bluuebunny/crossref_metadata_2025 huggingface dataset:
Long‐Term Oxygen Storage Nanosystem for Near‐Infrared Light‐Triggered Oxygen Supplies to Antagonize Hypoxia‐Induced Therapeutic Resistance in Nasopharyngeal Carcinoma
Authors: You Yuanyuan , Zhao Zhennan , He Lizhen , Sun Zhibo , Zhang Dong , Shi Changzheng , Cheng Qingqing , Liu Yiyong , Luo Liangping , Chen Tianfeng
Published: May 2020

O2‐delivering nanosystems have been used to antagonize hypoxia‐induced tumor therapeutic resistance. However, short‐time oxygen storage is still a bottleneck for these O2‐delivering nanosystems, which results in a decrease in blood circulation time and accumulation of oxygen in tumors, thus reducing the tumor therapeutic efficacy. Herein, a long‐term oxygen storage nanosystem (O2‐PIr@Si@PDA) is designed to overcome hypoxia for the treatment of nasopharyngeal carcinoma. This nanosystem is constructed by using perfluorooctyl bromide (PFOB) core as the oxygen carrier, functionalized with an oxygen sensitive probe (Ir(III) complex) and subsequently enclosed with an ultrathin‐walled silica shell. Due to the silica shell, this nanosystem can store oxygen for longer than 7 days. The oxygen in the O2‐PIr@Si@PDA nanosystem can be released quickly with the temperature‐responsive rupture of the silicon shell under near‐infrared (NIR) irradiation. The oxygen storage and release can be self‐monitored using the Ir(III) complex with its luminescence effect. As expected, this multifunctional nanosystem in combination with NIR irradiation not only inhibits tumor growth by alleviating hypoxia, but also enhances the effect of oxygen‐sensitized radiotherapy against nasopharyngeal carcinoma. Taken together, this study offers a novel strategy for designing long‐term oxygen storing nanosystem to relieve tumor hypoxia, thus improving the precise cancer therapeutic efficacy.
Pinecone‐Inspired Nanoarchitectured Smart Microcages Enable Nano/Microparticle Drug Delivery
Authors: Zhang Shichao , Zhou Sheng , Liu Hui , Xing Malcolm , Ding Bin , Li Bingyun
Published: May 2020

Drug delivery plays a vital role in medicine and health, but the on‐demand delivery of large‐sized drugs using stimuli‐triggered carriers is extremely challenging. Most present capsules consist of polymeric dense shells with nanosized pores (<10 nm), thus typically lack permeability for nano/microparticle drugs. Here, a pinecone‐inspired smart microcage with open network shells, assembled from cellulose nanofibrils (CNFs), is reported for nano/microparticle drug delivery. The approach allows the nanoarchitectured, functionalized CNFs to assemble into mechanically robust, haystack‐like network shells with tunable large‐through pores and polypeptide‐anchored points on a large scale. Such open network shells can intelligently open/close triggered by lesion stimuli, making the therapy “always on‐demand.” The resulting pinecone‐inspired microcages exhibit integrated properties of superior structural stability, superhydrophilicity, and pH‐triggered, smart across‐shell transport of emerging antimicrobial silver nanoparticles and bioactive silicate nanoplatelets (sizes of >100 nm), which enable both extraordinary anti‐infection and bone regeneration. This work provides new insights into the design and development of multifunctional encapsulation and delivery carriers for medical and environmental applications.
The Electron–Phonon Interaction of Low‐Dimensional and Multi‐Dimensional Materials from He Atom Scattering
Authors: Benedek Giorgio , Manson Joseph R. , Miret‐Artés Salvador
Published: May 2020

Atom scattering is becoming recognized as a sensitive probe of the electron–phonon interaction parameter λ at metal and metal‐overlayer surfaces. Here, the theory is developed, linking λ to the thermal attenuation of atom scattering spectra (in particular, the Debye–Waller factor), to conducting materials of different dimensions, from quasi‐1D systems such as W(110):H(1 × 1) and Bi(114), to quasi‐2D layered chalcogenides, and high‐dimensional surfaces such as quasicrystalline 2ML‐Ba(0001)/Cu(001) and d‐AlNiCo(00001). Values of λ obtained using He atoms compare favorably with known values for the bulk materials. The corresponding analysis indicates in addition, the number of layers contributing to the electron–phonon interaction, which is measured in an atom surface collision.
Ruthenium‐Catalyzed meta‐Selective C−H Nitration of Biologically Important Aryltetrazoles
Authors: Chen Jian , Huang Tianle , Gong Xinrui , Yu Zhu‐Jun , Shi Yuesen , Yan Yu‐Hang , Zheng Yang , Liu Xuexin , Li Guo‐Bo , Wu Yong
Published: May 2020

The first example of tetrazole‐directed meta‐selective C−H nitration is described. This transformation provided a straightforward approach for the synthesis of biologically important m‐nitroaryltetrazoles in moderate to excellent yields with good functional group compatibility. In addition, new metallo‐β‐lactamase inhibitors were obtained by further transformation of the synthesized m‐nitroaryltetrazoles.

