bluuebunny/crossref_metadata_2025 huggingface dataset:
Vertebral Comparative Anatomy and Morphological Differences in Anguine Lizards With a Special Reference to Pseudopus apodus
Authors: Čerňanský Andrej , Yaryhin Oleksandr , Ciceková Jana , Werneburg Ingmar , Hain Miroslav , Klembara Jozef
Published: October 2018

The article reports on the first detailed vertebral and rib morphology of anguine taxon Pseudopus apodus using micro‐computed tomography. A comparison shows significant morphological differences of vertebrae of Pseudopus relative to those of Anguis and Ophisaurus. Usually, there are 55 presacral vertebrae, two sacral, and 95–97 caudal vertebrae. Pseudopus apodus can be defined by 23 diagnostic features concerning the vertebral column. Although zygapophyseal articulation between atlas and axis is well developed in limbed anguid gerrhonotine lizards like Abronia or Barisia, it is absent in the extant representatives of the clade Anguinae, which are limbless. Thus, our study brings further support to the hypothesis about the complete reduction of this articulation in forms with reduced or absent limbs. Comparison of adult and juvenile morphology of vertebrae of P. apodus was also analyzed. Heterochrony in the evolution of this taxon was previously confirmed by its skull morphology and it can be also documented on the basis of vertebrae. Our data suggest that a peramorphic heterochronic process played a role in the evolution of this largest extant anguine species. Geometric morphometric analyses revealed a pattern of high vertebral disparity among species. We found a clear separation of limbless forms in morphospace. Pseudopus apodus always clusters within Ophisaurus‐species confirming molecular and some morphological phylogenies. Only the first tail vertebra shows a distinct difference to those of other anguids, which might be related to altered locomotion associated to the larger body size in this species. Anat Rec, 302:232–257, 2019. © 2018 Wiley Periodicals, Inc.
Donepezil–melatonin hybrids as butyrylcholinesterase inhibitors: Improving binding affinity through varying mode of linking fragments
Authors: Łozińska Iwona , Świerczyńska Aleksandra , Molęda Zuzanna , Hartman Alwin M. , Hirsch Anna K. H. , Czarnocki Zbigniew
Published: October 2018

Hybrid inhibitors of acetyl‐ and butyrylcholinesterase are compounds that combine structural motifs of two different classical inhibitors, leading to a dual binding ligand. A rapidly growing collection of those compounds involves a wide diversity of structural motifs, but the way of linking two active fragments and its impact on the affinity toward cholinesterases usually remains beyond the extent of investigation. We present hereby a detailed analysis of this aspect using melatonin–donepezil hybrids. A new series of compounds, in which two fragments are connected using a carbamate linker, exhibits excellent activity and selectivity toward butyrylcholinesterase.
Intermolecular Dehydrative Coupling and Intramolecular Cyclization of Ruthenium Vinylidene Complexes Formed from Aromatic Propynes Containing Carbonyl Functionalities
Authors: Chia Pi‐Yeh , Kuo Cheng‐Chen , Huang Shou‐Ling , Liu Yi‐Hong , Liu Ling‐Kang , Lin Ying‐Chih
Published: October 2018

A remarkable intermolecular dehydrative coupling reaction with the formation of a C−C bond was found for the vinylidene complex 2 a, yielding the dinuclear bisvinylidene complex 4 a. Complex 2 a containing 1‐hydroxyindan moiety was first formed from the reaction of o‐propynyl benzaldehyde 1 a with [Ru]–Cl ([Ru]=Cp(PPh3)2Ru) by a cyclization process. For analogous aldehyde 1 b containing an additional 1,3‐dioxolane group on the aryl ring, similar intermolecular coupling yields the dinuclear bisvinylidene complex 4 b. However, the fluoro group on the aryl ring in aldehyde 1 c inhibits the coupling reaction, giving only the vinylidene complex 2 c. For the reactions of [Ru]–Cl in MeOH with compounds 1 f, 1 g and 1 h, each with a ketone functionality, cyclization gives vinylidene complexes 2 f, 2 g and 2 h, respectively. However, no similar intermolecular coupling was observed, instead, the intramolecular dehydration yields 8 f, 8 g and 8 h, respectively. In CDCl3, catalytic cyclization is observed for the o‐propynylphenyl ketone 1 h with [Ru]–Cl at 50 °C giving the isochromene products 14 h. Furthermore, treatment of the o‐propynylaryl α,β‐unsaturated ketones 1 k–m and 1 n with [Ru]–Cl in MeOH affords the corresponding vinylidene complexes 10 k–m and 11 n each with 1‐benzosuberone moiety in the presence of NH4PF6. These intramolecular cyclization products were formed by the addition of Cβ onto the terminal carbon of the alkene moiety. All these reaction products were characterized by spectroscopic methods. In addition, structures of complexes 4 a, and 10 l were confirmed by single crystal X‐ray diffraction analysis.
Role of tropical intraseasonal oscillations in the South China Sea summer monsoon withdrawal in 2010
Authors: Hu Peng , Chen Wen , Huang Ruping
Published: October 2018

