bluuebunny/crossref_metadata_2025 huggingface dataset:
Adaptive radiotherapy based on statistical process control for oropharyngeal cancer
Authors: Wang Hesheng , Xue Jinyu , Chen Ting , Qu Tanxia , Barbee David , Tam Moses , Hu Kenneth
Published: August 2020

Purpose

The purpose of this study is to quantify dosimetric changes throughout the delivery of oropharyngeal cancer treatment and to investigate the application of statistical process control (SPC) for the management of significant deviations during the course of radiotherapy.

Methods

Thirteen oropharyngeal cancer patients with daily cone beam computed tomography (CBCT) were retrospectively reviewed. Cone beam computed tomography images of every other fraction were imported to the Velocity software and registered to planning CT using the 6 DOF (degrees of freedom) couch shifts generated during patient setup. Using Velocity “Adaptive Monitoring” module, the setup‐corrected CBCT was matched to planning CT using a deformable registration. Volumes and dose metrics at each fraction were calculated and rated with plan values to evaluate interfractional dosimetric variations using a SPC framework. T‐tests between plan and fraction volumes were performed to find statistically insignificant fractions. Average upper and lower process capacity limits (UCL, LCL) of each dose metric were derived from these fractions using conventional SPC guidelines.

Results

Gross tumor volume (GTV) and organ at risk (OAR) volumes in the first 13 fractions had no significant changes from the pretreatment planning CT. The GTV and the parotid glands subsequently decreased by 10% at the completion of treatment. There were 3–4% increases in parotid mean doses, but no significant differences in dose metrics of GTV and other OARs. The changes were organ and patient dependent. Control charts for various dose metrics were generated to assess the metrics at each fraction for individual patient.

Conclusions

Daily CBCT could be used to monitor dosimetric variations of targets and OARs resulting from volume changes and tissue deformation in oropharyngeal cancer radiotherapy. Treatment review with the guidance of a SPC tool allows for an objective and consistent clinical decision to apply adaptive radiotherapy.
Factors Associated With Functional Decline in Hand and Hip/Knee Osteoarthritis After One Year: Data From a Population‐Based Study
Authors: Siviero Paola , Limongi Federica , Gesmundo Antonella , Zambon Sabina , Cooper Cyrus , Dennison Elaine M. , Edwards Mark H. , van der Pas Suzan , Timmermans Erik J. , van Schoor Natasja M. , Schaap Laura A. , Dallmeier Dhayana , Denkinger Michael D. , Peter Richard , Castell Maria Victoria , Otero Ángel , Pedersen Nancy L. , Deeg Dorly J. H. , Maggi Stefania ,   for the European Project on Osteoarthritis Research Group
Published: August 2020

Objective

To investigate factors that together with hand or hip/knee osteoarthritis (OA) could contribute to functional decline over a year’s time in elderly individuals.

Methods

The data of 1,886 individuals between ages 65 and 85 years in a prospective, observational population‐based study with 12–18 months of follow‐up in the context of the European Project on Osteoarthritis were analyzed. The outcome measures were self‐reported hand and hip/knee functional decline, evaluated using a minimum clinically important difference of 4 on the Australian/Canadian Hand OA Index and of 2 on the Western Ontario and McMaster Universities Osteoarthritis Index hip/knee physical function subscales, both normalized to 0–100. Using regression models adjusted for sex, age, country, and education level, the baseline factors considered were clinical hand or hip/knee OA, pain, analgesic/antiinflammatory medications, comorbidities, social isolation, income, walking time, grip strength, physical activity time, and medical/social care.

Results

After a year, 453 participants were identified as having worse hand functionality and 1,389 as not worse. Hand OA, anxiety, walking time, and grip strength were risk factors for hand functional decline; pain was a confounder of the effect of hand OA.

Analgesic/antiinflammatory medications mediated the combined effect of hip/knee OA plus pain on functional decline in the 554 individuals classified as having worse hip/knee functionality and the 1,291 persons who were not worse. Peripheral artery disease, obesity, and cognitive impairment were other baseline risk factors.