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Thermoelectric Enhancements in PbTe Alloys Due to Dislocation‐Induced Strains and Converged Bands
Authors: Wu Yixuan , Nan Pengfei , Chen Zhiwei , Zeng Zezhu , Liu Ruiheng , Dong Hongliang , Xie Li , Xiao Youwei , Chen Zhiqiang , Gu Hongkai , Li Wen , Chen Yue , Ge Binghui , Pei Yanzhong
Published: May 2020

In‐grain dislocation‐induced lattice strain fluctuations are recently revealed as an effective avenue for minimizing the lattice thermal conductivity. This effect could be integratable with electronic enhancements such as by band convergence, for a great advancement in thermoelectric performance. This motivates the current work to focus on the thermoelectric enhancements of p‐type PbTe alloys, where monotelluride‐alloying and Na‐doping are used for a simultaneous manipulation on both dislocation and band structures. As confirmed by synchrotron X‐ray diffractions and Raman measurements, the resultant dense in‐grain dislocations induce lattice strain fluctuations for broadening the phonon dispersion, leading to an exceptionally low lattice thermal conductivity of ≈0. 4 W m‐K−1. Band structure calculations reveal the convergence of valence bands due to monotelluride‐alloying. Eventually, the integration of both electronic and thermal improvements lead to a realization of an extraordinary figure of merit zT of ≈2.5 in Na0.03Eu0.03Cd0.03Pb0.91Te alloy at 850 K.
Management strategies for early‐ and late‐planted soybean in the north‐central United States
Authors: Matcham Emma G. , Mourtzinis Spyridon , Conley Shawn P. , Rattalino Edreira Juan I. , Grassini Patricio , Roth Adam C. , Casteel Shaun N. , Ciampitti Ignacio A. , Kandel Hans J. , Kyveryga Peter M. , Licht Mark A. , Mueller Daren S. , Nafziger Emerson D. , Naeve Seth L. , Stanley Jordan D. , Staton Michael J. , Lindsey Laura E.
Published: May 2020

It is widely recognized that planting soybean [Glycine max (L.) Merr.] early is critical to maximizing yield, but the influence of changing management factors when soybean planting is delayed is not well understood. The objectives of this research were to (a) identify management decisions that increase seed yield in either early‐ or late‐planted soybean scenarios, and (b) estimate the maximum break‐even price of each management factor identified to influence soybean seed yield in early‐ or late‐planted soybean. Producer data on seed yield and management decisions were collected from 5682 fields planted with soybean during 2014−2016 and grouped into 10 technology extrapolation domains (TEDs) based on growing environment. A subsample of 1512 fields was classified into early‐ and late‐planted categories using terciles. Conditional inference trees were created for each TED to evaluate the effect of management decisions within the two planting date timeframes on seed yield. Management strategies that maximized yield and associated maximum break‐even prices varied across TEDs and planting date. For early‐planted fields, higher yields were associated with artificial drainage, insecticide seed treatment, and lower seeding rates. For late‐planted fields, herbicide application timing and tillage intensity were related to higher yields. There was no individual management decision that consistently increased seed yield across all TEDs.
Modeling and simulation of gas separations with spiral‐wound membranes
Authors: DeJaco Robert F. , Loprete Kenneth , Pennisi Kenneth , Majumdar Sudip , Siepmann J. Ilja , Daoutidis Prodromos , Murnen Hannah , Tsapatsis Michael
Published: May 2020

Models for gas separations with spiral‐wound membranes are developed and found to exhibit good agreement with experiments performed on N2/O2 mixtures. The two‐dimensional (2D) model can be accurately approximated by a one‐dimensional (1D) surrogate model when the spacer widths are chosen to make the channel pressure drops small. Subsequently, the separation of propane/propylene mixtures from the recycle purge stream of a polypropylene reactor is investigated. Assuming ideal gas is found to lead to significant overestimations in membrane stage cuts (sometimes more than 10%), an extent comparable to that associated with extrapolating constant olefin permeance from a low‐pressure condition. While olefin permeance can change significantly with pressure, using a constant‐permeance formulation can result in a small (< 2.5%) underprediction in stage cut if the value for the permeance is taken from the feed condition. Finally, membrane properties and costs necessary for a viable separation process are discussed.
Shortfall of exome analysis for diagnosis of Shwachman‐Diamond syndrome: Mismapping due to the pseudogene SBDSP1
Authors: Yamada Mamiko , Uehara Tomoko , Suzuki Hisato , Takenouchi Toshiki , Inui Ayano , Ikemiyagi Masako , Kamimaki Isamu , Kosaki Kenjiro
Published: May 2020

Shwachman‐Diamond syndrome characterized by metaphyseal dysplasia, pancreatic insufficiency, and pancytopenia is caused by biallelic mutations in SBDS. Gene conversion between SBDS and its pseudogene SBDSP1 is the major cause. Here, we report two unrelated patients with Shwachman‐Diamond syndrome who were shown to be compound heterozygotes for relatively frequent pathogenic alleles (the 258+2T>C allele and another allele composed of 183‐184TA>CT and 201A>G) using an established polymerase chain reaction sequencing assay with SBDS‐specific primers. Exome analysis of the patients showed discrepant results: 258+2T>C with variant allele frequency around 0.85, and no variants detected for the 183‐184TA>CT allele. Parental exome analysis of the two families further supported this notion. Confronted with two patients with an unexpected segregation pattern, we performed a transcriptome analysis of peripheral blood‐derived mRNA to demonstrate that the results were compatible with those obtained using SBDS‐specific PCR primers. Both alleles could be accounted for by gene conversion events. The diagnostic discrepancy can be accounted for by a decreased efficiency in the computational mapping of the reads with 183‐184TA>CT and 201A>G to the reference sequence of the SBDS locus during exome analysis. This report highlights the pitfall of exome analysis for genes with pseudogenes, such as SBDS and the alternative use of RNA‐seq is recommended to circumvent this problem.
Germ cell loss in Klinefelter syndrome: When and why?
Authors: Willems Margo , Gies Inge , Van Saen Dorien
Published: May 2020