Based on the ensemble empirical mode decomposition of low‐level winds and outgoing longwave radiation, this paper analyzes the influence of tropical intraseasonal oscillations (ISOs) on one extremely late case of South China Sea (SCS) summer monsoon withdrawal (SMW). Compared to the climatological monsoon withdrawal of September 25, the South China Sea summer monsoon withdrawal in 2010 was delayed for approximately 1 month (October 26) and is the latest in the past 60 years. The quasi‐biweekly oscillation (QBWO) and Madden‐Julian oscillation (MJO) originating from the equatorial Indian Ocean propagate northeastward to the SCS. The accompanying circulation first induced a westerly burst event and prolonged the lifespan of the summer monsoon. After this transitory recovery, the circulation anomalies associated with the current propagation of ISOs into the SCS contributed to the large‐scale circulation adjustment, leaded to the shift of zonal wind (from westerlies to easterlies) and triggered the SCSSM withdrawal. This case study shows that, in addition to the well‐studied impacts of ISOs on the monsoon onset and active/break cycle, the ISOs can also trigger the monsoon withdrawal.
Insistence on sameness and broader autism phenotype in simplex families with autism spectrum disorder
Authors: Esler Amy N. , Stronach Sheri T. , Jacob Suma
Published: October 2018

Insistence on sameness (IS) in individuals with autism spectrum disorder (ASD) and their families may have utility in identifying meaningful subgroups for studying the pathophysiological and genetic pathways affected in ASD. The primary objectives of the current study were to (1) characterize features of IS in parents of children with ASD and (2) examine their relationships with child IS symptoms. Participants were 2760 families who participated in the Simons Simplex Collection. Levels of parent IS were measured using the Broader Autism Phenotype Questionnaire (BAPQ). A factor analysis generated a BAPQ‐IS scale, consisting of a subset of 11 items from the original BAPQ‐Rigid scale. Correlations were run to examine the relationship between parent BAP and child IS variables. Correlations were found between parent IS and measures of child IS. Although relationships between parent and child IS features were statistically significant in this large sample, effect sizes were small. Results may be reflective of sample design that only included simplex families, where ASD severity may be predominantly driven by spontaneous mutations and less by common inherited risk from parents. In addition, child and parent measures used may have differentially captured features and severity of IS. Further research is needed on how IS can be accurately measured throughout development and across individuals with ASD and their unaffected family members to facilitate future studies on IS as a possible endophenotype for ASD.Autism Res2018, 11: 1253–1263. © 2018 International Society for Autism Research, Wiley Periodicals, Inc.

Lay Summary

Previous research has suggested that insistence on sameness (IS) may be a heritable trait in autism spectrum disorder (ASD). The study examined whether children with high levels of IS had parents with IS tendencies. A small relationship was found between parent and child measures of IS. Future research is needed on measurement of insistence on sameness across individuals with and without ASD to further examine this relationship and improve understanding of the genetics of ASD.
Einfluss geometrischer und hydraulischer Parameter auf das Verhalten abwandernder Fische an Wasserkraftanlagen
Authors: Klopries Elena‐Maria , Böckmann Imke , Hoffmann Andreas , Schüttrumpf Holger
Published: October 2018

Für den Schutz abwandernder Fische vor einer schädlichen Turbinenpassage können Rechen‐Bypass‐Systeme eine wirksame Maßnahme sein. Um möglichst viele Fische auf ihrer abwärtsgerichteten Wanderung durch ein solches System zu schützen, sollten die Verhaltensweisen der Fische bei der Bemessung des Systems Berücksichtigung finden. In ethohydraulischen Untersuchungen mit Aalen, Äschen, Flussbarschen, Lachssmolts und Rotaugen wurden geometrische und hydraulische Parameter eines Vertikalrechens getestet, um über die Kombination aus Verhaltensbeobachtungen der Fische und Strömungsmessungen Erkenntnisse über die Wirkung des Rechens zu ermitteln. Die Ergebnisse der Auswertung der Verhaltensweisen zeigen, dass neben der Anströmgeschwindigkeit vor allem der Rechenstababstand einen maßgebenden Einfluss auf die Filterwirkung eines Rechens und das Suchverhalten der Fische hat.
Osteoclastogenesis Inhibitory Polyketides from the Sponge‐Associated Fungus Xylaria feejeensis
Authors: Wang Jie , Xu Cong‐Cong , Tang Hua , Su Li , Chou Yalan , Soong Keryea , Li Jiao , Zhuang Chun‐Lin , Luo Yan‐Ping , Zhang Wen
Published: October 2018

A new ten‐membered macrolide (1) and a new α‐pyrone derivative, (−)‐annularin C (2), together with 14 known analogs (3–16) were isolated from the AcOEt extract of the fungus Xylaria feejeensis isolated from the South China Sea sponge Stylissa massa. The structures of the new compounds were elucidated by the spectroscopic analysis and by comparison with reported data. The absolute configuration was determined by the optical rotation and ECD experiments. In an in vitro test, compounds 1, 5 and 9 exhibited significant down‐regulating activity of osteoclast cell differentiation at 0.5 and 1 μm. This is the first report of the fungus X. feejeensis from a marine sponge and of osteoclastogenesis inhibitory activity for the metabolites of these kinds.
Planning percutaneous coronary interventions using computed tomography angiography and fractional flow reserve‐derived from computed tomography: A state‐of‐the‐art review
Authors: Feldmann Kyle , Cami Elvis , Safian Robert D.
Published: October 2018

Fractional flow reserve derived by coronary computed tomography angiography (CTA; FFRCT) is an accurate noninvasive method for identifying coronary artery disease (CAD) and detecting hemodynamically significant stenosis. Although initially proposed as noninvasive tools to “rule out” significant CAD in low‐risk patients, CTA and FFRCT are now utilized in higher‐risk patients. Furthermore, new applications of CTA and FFRCT include a planning tool for percutaneous coronary intervention (PCI), which allows the cardiologist to assess lesion‐specific ischemia, plan stent locations and sizes, and use virtual remodeling of the lumen (virtual stenting) to assess the functional impact of PCI. The purpose of this review is to discuss the principles of CTA and FFRCT acquisition, and their application for PCI planning, even before invasive angiography is performed.
Missense variants in TMEM67 in a patient with Joubert syndrome
Authors: Huynh Julie M. , Galindo Maureen , Laukaitis Christina M.
Published: October 2018

