cell‐level metabolic imaging to distinguish proliferating, quiescent, and apoptotic populations. Two‐photon microscopy and time‐correlated single photon counting are used to measure optical redox ratio (NAD(P)H fluorescence intensity divided by FAD intensity), NAD(P)H and FAD fluorescence lifetime parameters. Redox ratio, NAD(P)H and FAD lifetime parameters alone exhibit significant differences (p<0.05) between population means. To improve separation between populations, linear combination models derived from partial least squares ‐ discriminant analysis (PLS‐DA) are used to exploit all measurements together. Leave‐one‐out cross validation of the model yielded high classification accuracies (92.4 and 90.1 % for two and three populations, respectively). OMI and PLS‐DA also identifies each sub‐population within heterogeneous samples. These results establish single‐cell analysis with OMI and PLS‐DA as a label‐free method to distinguish cell‐cycle status within intact samples. This approach could be used to incorporate cell‐level tumor heterogeneity in cancer drug development.

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Apheresis education in pathology residency
Authors: Peedin Alexis R. , Park Yara A. , Raval Jay S.
Published: May 2017

Introduction

Physicians from diverse training backgrounds practice apheresis medicine. Pathology residents' exposure to apheresis may vary depending on which department performs these procedures. Milestones for Apheresis education were published in 2012, but the degree of utilization in residency curriculum development is unknown. This study describes the current state of apheresis education for pathology residents.

Methods

We sent a 15 question electronic survey to 141 pathology programs identified through the American Medical Association Residency and Fellowship Database.

Results

Forty‐three (30.5%) of the 141 programs responded. Pathology performed apheresis procedures in 29 (67.4%) programs. In the remaining 14 programs, apheresis was performed by nephrology (10), hematology (4), and a regional blood center (1); in one program, both nephrology and hematology performed apheresis procedures. For combined anatomic and clinical pathology (AP/CP) residents, 26 of 28 (93%) were required to train in apheresis medicine when pathology performed the procedures compared to only 5 of 14 (36%) when they were performed by another department (P = 0.0002). For CP‐only residents, 18 of 19 (95%) were required to train in apheresis medicine when pathology performed the procedures compared to 5 of 7 (71%) when they were performed by another department (P = 0.1669). Thirty (68.9%) respondents had a written apheresis medicine curriculum. Seventeen (39.5%) of the 43 respondents were aware of the Milestones for Apheresis education, and 8 (18.6%) used the milestones in creating their apheresis curriculum.

Conclusions

The pathology department performed apheresis procedures in two‐thirds of pathology residency programs surveyed. AP/CP residents were more likely to be required to train in apheresis medicine if the pathology department performed these procedures at their institution. Apheresis medicine practitioners should review the Milestones for Apheresis education with their residency program director to optimize learning and clinical skills development.
Clotting during autologous hematopoietic progenitor cells collection
Authors: Gokhale Amit , Quraishy NurJehan , Veemara Viva , Howdyshell Heather , Murray Lynn , Royer Jennifer , Salmi Linda , Ricci Kristin , Liu Hien
Published: May 2017

Autologous hematopoietic progenitor cell (HPC) transplant through peripheral blood mobilization and leukapheresis is a standard treatment for many patients with hematopoietic malignancies. Although leukapheresis is usually completed with no complications, we present a case in which the hematopoietic progenitor cells clotted during collection. The patient had no history of hypercoagulopathy. It was identified that the anticoagulant infusion line was partially constricted by a blood warmer clamp. The machine did not alarm. Most of the multiple Food and Drug Administration reports of clotting occurring during apheresis procedures were due to the patients' preexisting hypercoagulopathy or insufficient anticoagulant solution being used. The machine alarmed in most of these cases. Our case demonstrates that inadequate anticoagulation can occur during an HPC collection procedure without activation of an alarm.
A prospective study comparing tryptophan immunoadsorption with therapeutic plasma exchange for the treatment of chronic inflammatory demyelinating polyneuropathy*
Authors: Lieker Ina , Slowinski Torsten , Harms Lutz , Hahn Katrin , Klehmet Juliane
Published: May 2017

Background

Chronic inflammatory demyelinating polyneuropathy (CIDP) is a rare paralyzing inflammatory neuropathy with probably autoimmune origin. While plasma exchange (PE) constitutes a first‐line treatment option for CIDP, there is only little known about the efficacy and safety of immunoadsorption (IA), a more selective apheresis procedure with assumed better tolerability.