Klinefelter syndrome (KS) is a quite common disorder with an incidence of 1–2 in 1,000 new‐born males. Most patients are diagnosed in the light of a clinical checkup when consulting a fertility clinic with an unfulfilled child wish. Infertility in KS patients is caused by a massive germ cell loss, leading to azoospermia in more than 90% of the adult patients. Most seminiferous tubules in the adult KS testis are degenerated or hyalinized and testicular fibrosis can be observed, starting from puberty. However, focal spermatogenesis can be found in the testis of some patients. This offers the opportunity to extract spermatozoa from the testis by testicular sperm extraction (TESE). Nevertheless, TESE is only successful in about half of the KS adults seeking to father children. The reason for the germ cell loss remains unclear. To date, it is still debated whether the testicular tissue changes and the germ cell loss seen in KS is directly caused by an altered X‐linked gene expression, the altered somatic environment, or a deficiency in the germ cells. In this review, we provide an overview of the current knowledge about the germ cell loss in KS patients.
Development of CDK2 and CDK5 Dual Degrader TMX‐2172
Authors: Teng Mingxing , Jiang Jie , He Zhixiang , Kwiatkowski Nicholas P. , Donovan Katherine A. , Mills Caitlin E. , Victor Chiara , Hatcher John M. , Fischer Eric S. , Sorger Peter K. , Zhang Tinghu , Gray Nathanael S.
Published: May 2020

Cyclin‐dependent kinase 2 (CDK2) is a potential therapeutic target for the treatment of cancer. Development of CDK2 inhibitors has been extremely challenging as its ATP‐binding site shares high similarity with CDK1, a related kinase whose inhibition causes toxic effects. Here, we report the development of TMX‐2172, a heterobifunctional CDK2 degrader with degradation selectivity for CDK2 and CDK5 over not only CDK1, but transcriptional CDKs (CDK7 and CDK9) and cell cycle CDKs (CDK4 and CDK6) as well. In addition, we demonstrate that antiproliferative activity in ovarian cancer cells (OVCAR8) depends on CDK2 degradation and correlates with high expression of cyclin E1 (CCNE1), which functions as a regulatory subunit of CDK2. Collectively, our work provides evidence that TMX‐2172 represents a lead for further development and that CDK2 degradation is a potentially valuable therapeutic strategy in ovarian and other cancers that overexpress CCNE1.
Iron in a Cage: Fixation of a Fe(II)tpy2 Complex by Fourfold Interlinking
Authors: Brandl Thomas , Johannsen Sven , Häussinger Daniel , Suryadevara Nithin , Prescimone Alessandro , Bernhard Stefan , Gruber Manuel , Ruben Mario , Berndt Richard , Mayor Marcel
Published: May 2020

The coordination sphere of the Fe(II) terpyridine complex 1 is rigidified by fourfold interlinking of both terpyridine ligands. Profiting from an octa‐aldehyde precursor complex, the ideal dimensions of the interlinking structures are determined by reversible Schiff‐base formation, before irreversible Wittig olefination provided the rigidified complex. Reversed‐phase HPLC enables the isolation of the all‐trans isomer of the Fe(II) terpyridine complex 1, which is fully characterized. While temperature independent low‐spin states were recorded with superconducting quantum interference device (SQUID) measurements for both, the open precursor 8 and the interlinked complex 1, evidence of the increased rigidity of the ligand sphere in 1 was provided by proton T2 relaxation NMR experiments. The ligand sphere fixation in the macrocyclized complex 1 even reaches a level resisting substantial deformation upon deposition on an Au(111) surface, as demonstrated by its pristine form in a low temperature ultra‐high vacuum scanning tunneling microscope experiment.
A new nanocomposite catalyst based on clay‐supported heteropolyacid for the green synthesis of 2,4,5‐trisubstituted imidazoles
Authors: Masteri‐Farahani M. , Ezabadi A. , Mazarei R. , Ataeinia P. , Shahsavarifar S. , Mousavi F.
Published: May 2020

Intercalation of cetyltrimethylammonium (CTA+) cations within the nanolayers of montmorillonite (MMT) clay followed by reaction with Keggin‐type phosphomolybdic acid (PMo) resulted in the synthesis of (CTA)3PMo‐MMT nanocomposite catalyst. The prepared nanocomposite catalyst was characterized using different physicochemical methods such as Fourier‐transform infrared and inductively coupled plasma–optical emission spectroscopies, X‐ray diffraction, and nitrogen adsorption–desorption (Brunauer–Emmett–Teller method) analyses. Characterization techniques demonstrated the intercalation of (CTA)3PMo species into the nanolayers of MMT. The resulting (CTA)3PMo‐MMT nanocomposite catalyst efficiently catalyzed the synthesis of 2,4,5‐trisubstituted imidazoles under solvent‐free conditions. The efficiency is due to the fact that the presence of CTA+ species makes the nanocomposite catalyst hydrophobic and facilitates the accessibility of hydrophobic reactants to active sites in the course of the reaction. High activity and selectivity were achieved in the presence of the prepared nanocomposite catalyst. The nanocomposite catalyst was readily isolated from the reaction mixture using simple filtration, washed with ethanol, and recycled five times without a major loss of activity.
The influence of ultrasonic irradiation on catalytic performance of ZnO nanoparticles toward the synthesis of chiral 1‐substituted‐1H‐tetrazolederivatives from α‐amino acid ethyl esters
Authors: Mohamed Yasser Mahmoud A. , Attia Yasser A.
Published: May 2020