Key Clinical Message

We present a patient with a clinical diagnosis of Joubert syndrome with COACH phenotype who carries two TMEM67 variants of uncertain significance (VUS). One VUS can be reclassified as “likely pathogenic” by adding clinical data. As genetic testing becomes more accessible, more VUS will require clinical correlation for accurate classification.
Gold Catalysis in (Supra)Molecular Cages to Control Reactivity and Selectivity
Authors: Jans Anne C. H. , Caumes Xavier , Reek Joost N. H.
Published: October 2018

Gold catalysis has experienced a tremendous development over the past decades, and is nowadays widely used in organic synthesis to perform chemical transformations of π‐bond‐containing molecules. Catalyst development has been based mostly on ligand development and counter‐ion strategies. More recently, the encapsulation of gold catalysts in (supra)molecular cages was explored as a new way to control selectivity and reactivity of gold catalysts. In this review, we describe the cages that have been employed as hosts for gold complexes, along with their impact on the catalytic performance. Covalent and supramolecular approaches to encapsulate single metal complexes will be described and the impact on the catalytic performance will be discussed. Also, recent strategies to pre‐organize multiple metal centers will be discussed.
Size Engineering and Crystallinity Control Enable High‐Capacity Aqueous Potassium‐Ion Storage of Prussian White Analogues
Authors: Li Chang , Wang Xusheng , Deng Wenjun , Liu Chunyi , Chen Jitao , Li Rui , Xue Mianqi
Published: October 2018

Aqueous potassium‐ion batteries have demonstrated huge potential in the field of energy storage, owing to their low cost, environmental friendliness, and high safety, yet with poor cycling stability and rate capability. Here, potassium Prussian white analogues (K‐PW) with different gradients in crystallinity and size have been synthesized by controlling the acidity of hydrothermal environment. The as‐synthesized K1.93Fe[Fe(CN)6]0.97 ⋅ 1.82H2O nanoparticles deliver considerable reversible capacities of 142 mAh g−1 at 75 mA g−1, even 40 mAh g−1 at 9000 mA g−1, and high capacity retention of 88 % after 300 cycles at 1500 mA g−1 in a KNO3 aqueous electrolyte. High crystallinity and short ion‐diffusion length determine the fast ion‐intercalation kinetics and, thus, enable the superior rate capability. These results reveal the feasibility of using K‐PW for practical applications in aqueous potassium‐ion batteries.
Visible‐Light‐Active Mixed‐Valent Copper‐Ion‐Coordinated 2,5‐Dimercapto‐1,3,4‐thiadiazole‐Based p‐Type Metallopolymer
Authors: Udachyan Iranna , Kumara Pradeepa , Vishwanath R. S. , Kandaiah Sakthivel
Published: October 2018

Visible‐light‐active coordination metallopolymer and metal‐organic frameworks have gained substantial attention in recent years, owing to their tunable electronic properties. Herein, we present a novel copper‐ion‐containing metallopolymer, which exhibits visible‐light absorption and p‐type photoelectrochemical behavior. The functional thiadiazole‐based metallopolymer thin films were prepared by using both chemical and electrochemical methods on fluorine‐doped tin oxide substrates. XPS, Raman, and FTIR spectral investigations evidence the presence of Cu(II), Cu(I), Cu−S, and disulfide (S−S)2− linkages in the polymeric network. The swift photoresponses, repeatable photovoltage of approximately 55 mV with zero applied current, and high photocurrent values at different bias potentials (ca. 24 μA cm−2 @ −0.6 V vs. Ag/AgCl in 0.1 KCl) in acidic electrolytes (0.5 M H2SO4) suggest that this metallopolymer as an acid‐stable p‐type photocathode material. In contrast, the electropolymerized non‐metallated polymers exhibit n‐type photoactivity. Photoelectrochemical sensing studies reveal the analyte‐induced reduction in photoactivity.
Molecular Receptors for Recognition and Sensing of Nucleotides
Authors: Agafontsev Aleksandr M. , Ravi Anil , Shumilova Tatiana A. , Oshchepkov Aleksandr S. , Kataev Evgeny A.
Published: October 2018

Nucleotides are constituents of nucleic acids and they have a variety of functions in cellular metabolism. Synthetic receptors and sensors are required to reveal the role of nucleotides in living organisms and mechanisms of signal transduction events. In recent years, a large number of nucleotide‐selective synthetic receptors have been devised, which utilize different molecular designs and sensing mechanisms. This Minireview presents recent progress in the design of synthetic molecular receptors for selective recognition of nucleotides in aqueous solution. The binding properties of receptors and the origins of their selectivity for a particular nucleotide are discussed.
Synthesis, Structure and Nickel Carbonyl Complexes of Dialkylterphenyl Phosphines
Authors: Marín Mario , Moreno Juan J. , Navarro‐Gilabert Carlos , Álvarez Eleuterio , Maya Celia , Peloso Riccardo , Nicasio M. Carmen , Carmona Ernesto
Published: October 2018