Conclusion

Study findings showed that together with emotional status and chronic physical and cognitive conditions, OA affects hand and hip/knee functional decline.
Differences in Capacity of High‐Density Lipoprotein Cholesterol Efflux Between Patients With Systemic Lupus Erythematosus and Rheumatoid Arthritis
Authors: Quevedo‐Abeledo Juan C. , Sánchez‐Pérez Hiurma , Tejera‐Segura Beatriz , de Armas‐Rillo Laura , Armas‐González Estefanía , Machado José David , González‐Gay Miguel A. , Díaz‐González Federico , Ferraz‐Amaro Iván
Published: August 2020

Objective

Cholesterol efflux capacity (CEC) is the ability of high‐density lipoprotein (HDL) cholesterol to accept cholesterol from macrophages. Lipid profiles and CEC appear to be altered in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) due to disease activity and inflammation. CEC has been linked to cardiovascular events in the general population and to subclinical atherosclerosis in SLE and RA patients. The aim of this study was to establish whether CEC varies between patients with SLE and those with RA.

Methods

The study encompassed 460 individuals (195 SLE patients and 265 patients with RA). CEC (using an in vitro assay) and concentrations of lipoprotein serum were assessed in both populations. A multivariable regression analysis was performed to study whether CEC differs between SLE patients and RA patients.

Results

Comparison of lipid patterns revealed that patients with RA have lower HDL cholesterol and higher apolipoprotein B serum levels than SLE patients. CEC was downregulated in SLE patients compared to patients with RA (β –12 [95% confidence interval –13, –10], P < 0.001). It occurred independently of traditional cardiovascular risk factors, statin use, disease‐related data, and other variations in the lipid profile related to the diseases.

Conclusion

Patients with RA have a more proatherogenic lipid pattern compared to those with SLE. However, CEC seems to be more damaged in SLE patients than in RA patients.
Significant Decline in the Incidence of Behçet’s Disease in South Korea: A Nationwide Population‐Based Study (2004–2017)
Authors: Jun Jae‐Bum , Kim Hyun Jung , Kazmi Sayada Zartasha , Kang Taeuk , Kim Kyoung‐Beom , Kang Min Ji , Ahn Hyeong Sik
Published: August 2020

Objective

Long‐term population‐based data on change in the incidence of Behçet’s disease (BD) are scarce, although a possible decline has been reported. The present study was undertaken to investigate the incidence, survival, and mortality of BD patients from 2004 to 2017 in the Republic of Korea.

Methods

We analyzed a registry of rare intractable diseases and a claims database from the Health Insurance and Review Agency with information on BD patients between 2004 and 2017 using uniform diagnostic criteria. The study period was divided into 3 time periods: 2004–2006, 2007–2010, and 2011–2017.

Results

The annual incidence of BD decreased from 8.15 per 100,000 in 2004 to 1.51 in 2017, an 81.5% decrease. The annual percentage change was 6.32% for female patients and 6.15% for male patients. The decrease in BD incidence was greater for women and middle‐aged people. The 3‐year survival rate of BD patients during the 2011–2017 period was lower than that of BD patients in 2004–2006 and 2007–2010, although there was no statistical difference. The standardized mortality rates increased significantly in the 2011–2017 period compared to the first 2 periods.

Conclusion

BD incidence decreased from 2004 to 2017 in the Republic of Korea. This decline in incidence might be attributable to changes in environmental factors, including a reduction in the burden of infectious diseases in the past decades and improvement in oral health during childhood. The unprecedented decline in the incidence of BD in the Republic of Korea without major changes in genetic background suggests that environmental factors are very important to the development of BD.
A Review of the Selective Laser Melting Lattice Structures and Their Numerical Models
Authors: Alomar Zaki , Concli Franco
Published: August 2020

The high‐fidelity metal additive manufacturing (MAM) processes promote the development of complex lattice structure designs with tailored physical and mechanical properties. Particularly, the unique characteristics of the selective laser melting (SLM) lattice structures make them desirable in many leading application areas. However, the full‐scale adoption of lattices is limited by the lack of a standard numerical model that can reliably predict and assess their mechanical and failure response. Most of the studies follow a unique methodology that differs greatly from their counterparts. In this context, herein a review of the numerical methods developed specifically to analyze the mechanical behavior of lattice structures is presented, while the potentials and limitations of each model are showcased. The numerical models’ key differences are identified, and their impacts on the finite models are highlighted. Correlations between the relative density and the compressive mechanical properties of the collected data are established following the Gibson–Ashby model. In addition, an overview of the lattice's designs, properties, performance, and defects is provided. Overall, this review is intended to provide the reader with comprehensive knowledge about lattice structures and accelerate the process of developing a reliable yet computationally inexpensive standardized numerical model.
Computational modeling of microbubble coalescence and breakup using large eddy simulation and Lagrangian tracking
Authors: Asiagbe Kenneth S. , Colombo Marco , Fairweather Michael , Njobuenwu Derrick O.
Published: August 2020