In this work, a simple and greener protocol for the synthesis of 1‐substituted 1H‐tetrazole derived from α‐amino acid ethyl esters was demonstrated in the presence of zinc oxide nanoparticles (ZnO NPs) under conventional conditions, with heating (at 60 and 80°C and under reflux) compared with ultrasonic. The effect of solvent was investigated to reveal that the solvent system CH3CN/H2O was optimum to obtain 1‐substituted 1H‐tetrazole in high yield. In addition, the effect of irradiation power was studied, which showed that the yield of the reaction was improved at 200 W and the reaction time was shortened to be 30 min. Also, an improvement in the rate of the reaction and the yield of the products was observed when reactions were carried out under sonication conditions in the presence of ZnO NPs compared with conventional methods using various zinc salts as catalysts. The yields of tetrazole compounds 2a–i under sonication were determined (88–96%). Furthermore, the investigated heterogeneous catalytic system was recycled and reused for five runs with significant production of tetrazole 2a as a model target compound in excellent yields at each reaction cycle. In general, the investigated synthetic strategy for the heterocyclization of α‐amino acid ethyl ester derivatives to 1‐substituted 1H‐tetrazoles was in agreement with the green chemistry point of view.
Radiosynthesis and evaluation of novel [99mTc(I)]+ and [99mTc(I)(CO)3]+ complexes with a 4‐nitroimidazole isocyanide for imaging tumor hypoxia
Authors: Ruan Qing , Zhang Xuran , Zhang Junbo
Published: May 2020

[99mTc(I)]+ and [99mTc(I)(CO)3]+ complexes with isocyanide exhibit high stability, which makes them suitable platforms to develop novel 99mTc radiopharmaceuticals. To develop novel 99mTc radiotracers for imaging hypoxia, in this study, a novel L ligand (4‐nitroimidazole isocyanide derivative) was synthesized and labelled using [99mTc(I)]+ core and [99mTc(I)(CO)3]+ core to produce [99mTc(L)6]+ and [99mTc(CO)3(L)3]+ with high yields. To verify the structure of the 99mTc complexes, corresponding rhenium analogues were synthesized and characterized. Both of the 99mTc complexes were stable and hydrophilic. in vitro cellular uptake results showed they could exhibit good hypoxic selectivity. The evaluation of biodistribution in mice bearing S180 tumors indicated both of them could accumulate in tumor. Between them, [99mTc(L)6]+ exhibited higher tumor uptake and tumor/non‐target ratio than [99mTc(CO)3(L)3]+. Further, single photon emission computed tomography (SPECT) imaging studies of [99mTc(L)6]+ indicated an obvious accumulation in tumor and the value of the region‐of‐interest (ROI) ratio of the uptake for the tumor site to the corresponding non‐tumor region was 5.64 ± 0.52. The above results suggested [99mTc(L)6]+ would be a potential tracer for imaging tumor hypoxia.
Construction of layer‐by‐layer assembled green coating on titanate nanotubes to improve the flame retardancy of epoxy resin
Authors: Pan Haifeng , Ma Wenbin , Zhang Zinan , Liu Yifan , Lu Fuqiang , Yu Bihao
Published: May 2020

In this study, phosphorus‐modified titania nanotubes (CH/PT‐TNTs) were obtained through the layer‐by‐layer assembly using titanium dioxide nanotubes (TNTs), Chitosan (CH) and synthetic phosphatized chitin (PT). Subsequently, CH/PT‐TNTs were incorporated into epoxy resin (EP) to improve the fire safety of epoxy resin. The results of TEM, FTIR, and XPS demonstrated that CH/PT coating was successfully constructed on the surface of TNTs. According to the results of Cone, the addition of CH/PT‐TNTs induced a significant improvement on the flame retardancy of EP, with only 2 wt% addition resulted in a remarkable reduction of peak heat release rate (48.8%) and total heat release (42.1%) compared to the pure EP, which is superior to TNTs at the same amount of addition. Moreover, the results of Raman spectroscopy indicated that the CH/PT coating helps to increase the degree of graphitization of the carbon layer. A possible flame‐retardant mechanism has been speculated on the synergistic effect between the CH/PT coating and the TNTs. Therefore, it is an effective method to improve the fire safety of epoxy resin, which provides a new idea for developing new environmentally friendly flame‐retardant epoxy resins.
A New Technique for In Situ Determination of the Active Surface Area Changes of Li–Ion Battery Electrodes
Authors: Ratynski Maciej , Hamankiewicz Bartosz , Buchberger Dominika A. , Boczar Maciej , Krajewski Michał , Czerwinski Andrzej
Published: May 2020

Li‐ion batteries have been of a great interest for over three decades. A geometric electrode surface area is generally used for Li‐ion electrochemical parameters calculations. Since the real electrode is a complex system composed of the thick porous structure, the contact surface area between the active mass and electrolyte is far larger than geometrical. This approximation leads to a large deviation of obtained results, especially within different laboratories and for volume and surface changing materials, e. g., silicon. The article presents a new method of in situ analysis of active surface area variations applicable for Li‐ion electrodes. The method relies on the electrochemical impedance spectroscopy measurement (EIS) performed at an arbitrarily chosen state of charge during superimposed DC current flow. The correlation between a local ion concentration with a charge transfer resistance allows to evaluate the differences of the active surface area. The presented method is not affected by the SEI layer presence, the material composition, nor the lithiation mechanism. Due to limited EIS frequency range the presented method can be performed with a relatively short time. Our new in situ surface area determination can greatly improve the accuracy of the electrochemical parameters evaluation and enable the proper result analysis. We believe that our method can become a standard procedure implemented in every research focusing on the electrochemical parameter determination of the volume changing active materials.
Routes through higher education: BME students and the development of a ‘specialisation of consciousness’
Authors: Bhopal Kalwant , Myers Martin , Pitkin Clare
Published: May 2020