The experimental and computational characterization of a series of dialkylterphenyl phosphines, PR2Ar′ is described. The new P‐donors comprise five compounds of general formula PR2Ar
(R=Me, Et, iPr, c‐C5H9 and c‐C6H11); Ar
= 2,6‐C6H3‐(3,5‐C6H3‐(CMe3)2)2), and another five PR2Ar′ phosphines containing the bulky alkyl groups iPr, c‐C5H9 or c‐C6H11, in combination with Ar′=Ar
, Ar
, or Ar
(L1–L10). Steric and electronic parameters have been determined computationally and from IR and X‐ray data obtained for the phosphines and for some derivatives, including tricarbonyl and dicarbonyl nickel complexes, Ni(CO)3(PR2Ar′) and Ni(CO)2(PR2Ar′). In the solid state, the free phosphines PR2Ar′ adopt one of the three possible structures formally related by rotation around the Cipso−P bond. Details on their relative energies and on the influence of the free phosphine structure on its coordination chemistry towards Ni(CO)n (n = 2, 3) fragments has been obtained by experimental and computational methods.
Imide‐Functionalized Polymer Semiconductors
Authors: Sun Huiliang , Wang Lei , Wang Yingfeng , Guo Xugang
Published: October 2018

Imide‐functionalized π‐conjugated polymer semiconductors have received a great deal of interest owing to their unique physicochemical properties and optoelectronic characteristics, including excellent solubility, highly planar backbones, widely tunable band gaps and energy levels of frontier molecular orbitals, and good film morphology. The organic electronics community has witnessed rapid expansion of the materials library and remarkable improvement in device performance recently. This review summarizes the development of imide‐functionalized polymer semiconductors as well as their device performance in organic thin‐film transistors and polymer solar cells, mainly achieved in the past three years. The materials mainly cover naphthalene diimide, perylene diimide, and bithiophene imide, and other imide‐based polymer semiconductors are also discussed. The perspective offers our insights for developing new imide‐functionalized building blocks and polymer semiconductors with optimized optoelectronic properties. We hope that this review will generate more research interest in the community to realize further improved device performance by developing new imide‐functionalized polymer semiconductors.
Regioselective Activation of a Sterically More Hindered C−C Bond of Biphenylenes Using an Alkene as Both a Directing Group and a Reaction Moiety
Authors: Takano Hideaki , Ito Takeharu , Kanyiva Kyalo Stephen , Shibata Takanori
Published: October 2018

The Rh‐catalyzed intramolecular reaction of 1‐(2‐vinylaryl)‐substituted biphenylenes was used to construct a dihydrobenzo[b]fluoranthene skeleton. This transformation was achieved by regioselective C−C bond cleavage of a sterically more hindered biphenylene site by using alkene as both a directing group and a reaction moiety. Furthermore, we measured and analyzed the photophysical properties of the new multicyclic fused compounds.
Deaminative Borylation of Aliphatic Amines Enabled by Visible Light Excitation of an Electron Donor–Acceptor Complex
Authors: Sandfort Frederik , Strieth‐Kalthoff Felix , Klauck Felix J. R. , James Michael J. , Glorius Frank
Published: October 2018

A deaminative strategy for the borylation of aliphatic primary amines is described. Alkyl radicals derived from the single‐electron reduction of redox‐active pyridinium salts, which can be isolated or generated in situ, were borylated in a visible light‐mediated reaction with bis(catecholato)diboron. No catalyst or further additives were required. The key electron donor–acceptor complex was characterized in detail by both experimental and computational investigations. The synthetic potential of this mild protocol was demonstrated through the late‐stage functionalization of natural products and drug molecules.
Highly enantioselective Michael addition of α‐nitroacetate to α,β‐unsaturated pyrazolamide catalyzed by a bifunctional squaramide
Authors: Liu Yingying , Ye Ling , Shi Zhichuan , Yang Xuejun , Zhao Zhigang , Li Xuefeng
Published: October 2018

A highly enantioselective (91‐ > 99% ee) Michael addition of α‐nitroacetate to α,β‐unsaturated pyrazolamide was developed in the presence of a bifunctional squaramide. Satisfactory isolated yields (42%‐99%) have been achieved with a wide range of α,β‐unsaturated pyrazolamides, albeit acceptor of this type displayed poor reactivity in the precedent reports. The adducts resulting from this protocol are useful synthetic intermediates for further synthetic modification.
Application of nuclear magnetic resonance permeability models in tight reservoirs
Authors: Solatpour Razieh , Kantzas Apostolos
Published: October 2018

Tight reservoir permeability with values ranging from a few nD–0.1 mD is a challenging parameter to measure. Since the 1970s, many correlations were applied to estimate the permeability of tight formations using the nuclear magnetic resonance (NMR) technique. Due to increasing interest in tight reservoir recovery, each year many papers are published on the Timur‐Coates and Kenyon models and their modification on estimating the NMR permeability of tight reservoirs. It brings up the question of which is the most accurate, reliable, and feasible model to be used for predicting tight NMR permeability.

The first part of this paper is dedicated to introducing the existing models for NMR‐based estimates of tight reservoir permeability. The second part compares these models by applying them on tight reservoirs from North America, Asia, and Europe. NMR experiments were conducted on 150 cores. NMR T2 relaxation times were measured and effective and total porosities, the geometric mean of relaxation time (T2gm), irreducible bulk volume (BVI), and free fluid index (FFI) were calculated. For validation of the models, the cross plots of NMR permeability versus the Klinkenberg gas permeability are presented. Comparison of the model is based on the calculated standard error of these two independently measured permeabilities.