The flow of dispersed microbubbles was studied with an Eulerian–Lagrangian technique using large eddy simulation to predict the continuous liquid flow and Lagrangian tracking to compute bubble trajectories. The model fully accounts for bubble coalescence and breakup and was applied to horizontal and vertical channel flows. With low levels of turbulence, gravity in horizontal, and lift in vertical, channel flows govern the bubble spatial and collision distribution. When turbulence is sufficiently high to, at least partially, oppose bubble preferential concentration, more uniform collision and coalescence distributions are found, although these remain peaked near the wall in both configurations. Almost 100% coalescence efficiency was always found, due to bubbles colliding along similar trajectories, with breakup only recorded in a flow of low surface tension refrigerant R134a. Models like this can provide the required quantitative understanding of the microbubbles complex behavior, as well as supporting the development of more macroscopic modeling closures.
Fabricating Janus membranes via physicochemical selective chemical vapor deposition
Authors: Mohammadi Ghaleni Mahdi , Tavakoli Elham , Bavarian Mona , Nejati Siamak
Published: August 2020

Membranes with asymmetric wettability‐Janus membranes‐have recently received considerable attention for a variety of critical applications. Here, we report on a simple approach to introduce asymmetric wettability into hydrophilic porous domains. Our approach is based on the physicochemical‐selective deposition of polytetrafluoroethylene (PTFE) on hydrophilic polymeric substrates. To achieve selective deposition of PTFE, we inhibit the polymerization reaction within the porous domain. We prefill the substrates with glycerol, containing a known amount of free radical inhibitor, and utilize initiated chemical vapor deposition (iCVD) for the polymerization of PTFE. We show that the glycerol/inhibitor mixture hinders the deposition of PTFE within the membrane pores. As a result, the surface of the substrates remains open and porous. The fabricated Janus membranes show stable wetting‐resistant properties, evaluated through sessile drop contact angle measurements and direct contact membrane distillation (DCMD).
A genetic and clinical study of individuals with nonsyndromic retinopathy consequent upon sequence variants in HGSNAT, the gene associated with Sanfilippo C mucopolysaccharidosis
Authors: Schiff Elena R. , Daich Varela Malena , Robson Anthony G. , Pierpoint Karen , Ba‐Abbad Rola , Nutan Savita , Zein Wadih M. , Ullah Ehsan , Huryn Laryssa A. , Tuupanen Sari , Mahroo Omar A. , Michaelides Michel , Burke Derek , Harvey Katie , Arno Gavin , Hufnagel Robert B. , Webster Andrew R.
Published: August 2020

Pathogenic variants in the gene HGSNAT (heparan‐α‐glucosaminide N‐acetyltransferase) have been reported to underlie two distinct recessive conditions, depending on the specific genotype, mucopolysaccharidosis type IIIC (MPSIIIC)—a severe childhood‐onset lysosomal storage disorder, and adult‐onset nonsyndromic retinitis pigmentosa (RP). Here we describe the largest cohort to‐date of HGSNAT‐associated nonsyndromic RP patients, and describe their retinal phenotype, leukocyte enzymatic activity, and likely pathogenic genotypes. We identified biallelic HGSNAT variants in 17 individuals (15 families) as the likely cause of their RP. None showed any other symptoms of MPSIIIC. All had a mild but significant reduction of HGSNAT enzyme activity in leukocytes. The retinal condition was generally of late‐onset, showing progressive degeneration of a concentric area of paramacular retina, with preservation but reduced electroretinogram responses. Symptoms, electrophysiology, and imaging suggest the rod photoreceptor to be the cell initially compromised. HGSNAT enzymatic testing was useful in resolving diagnostic dilemmas in compatible patients. We identified seven novel sequence variants [p.(Arg239Cys); p.(Ser296Leu); p.(Phe428Cys); p.(Gly248Ala); p.(Gly418Arg), c.1543‐2A>C; c.1708delA], three of which were considered to be retina‐disease‐specific alleles. The most prevalent retina‐disease‐specific allele p.(Ala615Thr) was observed heterozygously or homozygously in 8 and 5 individuals respectively (7 and 4 families). Two siblings in one family, while identical for the HGSNAT locus, but discordant for retinal disease, suggest the influence of trans‐acting genetic or environmental modifying factors.
Transition Metal Catalyzed Insertion Reactions with Donor/Donor Carbenes
Authors: Bergstrom Benjamin D. , Nickerson Leslie A. , Shaw Jared T. , Souza Lucas W.
Published: August 2020