With changing demographics and the advent of mass higher education, there has been a significant impact on graduate transitions which has led to greater inequalities in access to social support during the transitionary period between undergraduate study and entrance into the labour market. This article explores the experiences of students in their final year of undergraduate study by drawing on 43 interviews with Black and Minority Ethnic (BME) students. Using Bourdieu, we argue that BME students preparing to enter the labour market display a ‘specialisation of consciousness’: a set of practices framed by their prior background and experience, choice of university and the support derived from attending university. ‘Specialisation of consciousness’ is an ongoing process in which BME students identify and understand racial inequalities in higher education and accept the limiting consequences these have on transitions into the labour market or further study.
Exemplarity and education: Retuning educational research
Authors: Korsgaard Morten T.
Published: May 2020

This article explores the idea of exemplarity in relation to educational research and teacher education. Exemplarity is introduced as an alternative to the paradigm of evidence and ‘what works’, which seems to be omnipresent in educational research at present. The idea of exemplarity relates to the particularity of educational practice. The claim of this article is that we need to skew the dominance of functionalistic studies of education, which focus on skills and solutions to problems, or on providing quick fixes and methods to be applied in practice. I will argue that this tactic shuts down interpretive spaces and gives the teacher an illusion of simplicity and efficacy that connects poorly with the complexities of pedagogical practice. Exemplarity provides a different way of answering the question of ‘what works’, since it does not claim generalisability, but instead offers a path to reflective engagement with the complexities of educational processes. The idea of exemplarity highlights how educators can be invited to lend an ear to practical experience and pedagogical theorising, and through these develop their tact and reflective abilities through exemplars that display pedagogical principles. This, in turn, offers the possibility of retuning one’s practice, and in the scope of this article, retuning educational research itself.
Common Obstacles to Effective Incentive Comp
Authors: Milano Gregory V.
Published: May 2020

Gregory V. Milano is the founder and chief executive officer of Fortuna Advisors LLC, a New York City–based corporate strategy and consulting firm. The following article is adapted from his recent book Curing Corporate Short‐Termism: Future Growth vs. Current Earnings.
Alternatives to In‐Person Directors' Meetings
Authors: Polubinski Edmund
Published: May 2020

Edmund Polubinski, Jr. is a corporate lawyer at Lyne, Woodworth & Evarts LLP, a Boston‐based law firm. In this article, he notes the rise in virtual directors' meetings due to the COVID‐19 crisis and discusses how virtual meetings and several other alternatives to in‐person meetings can be a useful tool for many boards.
Assessment of synthetic cannabinoid FUB‐AMB and its ester hydrolysis metabolite in human liver microsomes and human blood samples using UHPLC–MS/MS
Authors: Presley Brandon C. , Castaneto Marisol S. , Logan Barry K. , Jansen‐Varnum Susan A.
Published: May 2020

FUB‐AMB, an indazole carboxamide synthetic cannabinoid recreational drug, was one of the compounds most frequently reported to governmental agencies worldwide between 2016 and 2019. It has been implicated in intoxications and fatalities, posing a risk to public health. In the current study, FUB‐AMB was incubated with human liver microsomes (HLM) to assess its metabolic fate and stability and to determine if its major ester hydrolysis metabolite (M1) was present in 12 authentic forensic human blood samples from driving under the influence of drug cases and postmortem investigations using UHPLC–MS/MS. FUB‐AMB was rapidly metabolized in HLM, generating M1 that was stable through a 120‐min incubation period, a finding that indicates a potential long detection window in human biological samples. M1 was identified in all blood samples, and no parent drug was detected. The authors propose that M1 is a reliable marker for inclusion in laboratory blood screens for FUB‐AMB; this metabolite may be pharmacologically active like its precursor FUB‐AMB. M1 frequently appears in samples in which the parent drug is undetectable and can point to the causative agent. The results suggest that it is imperative that synthetic cannabinoid laboratory assay panels include metabolites, especially known or potential pharmacologically active metabolites, particularly for compounds with short half‐lives.
The wasp venom antimicrobial peptide polybia‐CP and its synthetic derivatives display antiplasmodial and anticancer properties
Authors: Torres Marcelo D. T. , Silva Adriana F. , Andrade Gislaine P. , Pedron Cibele N. , Cerchiaro Giselle , Ribeiro Anderson O. , Oliveira Vani X. , de la Fuente‐Nunez Cesar
Published: May 2020

The wasp venom‐derived antimicrobial peptide polybia‐CP has been previously shown to exhibit potent antimicrobial activity, but it is also highly toxic. Previously, using a physicochemical‐guided peptide design strategy, we reversed its toxicity while preserving and even enhancing its antibacterial properties. Here, we report on several additional unanticipated biological properties of polybia‐CP and derivatives, namely their ability to target Plasmodium sporozoites and cancer cells. We leverage a physicochemical‐guided approach to identify features that operate as functional hotspots making these peptides viable antiplasmodial and anticancer agents. Helical content and net positive charge are identified as key structural and physicochemical determinants for antiplasmodial activity. In addition to helicity and net charge, hydrophobicity‐related properties of polybia‐CP and derivatives were found to be equally critical to target cancer cells. We demonstrate that by tuning these physicochemical parameters, it is possible to design synthetic peptides with enhanced submicromolar antiplasmodial potency and micromolar anticancer activity. This study reveals novel and previously undescribed functions for Polybia‐CP and analogs. Additionally, we demonstrate that a physicochemical‐guided rational design strategy can be used for identifying functional hotspots in peptide molecules and for tuning structure–function to generate novel and potent new‐to‐nature therapies.
Clinical characteristics and predictive factors of survival of 761 cancer patients on home parenteral nutrition: A prospective, cohort study
Authors: Cotogni Paolo , Monge Taira , Passera Roberto , Brossa Laura , De Francesco Antonella
Published: May 2020

Background

Robust data reporting the survival of cancer patients on home parenteral nutrition (HPN) are lacking. The aim of this prospective, cohort study was to investigate clinical characteristics, predictive factors, and overall survival (OS) of adult‐malnourished cancer patients eligible for HPN according to the European guideline recommendations.