This paper is beneficial in understanding existing tight reservoir NMR permeability models. The results can be used as a guide for choosing the best NMR permeability estimation model for tight reservoirs data.
11‐Aza‐artemisinin Derivatives Exhibit Anticancer Activities by Targeting the Fatty Acid Binding Protein 6 (FABP6)
Authors: Chen Xin‐Ya , Yin Yue , Xi Jie , Yuan Yi , Li Yan , Li Qing , Wang Ren‐Xiao , Yao Zhu‐Jun , Tang Gong‐Li
Published: October 2018

Artemisinin (Qinghaosu), a sesquiterpene lactone isolated from the Chinese medicinal herb Artemisia annua, is famous as the first‐line antimalarial drug, and reported to also possess anticancer properties. Though many studies have proceeded focusing on artemisinin and bioactive derivatives in clinic or laboratory, their cellular targets and mechanism of actions have still remained obscure. Here, two new 11‐aza‐artemisinin derivatives AAD1 and AAD2, which displayed cytotoxity against multiple cancer cell lines, were synthesized and applied as the probes for target identification and anticancer mechanism research. Using T7 phage display screen method, fatty acid binding protein 6 (FABP6) was identified and verified as one of the potential targets. Further studies showed FABP6 is a direct binding protein of AAD1 and AAD2, and mediated the corresponding anticancer activities of these artemisinin derivatives.
Perioperative biobehavioral interventions to prevent cancer recurrence through combined inhibition of β‐adrenergic and cyclooxygenase 2 signaling
Authors: Ricon Itay , Hanalis‐Miller Tsipi , Haldar Rita , Jacoby Rebecca , Ben‐Eliyahu Shamgar
Published: October 2018

Evidence suggests that excess perioperative activation of the sympathetic nervous system and the consequent release of catecholamines (ie, epinephrine and norepinephrine) in the context of cancer surgery and inflammation may significantly facilitate prometastatic processes. This review first presents biomedical processes that make the perioperative timeframe pivotal in determining long‐term cancer outcomes nonproportionally to its short duration (days to weeks). Then, it analyzes the various mechanisms via which the excess release of catecholamines can facilitate the progression of cancer metastases in this context by directly affecting the malignant tissues and by regulating, via indirect pathways, immunological and other mechanisms that affect metastatic progression in the tumor microenvironment and systemically. In addition, this review addresses the need to supplement β‐adrenoreceptor blockade with cyclooxygenase 2 inhibition, especially during surgery and shortly thereafter, because similar mechanisms are simultaneously activated by surgery‐induced inflammatory responses. Importantly, this review presents translational and clinical evidence showing that perioperative β‐adrenoreceptor blockade and cyclooxygenase 2 inhibition can reduce the prometastatic process and cancer recurrence, and the clinical feasibility and safety of this approach are demonstrated as well. Lastly, alternative psychophysiological approaches to the use of β‐adrenergic blockers are presented because a substantial portion of patients have medical contraindications to this pharmacological treatment. The adaptation of existing psychophysiological interventions to the perioperative period and principles for constructing new approaches are discussed and exemplified. Overall, pharmacobehavioral interventions, separately or in combination, could transform the perioperative timeframe from being a prominent facilitator of metastatic progression to an opportunity for arresting or eliminating residual disease, potentially improving long‐term survival rates in cancer patients.
Frequent PTEN loss and differential HER2/PI3K signaling pathway alterations in salivary duct carcinoma: Implications for targeted therapy
Authors: Saintigny Pierre , Mitani Yoshitsugu , Pytynia Kristen B. , Ferrarotto Renata , Roberts Dianna B. , Weber Randal S. , Kies Merrill S. , Maity Sankar N. , Lin Sue‐Hwa , El‐Naggar Adel K.
Published: October 2018

BACKGROUND

Patients with advanced primary and recurrent salivary duct carcinoma (SDC), a rare and lethal malignancy, have limited therapeutic options. Novel small‐molecule agents aimed at targeting critical signaling associated with SDC tumorigenesis may lead to new therapeutic options for patients with these tumors. The human epidermal growth factor receptor 2 (HER2)/phosphoinositide 3‐kinase (PI3K) axis, an important oncogenic pathway, has been targeted for therapy in several solid tumors. Currently, little is known about the role and clinical implications of alterations of the HER2/PI3K pathway in patients with SDC.

METHODS

The authors investigated the clinicopathologic features, genetic alterations, and expression of key members of the HER2/PI3K pathway in 43 primary tumors and conducted in vitro functional and targeted drug‐response analyses on cell lines derived from salivary epithelial carcinomas.

RESULTS

In primary tumors, loss of phosphatase and tensin homolog (PTEN) expression was identified in 22 of 43 tumors (51%), overexpression of HER2 was observed in 12 of 43 tumors (28%), and phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha (PIK3CA) mutations were identified in 12 of 43 tumors (28%). Phosphorylated protein kinase B (p‐AKT) was highly expressed in most tumors. Most tumors (70%) displayed mutually exclusive alterations of PI3K members, whereas 8 tumors (19%) had 2 or more concurrent abnormalities. In vitro studies demonstrated a direct association between PTEN loss and PI3K pathway activation and evidence of response to combined PI3Kα and PI3Kβ and/or pan‐PI3K inhibitors.

CONCLUSIONS

The current analyses reveal frequent PTEN loss and mutually exclusive alterations of key PI3K pathway members in SDC and demonstrate in vitro evidence of a response to pan‐PI3K inhibitors. These results provide a framework for a biomarker‐based substratification of patients with SDC in future targeted therapy. Cancer 2018;124:3523‐32. © 2018 American Cancer Society.
Self‐reported fatigue in children with advanced cancer: Results of the PediQUEST study
Authors: Ullrich Christina K. , Dussel Veronica , Orellana Liliana , Kang Tammy I. , Rosenberg Abby R. , Feudtner Chris , Wolfe Joanne
Published: October 2018

BACKGROUND

Pediatric cancer‐related fatigue is prevalent and significantly impairs health‐related quality of life, yet its patterns and correlates are poorly understood. The objectives of this study were to describe fatigue as prospectively reported by children with advanced cancer and to identify the factors associated with fatigue and associated distress.