Methods

In this prospective‐randomized pilot trial, patients were randomly assigned to receive 6 sessions of PE (n = 10) or IA (n = 10) treating equal plasma volumes. To evaluate efficacy, we calculated the adjusted Inflammatory Neuropathy Cause and Treatment (INCAT) disability score and the Medical Research Council (MRC) sum score at baseline (V1), after completion of 6 sessions (V2) as well as 4 weeks after completion (V3) in 9 patients per group (1 patient in each group did not complete follow‐up). We additionally assessed safety and tolerability of treatments by monitoring adverse event and blood parameters.

Results

With IA, 6 out of 9 (66.7%) patients improved clinically, whereas with PE, 4 out of 9 (44.4%) patients improved, most of them immediately with completion of the apheresis treatment series. There was one adverse event (AE) out of 52 treatment sessions for the 9 patients in the IA group. In the PE group of 9 patients, there was 1 AE out of 51 sessions and a trend of greater fibrinogen reduction. No severe AE occurred in either group.

Conclusion

The results of this pilot study suggest that IA is at least equally effective and safe compared to PE in CIDP patients.
Therapeutic plasma exchange in children: One center's experience
Authors: Cortina Gerard , Ojinaga Violeta , Giner Thomas , Riedl Magdalena , Waldegger Siegfried , Rosales Alejandra , Trojer Raphaela , Hofer Johannes
Published: May 2017

Background

Therapeutic plasma exchange (TPE) has evolved to an accepted therapy for selected indications. However, it is technically challenging in children. Moreover, data on safety and efficacy are mainly derived from adult series. The aim of this study was to review the procedure in the context of clinical indications, effectiveness, and safety.

Study Design and Methods

All TPE procedures performed at a tertiary care hospital during a 12‐year period (2005–2016) were retrospectively evaluated.

Results

Eighteen patients with a median age of 8.5 (0.2–17) years underwent a total of 280 TPE sessions. Eleven (61%) patients were treated for renal diseases. Three (17%) patients were diagnosed with neurological diseases, two had liver failure, and one patient each had sepsis and stem cell transplant‐associated thrombotic microangiopathy. Seven patients (39%) were classified as American Society for Apheresis Category I, four (22%) as Category II, two (13%) each as Category III and IV, and two (13%) were not classified. Two patients with atypical hemolytic‐uremic syndrome received TPE as long‐term therapy over 2 and 5 years. All procedures were performed using the filtration technique and heparin anticoagulation. Twelve (67%) patients showed full or partial recovery after TPE, six had no response or an uncertain response. Minor adverse events occurred in 30/280 (10.6%) procedures, and one major complication (0.4%) was reported.

Conclusion

TPE is a safe apheresis method in children, even when performed as a long‐term therapy. Efficacy is high under selected conditions. A highly skilled and experienced staff is mandatory to ensure patient safety and efficacy.
Performance and safety of femoral central venous catheters in pediatric autologous peripheral blood stem cell collection
Authors: Cooling Laura , Hoffmann Sandra , Webb Dawn , Yamada Chisa , Davenport Robertson , Choi Sung Won
Published: May 2017

Introduction

Autologous peripheral blood hematopoietic progenitor cell collection (A‐HPCC) in children typically requires placement of a central venous catheter (CVC) for venous access. There is scant published data regarding the performance and safety of femoral CVCs in pediatric A‐HPCC.

Methods

Seven‐year, retrospective study of A‐HPCC in pediatric patients collected between 2009 and January 2017. Inclusion criteria were an age ≤ 21 years and A‐HPCC using a femoral CVC for venous access. Femoral CVC performance was examined by CD34 collection rate, inlet rate, collection efficiency (MNC‐FE, CD34‐FE), bleeding, flow‐related adverse events (AE), CVC removal, and product sterility testing. Statistical analysis and graphing were performed with commercial software.

Results

A total of 75/119 (63%) pediatric patients (median age 3 years) met study criteria. Only 16% of children required a CVC for ≥ 3 days. The CD34 collect rate and CD34‐FE was stable over time whereas MNC‐FE decreased after day 4 in 80% of patients. CD34‐FE and MNC‐FE showed inter‐ and intra‐patient variability over time and appeared sensitive to plerixafor administration. Femoral CVC showed fewer flow‐related AE compared to thoracic CVC, especially in pediatric patients (6.7% vs. 37%, P = 0.0005; OR = 0.12 (95%CI: 0.03‐0.45). CVC removal was uneventful in 73/75 (97%) patients with hemostasis achieved after 20–30 min of pressure. In a 10‐year period, there were no instances of product contamination associated with femoral CVC colonization.

Conclusion

Femoral CVC are safe and effective for A‐HPCC in young pediatric patients. Femoral CVC performance was maintained over several days with few flow‐related alarms when compared to thoracic CVCs.