Methods

During the study period, 1658 cancer patients were consecutively evaluated in a tertiary university hospital. Of these, 761 who received HPN were grouped into four cohorts according to the provision of supplemental PN (SPN) or total (TPN) and whether they received chemotherapy (CT+ or CT‐): SPN/CT+ (n = 376), TPN/CT+ (n = 99), SPN/CT‐ (n = 191), and TPN/CT‐ (n = 95). Patient demographics, nutritional status, cancer‐related characteristics, and prognostic scores assessed at HPN start. The primary outcome was OS.

Results

Median OS was 8.9, 4.3, 5.7, and 2.2 months for the SPN/CT+, TPN/CT+, SPN/CT‐, and TPN/CT‐ cohorts, respectively. In multivariable analysis, predictors showing significant association with decreased survival were patient cohorts, modified Glasgow Prognostic Score (1 and 2 scores), weight loss (>15%) in the 3 months before HPN start, and TNM IV stage while protective factors of survival were Karnofsky Performance Status (>50), albumin level (>3.5 g/dL), oral protein intake, BMI (>20.5), and weight at HPN start.

Conclusion

For the first time, in four different cohorts of cancer patients on HPN, clinical characteristics and survival were compared. This large study showed that survival is significantly correlated with patient characteristics at HPN start and that the presence of favorable factors may determine even a fourfold increase in survival. These data are expected to assist physicians in the appropriate prescription of HPN.
Chemical Composition and Bioactivities of Essential Oil from Leaves of Syzygium cumini (L.) Skeels Native to Punjab, Pakistan
Authors: Hanif Muhammad Usman , Hussain Abdullah Ijaz , Aslam Nosheen , Kamal Ghulam Mustafa , Chatha Shahzad Ali Shahid , Shahida Shabnam , Khalid Muhammad , Hussain Riaz
Published: May 2020

Herbal medicines are widely used for the treatment of different types of diseases like skin and throat infections and other diseases in developing countries. Syzygium cumini (L.) Skeels fruit, leaves and bark were used for the remedies of different diseases anciently. The aim of the present study was to evaluate the chemical profile of Syzygium cumini leaves essential oil (EO) from Punjab, Pakistan. The essential oil was isolated using hydrodistillation technique and analyzed by gas chromatography (GC) and gas chromatography‐mass spectrometry (GC/MS). Free radical scavenging capacity and antioxidant activity were assessed by using DPPH radical scavenging ability, inhibition of linoleic acid peroxidation, bleaching of β‐carotene in linoleic acid system and reducing power assays. Antimicrobial potential was assessed by disc diffusion assay and measurement of minimum inhibitory concentration (MIC) using resazurin microtiter‐plate assay. The anti‐heme biocrystallization activity of EO was also assessed. The major components (>3%) found in Syzygium cumini leaves EO were β‐farnesene (3.42 %), caryophyllenol (3.46 %), terpinen‐4‐ol (3.61 %), β‐myrcene (3.90 %), γ‐cadinene (4.09 %), fenchol (4.22 %), cis‐β‐ocimene (4.40 %) and 5‐methyl‐1,3,6‐heptatriene (4.90 %). Excellent antioxidant, antimicrobial and weak antimalarial potential was observed. It can be concluded that Syzygium cumini leaves EO has potential application for food and pharmaceutical industries.
Bacterial Cell Display as a Robust and Versatile Platform for Engineering Low‐Affinity Ligands and Enzymes
Authors: Csibra Eszter , Renders Marleen , Pinheiro Vitor B.
Published: May 2020

Directed evolution has been remarkably successful at expanding the chemical and functional boundaries of biology. That progress is heavily dependent on the robustness and flexibility of the available selection platforms, given the significant cost to (re)develop a given platform to target a new desired function. Bacterial cell display has a significant track record as a viable strategy for the engineering of mesophilic enzymes, as enzyme activity can be probed directly and free from interference from the cellular milieu, but its adoption has lagged behind other display‐based methods. Herein, we report the development of SNAP as a quantitative reporter for bacterial cell display, which enables fast troubleshooting and the systematic development of the display‐based selection platform, thus improving its robustness. In addition, we demonstrate that even weak interactions between displayed proteins and nucleic acids can be harnessed for the specific labelling of bacterial cells, allowing functional characterisation of DNA binding proteins and enzymes, thus making it a highly flexible platform for these biochemical functions. Together, this establishes bacterial display as a robust and flexible platform, ideally suited for the systematic engineering of ligands and enzymes needed for XNA molecular biology.
Mechanism of Palladium‐Catalyzed Spiroannulation of Naphthols with Alkynes: A Density Functional Theory Study
Authors: Luo Xiaoling , Zhong Kangbao , Lan Yu
Published: May 2020

Pd‐catalyzed spiroannulation of bromophenylnaphthalenols with acetylenes to achieve asymmetric dearomatization is a powerful way to construct chiral spiro‐compounds. DFT calculations with the M06 functional have been performed to reveal the mechanism and enantioselectivity of this reaction. After reversible oxidative addition of aryl bromide to Pd(0), acetylene insertion into the Pd−C(aryl) bond is considered to be the rate‐ and enantioselectivity determining step. Subsequent deprotonation and reductive elimination then give the spiroannulation product. The overlay and noncovalent interaction analysis of the critical transition states were used to reveal the origin of the enantioselectivity for this reaction. We found that the axial chirality of the naphthol moiety affects the relative free energies of the corresponding transition states, whereas the enantioselectivity is controlled by the steric repulsion between the naphthol moiety and the ligand.
Polystyrene‐Supported PPh3 in Monolithic Porous Material: Effect of Cross‐Linking Degree on Coordination Mode and Catalytic Activity in Pd‐Catalyzed C−C Cross‐Coupling of Aryl Chlorides
Authors: Matsumoto Hikaru , Hoshino Yu , Iwai Tomohiro , Sawamura Masaya , Miura Yoshiko
Published: May 2020