METHODS

Children (age ≥2 years) with advanced cancer (N = 104) or their parents at 3 academic hospitals reported symptoms at most weekly over 9 months using the computer‐based Pediatric Quality of Life Evaluation of Symptoms Technology (PediQUEST) system. PediQUEST administered a modified version of the Memorial Symptom Assessment Scale (PQ‐MSAS) as part of a randomized controlled trial. Clinical information was abstracted from medical records. Primary outcomes were: 1) fatigue prevalence (yes/no response to PQ‐MSAS fatigue item) and 2) fatigue distress (composite score of severity, frequency, and bother). Multivariable models were constructed to identify factors independently associated with fatigue prevalence and scores reflecting fatigue distress (ie, burden).

RESULTS

Of 920 reports, 46% (n = 425) noted fatigue. When reported, fatigue was of high frequency in 41% of respondents (n = 174), severity in 25%of respondents (n = 107), and bother in 34%of respondents (n = 143). Most reports (84%; n = 358) were associated with scores indicating fatigue distress. In multivariable analyses, fatigue was associated with older age, lower hemoglobin, and distress from particular symptoms (anorexia, nausea, sleep disturbance, sadness, and irritability). In contrast, fatigue distress was associated with distress from nausea, cough, and pain.

CONCLUSIONS

Fatigue is common among children with advanced cancer and is often highly distressing. Interventions focused on uncontrolled symptoms may ease fatigue distress in children with advanced cancer.
Phase 1 study of EGFR‐antisense DNA, cetuximab, and radiotherapy in head and neck cancer with preclinical correlatives
Authors: Bauman Julie E. , Duvvuri Umamaheswar , Thomas Sufi , Gooding William E. , Clump David A. , Karlovits Brian , Wehbe Ahmad , Miller Frank R. , Kim Seungwon , Sen Malabika , Heron Dwight E. , Grandis Jennifer R. , Argiris Athanassios
Published: October 2018

BACKGROUND

Cetuximab combined with radiation therapy (RT) is an evidence‐based treatment for locally advanced head and neck squamous cell carcinoma (HNSCC); however, locoregional failure remains the primary cause of cancer‐related death in this disease. Intratumoral injection of epidermal growth factor receptor (EGFR)‐antisense plasmid DNA (EGFR‐AS) is safe and has been associated with promising lesional responses in patients who have recurrent/metastatic HNSCC. For the current study, the authors investigated the antitumor effects of cetuximab and EGFR‐AS in preclinical HNSCC models and reported their phase 1 experience adding intratumoral EGFR‐AS to cetuximab RT.

METHODS

Antitumor mechanisms were investigated in cell line and xenograft models. Phase 1 trial eligibility required stage IVA through IVC HNSCC and a measurable lesion accessible for repeat injections. Patients received standard cetuximab was for 9 weeks. EGFR‐AS was injected weekly until they achieved a lesional complete response. RT was delivered by conventional fractionation for 7 weeks, starting at week 3. Research biopsies were obtained at baseline and week 2.

RESULTS

When added to cetuximab, EGFR‐AS decreased cell viability and xenograft growth compared with EGFR‐sense control, partially mediated by reduced EGFR expression. Six patients were enrolled in the phase 1 cohort. No grade 2 or greater EGFR‐AS–related adverse events occurred. The best lesional response was a complete response (4 patients), and 1 patient each had a partial response and disease progression. EGFR expression decreased in 4 patients who had available paired specimens.

CONCLUSIONS

In preclinical models, dual EGFR inhibition with cetuximab and EGFR‐AS enhanced antitumor effects. In a phase 1 cohort, intratumoral EGFR‐AS injections, cetuximab, and RT were well tolerated. A phase 2 trial is needed to conduct an extended evaluation of safety and to establish efficacy.
Optimal treatment of early stage HER2‐positive breast cancer
Authors: Pernas Sonia , Barroso‐Sousa Romualdo , Tolaney Sara M.
Published: October 2018

Significant advances have occurred in the treatment of human epidermal growth factor receptor 2 (HER2)‐positive breast cancer that have changed its natural history. The addition of trastuzumab to standard therapy has dramatically improved the prognosis for patients with early stage, HER2‐positive breast cancer to unprecedented survival outcomes. Yet, long‐term follow‐up data from adjuvant pivotal trials indicate that 15‐24% of patients still develop recurrent disease. Most of the research has focused on the addition of novel anti‐HER2 drugs to standard therapy, including studies evaluating the monoclonal antibody pertuzumab; the antibody‐drug conjugate trastuzumab‐emtansine (T‐DM1); the selective, reversible HER2/epidermal growth factor receptor kinase inhibitor lapatinib; or the irreversible pan‐HER2 inhibitor neratinib. Dual HER2 blockade has improved overall survival remarkably in metastatic breast cancer; however, in patients with early stage disease, it has led to small benefits in progression‐free survival. Moreover, biologic heterogeneity within HER2‐positive disease may determine response to treatment and prognosis. Different subgroups of patients with HER2‐positive breast cancer may benefit from different therapeutic approaches. Thus, there is ongoing work to optimize and de‐escalate treatment in patients who may do just as well with less therapy and can avoid unnecessary treatments and their related toxicities. The objective of this review is to summarize the background and latest evidence on the current management of early stage, HER2‐positive breast cancer and to present novel perspectives on its management.
Toward the potential cure of leukemias in the next decade
Authors: Kantarjian Hagop M. , Keating Michael J. , Freireich Emil J
Published: October 2018

Historically, progress in leukemia research has been slow, but it has accelerated recently as a result of understanding the pathophysiology of leukemias and implementing more effective and targeted therapies. This review summarizes the progress across leukemia subsets and projects the potential cure of most leukemias in the next decade.
Enrollment on clinical trials does not improve survival for children with acute myeloid leukemia: A population‐based study
Authors: Truong Tony H. , Pole Jason D. , Barber Randy , Dix David , Kulkarni Ketan P. , Martineau Emilie , Randall Alicia , Stammers David , Strahlendorf Caron , Strother Douglas , Sung Lillian
Published: October 2018

Background

It is questionable whether enrollment on clinical trials offers any survival advantage at the population level over standard‐of‐care treatment. The objectives of this study were to describe the impact of trial enrollment on event‐free survival and overall survival in pediatric acute myeloid leukemia (AML) using the Cancer in Young People in Canada (CYP‐C) database.

Methods

Children were included if they had had AML newly diagnosed between ages birth and 14 years from 2001 to 2012. CYP‐C is a national pediatric cancer population‐based database that includes all cases of pediatric cancer diagnosed and treated at 1 of the 17 tertiary pediatric oncology centers in Canada. Univariate and Cox proportional hazards models were used to evaluate the impact of initial trial enrollment on survival.

Results

In total, 397 eligible children with AML were included in the analysis, of whom 94 (23.7%) were enrolled on a clinical trial at initial diagnosis. The most common reason for non‐enrollment was that no trial was available. The event‐free survival rate at 5 years was 57.8% ± 5.2% for those enrolled versus 54.8% ± 2.9% for those not enrolled (P = .75). The overall survival rate at 5 years was 70.1% ± 4.9% for those enrolled versus 66.3% ± 2.8% for those not enrolled (P = .58). Enrollment on a trial was not associated with improved event‐free or overall survival in multiple regression analyses.

Conclusions

Enrollment on a clinical trial was not associated with improved survival for children with AML in a population‐based cohort. Rationale for trial enrollment should not include the likelihood of benefit compared with non‐enrollment.
Individualized survival prediction for patients with oropharyngeal cancer in the human papillomavirus era
Authors: Beesley Lauren J. , Hawkins Peter G. , Amlani Lahin M. , Bellile Emily L. , Casper Keith A. , Chinn Steven B. , Eisbruch Avraham , Mierzwa Michelle L. , Spector Matthew E. , Wolf Gregory T. , Shuman Andrew G. , Taylor Jeremy M. G.
Published: October 2018

Background

Accurate, individualized prognostication in patients with oropharyngeal squamous cell carcinoma (OPSCC) is vital for patient counseling and treatment decision making. With the emergence of human papillomavirus (HPV) as an important biomarker in OPSCC, calculators incorporating this variable have been developed. However, it is critical to characterize their accuracy prior to implementation.

Methods

Four OPSCC calculators were identified that integrate HPV into their estimation of 5‐year overall survival. Treatment outcomes for 856 patients with OPSCC who were evaluated at a single institution from 2003 through 2016 were analyzed. Predicted survival probabilities were generated for each patient using each calculator. Calculator performance was assessed and compared using Kaplan‐Meier plots, receiver operating characteristic curves, concordance statistics, and calibration plots.

Results

Correlation between pairs of calculators varied, with coefficients ranging from 0.63 to 0.90. Only 3 of 6 pairs of calculators yielded predictions within 10% of each other for at least 50% of patients. Kaplan‐Meier curves of calculator‐defined risk groups demonstrated reasonable stratification. Areas under the receiver operating characteristic curve ranged from 0.74 to 0.80, and concordance statistics ranged from 0.71 to 0.78. Each calculator demonstrated superior discriminatory ability compared with clinical staging according to the seventh and eighth editions of the American Joint Committee on Cancer staging manual. Among models, the Denmark calculator was found to be best calibrated to observed outcomes.

Conclusions

Existing calculators exhibited reasonable estimation of survival in patients with OPSCC, but there was considerable variability in predictions for individual patients, which limits the clinical usefulness of these calculators. Given the increasing role of personalized treatment in patients with OPSCC, further work is needed to improve accuracy and precision, possibly through the identification and incorporation of additional biomarkers.
A taxonomy of various attacks on smart card–based applications and countermeasures
Authors: Gupta B.B. , Quamara Megha
Published: October 2018

Deployment of smart card–based applications is becoming prevalent these days. Security of these applications depends upon the nature of underlying hardware and software platforms, cryptographic algorithms, along with a number of other security mechanisms. To develop a secure smart card–based application, preliminary evaluation of the security of embedded software as well as how that software will work in real time is required. Over the past few years, significant improvements have been made in smart card technology for its large‐scale acceptance. However, attackers are in continuous search for exploiting the unknown issues related to this technology. This survey discusses smart card technology in detail and provides a comprehensive taxonomy of security attacks on smart card–based applications and their countermeasures. In addition, it covers some of the open source tools available for its development. Finally, it provides a brief outline of some of the major open challenges and future research directions that are yet to be explored.
Explaining the Different Geometries of the Water Oxidising Complex in the Nominal S3 State Crystal Structures of Photosystem II at 2.25 Å and 2.35 Å
Authors: Petrie Simon , Stranger Robert , Pace Ron J.
Published: October 2018