Hybridization of porous synthetic polymer and sophisticated ligands play an important role in transition‐metal catalysis for chemical transformations at laboratory and industrial levels. A monolithic porous polymer, which is a single piece with continuous macropores, is desired for high permeability, fast mass transfer properties, high stability, and easy modification. Herein, we first develop a monolithic porous polystyrene containing three‐fold cross‐linked PPh3 (M‐PS‐TPP) for transition‐metal catalysis. The monolithic and macroporous structure of M‐PS‐TPP was fabricated via polymerization‐induced phase separation using porogenic solvent. Moreover, the M‐PS‐TPP was synthesized using different feed ratios of divinylbenzene (DVB) for site‐isolation and mono‐P‐ligating behavior of PPh3. 31P CP/MAS NMR analysis revealed that the different selectivity of M‐PS‐TPPs was obtained in formation of mono‐P‐ligation toward PdII. The macroporous properties and controlled mono‐P‐ligating behavior of M‐PS‐TPP facilitated the challenging Pd‐catalyzed Suzuki‐Miyaura cross‐coupling reaction of chloroarenes.
Determining the Efficiency of Photoelectrode Materials by Coupling Cavity‐Microelectrode Tips and Scanning Electrochemical Microscopy
Authors: Visibile Alberto , Baran Tomasz , Rondinini Sandra , Minguzzi Alessandro , Vertova Alberto
Published: May 2020

Photoelectrochemical water splitting (PEC‐WS) is a promising route to obtain hydrogen (and oxygen) from sunlight and water. However, too many semiconductors show poor stability, due to photodegradation phenomena in aqueous solutions, thus loosing efficiency under operative conditions. Aim of this paper is to introduce a simple and fast method for screening different semiconductor materials and identify their efficiency in H2 (or O2) production with respect to photocorrosion. This method could be used with any finely dispersed semiconductor (powder) for a fast, preliminary evaluation of the material's behaviour without interferences from the supporting material (i. e. FTO) or any binder. The method is based on the combination of scanning electrochemical microscopy (SECM) in the tip generation/substrate collection (TG/SC) mode and of cavity microelectrodes as SECM tips. Here, we show results obtained on three powder materials, namely core‐shell CuI/CuO, CuI and TiO2.
Pharmacological Profile and Molecular Modeling of Cyclic Opioid Analogues Incorporating Various Phenylalanine Derivatives
Authors: Adamska‐Bartłomiejczyk Anna , Lipiński Piotr F. J. , Piekielna‐Ciesielska Justyna , Kluczyk Alicja , Janecka Anna
Published: May 2020

Peptide‐based agonists of the μ opioid receptor (μOR) are promising therapeutic candidates for pain relief with reduced side effects compared to morphine. A deep understanding of μOR–ligand interactions is necessary for future design of peptide‐based opioid analgesics. To explore the requirements of the μOR binding pocket, eight new analogues of our cyclic peptide Tyr‐c[d‐Lys−Phe−Phe−Asp]NH2 displaying high μOR affinity were synthesized, in which Phe in either the third or fourth position was replaced by various derivatives of this amino acid (β3‐Phe, homoPhe, β3‐homoPhe and PhGly). The aim of this research was to examine the structural effects of such modifications on the bioactivity, and both experimental and theoretical methods were used. The binding of the cyclic analogues to all three OR types (μ, δ, κ) was assessed by radioligand competitive binding assay, and their functional activity was determined in a calcium mobilization assay. In order to provide structural hypotheses explaining the obtained experimental affinities, the complexes of the cyclic peptides with μOR were subjected to molecular modeling.
Estimation of the carrier frequency of fumarate hydratase alterations and implications for kidney cancer risk in hereditary leiomyomatosis and renal cancer
Authors: Shuch Brian , Li Shantao , Risch Harvey , Bindra Ranjit S. , McGillivray Patrick D. , Gerstein Mark
Published: May 2020

Background

Hereditary leiomyomatosis and renal cancer (HLRCC) is a cancer syndrome associated with a germline mutation in fumarate hydratase (FH). The syndrome is associated with cutaneous and uterine leiomyomas, and some patients develop a lethal form of kidney cancer. This study provides estimates for the FH carrier frequency and kidney cancer penetrance.

Methods

Data sets containing sequencing data for the FH gene were used: the 1000 Genomes Project (1000GP) and the Exome Aggregation Consortium (ExAC). Alterations in the FH gene were characterized on the basis of different variant risk tiers: 1) ClinVar annotated variants, 2) loss‐of‐function alterations, and 3) highly impactful missense alterations. The cumulative incidence of FH alterations overall and by different world populations was evaluated in 1000GP and ExAC. A lifetime penetrance of HLRCC kidney cancer risk was generated with 3 estimates of the annual incidence.

Results

The overall allele frequencies of tier 1 to 3 FH alterations in the ExAC and 1000GP data sets were 2.54 × 10–3 (1 in 393) and 1.20 × 10–3 (1 in 835), respectively. There were differences in the allele frequencies of FH alterations between world populations. Based on various estimates of the percentage of kidney cancers with FH alterations, the lifetime kidney cancer penetrance for carrier estimate 3 in ExAC was 1.7% to 5.8%.