Recently two atomic resolution crystal structures of Photosystem II, in the double flashed, nominal S3 intermediate state of its Mn4Ca water oxidising complex (WOC), have been presented (Young et al., Nature 2016, 540, 453; Suga et al., Nature 2017, 543, 131). These structures are at 2.25 Å and 2.35 Å resolution, respectively. Although highly similar in most respects, the structures differ in a key region within the WOC catalytic site. In the 2.25 Å structure, one oxy species (O5) is observed within the WOC cavity, weakly associated with the Mn centres, similar to that seen earlier in the 1.95 Å XRD structure of the S1 intermediate (Suga et al., Nature, 2015, 517, 99). In the 2.35 Å structure, two such species are seen (O5, O6), with the Mn centres and O5 positioned as in the 2.25 Å structure and an O5–O6 separation of ∼1.5 Å, consistent with peroxo formation. This suggests O5 and O6 are substrate water derived species in this double flashed form. Recently we have presented (Petrie, et al., Chem. Phys. Chem., 2017) a large scale (220 atom) quantum chemical model of the Young et al. 2.25 Å structure, which quantitatively explains all significant features within the WOC region of that structure, particularly the positions of the metal centres and O5 group. Critical to this was our assumption of a ‘low’ Mn oxidation paradigm (mean S1 Mn oxidation level of +3.0, Petrie et al., Angew. Chem. Int. Ed., 2015), rather than a ‘high’ oxidation model (mean S1 oxidation level of +3.5), widely assumed in the literature. Here we show that our same oxidation state model predicts two classes of energetically close S3 structural forms, analogous to the S1 state, one with the metal centres and O5 positioned as in the 2.25 Å structure, and the other with the metals similarly placed, but with O5 located in the O6 position of the 2.35 Å structure. We show that the Suga et al. 2.35 Å structure is likely a superposition of two such forms, one from each class, which is consistent with reported atomic occupancies for that structure and the relative total energies we calculate for the two structural forms.
Effect of Substitution Pattern of tert‐Butyl Groups in a Bisbenzofuropyrazine Core π‐System on Optical Properties: Unique Mechanochromic Fluorescence Behavior
Authors: Nakamura Shotaro , Tohnai Norimitsu , Nishii Yuji , Hinoue Tomoaki , Miura Masahiro
Published: October 2018

Bisbenzofuro[2,3‐b : 2′,3′‐e]pyrazine (BBFPy) and its 2,8‐ and 3,9‐di(tert‐butyl)‐substituted derivatives (2 a and 2 b) were synthesized by palladium‐catalyzed intramolecular direct arylation as the key step. The effect of introduction of two tert‐butyl groups to the BBFPy core at the different positions on the fluorescent properties was then investigated. The tert‐butyl groups not only enhance the tractability with increasing solubility, but also induce different crystal‐packing patterns as anticipated. The compounds 2 a and 2 b show relatively strong blue fluorescence in both the solution and solid state. The 2,8‐isomer 2 a specifically exhibits a unique mechanochromism in the solid state; 2 a exhibits two crystalline forms, both of which show green fluorescence by grinding, while different self‐recovering fluorescence patterns between them are observed by standing. The intriguing mechanochromism is rationally interpreted in terms of molecular arrangements determined by X‐ray crystallography.
C@TiO2/MoO3 Composite Nanofibers with 1T‐Phase MoS2 Nanograin Dopant and Stabilized Interfaces as Anodes for Li‐ and Na‐Ion Batteries
Authors: Zhou Huimin , Xia Xin , Lv Pengfei , Zhang Jin , Hou Xuebin , Zhao Min , Ao Kelong , Wang Di , Lu Keyu , Qiao Hui , Zimniewska Malgorzata , Wei Qufu
Published: October 2018

Integrating layered nanostructured MoS2 with a structurally stable TiO2 backbone to construct reciprocal MoS2/TiO2‐based nanocomposites is an effective strategy. C@TiO2/MoO3 composite nanofibers doped with 1T‐phase MoS2 nanograins were fabricated by partially sulfurizing MoOx/TiO2 precursors. By controlling a suitable preoxidation temperature before severe thermolysis of polyvinylpyrrolidone (PVP), the MoOx/TiO2 precursors formed a polymer‐embedded array through coordination of the Mo source and pyrrolidyl groups of PVP. Sulfidation under water/solvent hydrothermal conditions led to partial formation of metallic 1T‐phase MoS2 from the MoOx precursor with preoxidation at 200 °C. After carbonization, the TiO2/MoO3/MoS2 nanograins were encapsulated in a carbon backbone in a vertical pattern, providing both chemical contact for confined electron transport and sufficient space to adapt to volume changes. The obtained carbon‐based platform not only has the advantages of an integral structure, but also exhibited ultrastable specific capacities of 540 and 251 mAh g−1 for Li‐ion batteries and Na‐ion batteries, respectively, after 100 cycles.
Investigation of the Reaction Pathways of Biomass‐Derived Oxygenate Conversion into Monoalcohols in Supercritical Methanol with CuMgAl‐Mixed‐Metal Oxide
Authors: Galebach Peter H. , Thompson Sean , Wittrig Ashley M. , Buchanan J. Scott , Huber George W.
Published: October 2018

Reaction pathways for the conversion of cellulose into C2–C6 monoalcohols by supercritical methanol depolymerization and hydrodeoxygenation (SCM‐DHDO) over a CuMgAl oxide catalyst have been elucidated using a range of model compounds. SCM‐DHDO of intermediate oxygenates including glycerol, methyl lactate, and 1,2‐ethanediol produces similar products as those produced from the SCM‐DHDO of cellulose. The pathway to C2–C6 monoalcohols occurs through rapid C−C coupling reactions between methanol and diols followed by C−C scission between vicinal alcohol groups to produce two monoalcohols. Methyl‐branched monoalcohols are produced through a methyl shift in a secondary diol followed by dehydration. Esters are produced by dehydrogenative coupling between an adsorbed methoxy and a primary alcohol. Both dehydrogenation to a ketone and esterification to a methyl ester are in equilibrium with the corresponding alcohol and were reversible. Dehydration of diols is the slowest observed reaction and not a main pathway to monoalcohols. SCM‐DHDO of glucose, dihydroxyacetone, and cellulose all produced similar high molecular weight species indicating that condensation of intermediates can produce undesired side products.