Conclusions

FH alterations are common and are carried by approximately 1 in 1000 individuals according to the more conservative estimates. The lifetime kidney cancer penetrance appears lower than previously estimated. Although databases are not population cohorts, they provide a useful quantitative estimate of rare variants with low penetrance.
Complexities in estimating the true risk of hereditary leiomyomatosis and renal cell carcinoma and the development of kidney cancer
Authors: Ball Mark W. , Ricketts Christopher J.
Published: May 2020

Currently, the incidence of hereditary leiomyomatosis and renal cell cancer (HLRCC), as well as the penetrance of kidney cancer among patients with HLRCC, is unknown. Large‐scale genomic databases may be unable to accurately estimate the incidence of HLRCC.
Morbidity burden in survivors of multiple myeloma who underwent autologous transplantation: A Bone Marrow Transplantation Survivor Study
Authors: Arora Mukta , Chen Yanjun , Hageman Lindsey , Wu Jessica , Landier Wendy , Francisco Liton , Kung Michelle , Ness Emily , Bosworth Alysia , Pamukcuoglu Merve , Weisdorf Daniel J. , Forman Stephen J. , Armenian Saro H. , Bhatia Smita
Published: May 2020

Background

Autologous blood or bone marrow transplantation (aBMT) is considered the standard of care for patients with multiple myeloma (MM). Significantly improved survival necessitates an understanding of the morbidity burden borne by the growing survivor population.

Methods

The authors evaluated severe and/or life‐threatening chronic health conditions (CHCs) and subsequent neoplasms (SNs) in patients with MM who were treated with aBMT using the Bone Marrow Transplant Survivor Study. A total of 630 study participants had undergone aBMT for MM at 1 of 3 BMT centers, had survived ≥2 years after aBMT, and were aged ≥18 years at the time of survey completion. Survivors of aBMT identified 289 nearest‐age siblings to constitute an unaffected comparison group. Scoring of CHCs was based on version 5 of the National Cancer Institute Common Terminology Criteria for Adverse Events to determine severity (with grade 3 indicating serious and grade 4 indicating life‐threatening).

Results

The 10‐year cumulative incidence of any grade 3 to 4 CHC among survivors of aBMT was 57.6 ± 3.2%. Survivors of MM were found to be at 40% higher odds of developing grade 3 to 4 CHCs when compared with siblings (95% confidence interval [95% CI], 1.0‐1.9). Among SNs, 96% were solid tumors, yielding a 10‐year cumulative incidence of 13.6% ± 2.5%. Pre‐aBMT exposure to cyclophosphamide (hazard ratio [HR], 3.5; 95% CI, 1.5‐8.1) and immunomodulatory drugs (HR, 3.9; 95% CI, 1.5‐10.1) were associated with an increased risk of solid tumors. Melanoma (10‐year cumulative incidence: 3.3% ± 1.2%) and squamous cell carcinoma (10‐year cumulative incidence: 5.1% ± 1.8%), were the most common SNs. Pre‐aBMT exposure to cyclophosphamide (HR, 6.02; 95% CI, 1.4‐26.1) and immunomodulatory drugs (HR, 7.9; 95% CI, 0.9‐68.5) was associated with an increased risk of melanoma.

Conclusions

The 10‐year cumulative incidence of severe and/or life‐threatening CHCs was found to approach 60% in long‐term survivors of MM, with solid SNs constituting a large morbidity burden. The current study has provided evidence supporting the close monitoring of survivors to manage morbidity.
GSTM1 null variant associated with anthracycline‐related cancer in pediatric cancer
Authors: Rassekh Shahrad Rod
Published: May 2020

Anthracyclines are an important chemotherapeutic agent in the treatment of many childhood cancers, but their use is associated with a significant rate of cardiomyopathy in survivors. This editorial discusses an article in this issue of Cancer by Singh and colleagues, who have found an association of the GSTM1 null variant with anthracycline‐associated heart toxicity.
Sex differences in c‐Fos and EGR‐1/Zif268 activity maps of rat sacral spinal cord following cystometry‐induced micturition
Authors: Wiedmann Nicole M. , Wong Agnes W. , Keast Janet R. , Osborne Peregrine B.
Published: May 2020

Storage and voiding of urine from the lower urinary tract (LUT) must be timed precisely to occur in appropriate behavioral contexts. A major part of the CNS circuit that coordinates this activity is found in the lumbosacral spinal cord. Immediate early gene (IEG) activity mapping has been widely used to investigate the lumbosacral LUT‐related circuit, but most reports focus on the effects of noxious stimulation in anesthetized female rats. Here we use c‐Fos and EGR‐1 (Zif268) activity mapping of lumbosacral spinal cord to investigate cystometry‐induced micturition in awake female and male rats. In females, after cystometry c‐Fos neurons in spinal cord segments L5–S2 were concentrated in the sacral parasympathetic nucleus (SPN), dorsal horn laminae II–IV, and dorsal commissural nucleus (SDCom). Comparisons of cystometry and control groups in male and female revealed sex differences. Activity mapping suggested dorsal horn laminae II–IV was activated in females but showed net inhibition in males. However, inhibition in male rats was not detected by EGR‐1 activity mapping, which showed low coexpression with c‐Fos. A class of catecholamine neurons in SPN and SDCom neurons were also more strongly activated by micturition in females. In both sexes, most c‐Fos neurons were identified as excitatory by their absence of Pax2 expression. In conclusion, IEG mapping in awake male and female rats has extended our understanding of the functional molecular anatomy of the LUT‐related circuit in spinal cord. Using this approach, we have identified sex differences that were not detected by previous studies in anesthetized rats.