Donor/donor carbenes are relatively new in the field of carbene chemistry; although applications in C−H and X−H insertion reactions are few in number, they demonstrate exquisite chemo‐ and stereo‐selectivity. Recent reports have shown that C−H, N−H, B−H, O−H, S−H, Si−H, Ge−H, Sn−H and P−H insertion reactions are feasible with a variety of transition metal catalysts, both inter‐ and intramolecularly. Furthermore, high degrees of diastereo‐ and enantioselectivity have been observed in several cases. Methods typically involve the formation of a diazo‐based carbene precursor, but procedures using diazo‐free metal carbenes have been developed with significant success. This Minireview covers transition‐metal catalyzed insertion reactions with donor/donor and donor carbenes, providing context for future developments in this emerging field.
Disulfide‐Linked Allosteric Modulators for Multi‐cycle Kinetic Control of DNA‐Based Nanodevices
Authors: Del Grosso Erica , Ponzo Irene , Ragazzon Giulio , Prins Leonard J. , Ricci Francesco
Published: August 2020

Nature employs sulfur switches, that is, redox‐active disulfides, to kinetically control biological pathways in a highly efficient and reversible way. Inspired by this mechanism, we describe herein a DNA‐based synthetic nanodevice that acts as a sulfur switch and can be temporally controlled though redox regulation. To do this, we rationally designed disulfide DNA strands (modulators) that hybridize to a ligand‐binding DNA nanodevice and act as redox‐active allosteric regulators inducing the nanodevice to release or load its ligand. Upon reduction, the allosteric modulator spontaneously de‐hybridizes from the nanodevice and, as a result, its effect is transient. The system is reversible and has an unprecedented high tolerance to waste products and displays transient behavior for over 40 cycles without significant loss of efficiency. Kinetic control of DNA‐based ligand‐binding nanodevices through purely chemical reactions paves the way for temporal regulation of more complex chemical pathways.
Chiral Macrocycles Having C3 Symmetry Resulting from Orientation of Thiophene Rings
Authors: Miura Tomoya , Nakamuro Takayuki , Ishihara Yumi , Nagata Yuuya , Murakami Masahiro
Published: August 2020

An chiral RhII‐catalyzed cyclooligomerization reaction of thiophenes having triazolyl and vinyl substituents at the 2‐ and 4‐positions was studied. Structurally interesting cyclic trimers, having chirality that is ascribed only to the orientation of the 2,4‐disubstituted thiophene rings, are obtained. The 2,4‐disubstitution of the starting thiophene monomer allows production of each of the enantiomers. The observed electronic circular‐dichroism spectra are in accord with those simulated by density‐functional theory calculations.
Photocontrolled Cobalt Catalysis for Selective Hydroboration of α,β‐Unsaturated Ketones
Authors: Beltran Frédéric , Bergamaschi Enrico , Funes‐Ardoiz Ignacio , Teskey Christopher J.
Published: August 2020

Selectivity between 1,2 and 1,4 addition of a nucleophile to an α,β‐unsaturated carbonyl compound has classically been modified by the addition of stoichiometric additives to the substrate or reagent to increase their “hard” or “soft” character. Here, we demonstrate a conceptually distinct approach that instead relies on controlling the coordination sphere of a catalyst with visible light. In this way, we bias the reaction down two divergent pathways, giving contrasting products in the catalytic hydroboration of α,β‐unsaturated ketones. This includes direct access to previously elusive cyclic enolborates, via 1,4‐selective hydroboration, providing a straightforward and stereoselective route to rare syn‐aldol products in one‐pot. DFT calculations and mechanistic experiments confirm two different mechanisms are operative, underpinning this unusual photocontrolled selectivity switch.
Mechanochemical Synthesis of Corannulene‐Based Curved Nanographenes
Authors: Báti Gábor , Csókás Dániel , Yong Teoh , Tam Si Man , Shi Raymond R. S. , Webster Richard D. , Pápai Imre , García Felipe , Stuparu Mihaiela C.
Published: August 2020

It is shown that corannulene‐based strained π‐surfaces can be obtained through the use of mechanochemical Suzuki and Scholl reactions. Besides being solvent‐free, the mechanochemical synthesis is high‐yielding, fast, and scalable. Therefore, gram‐scale preparation can be carried out in a facile and sustainable manner. The synthesized nanographene structure carries positive (bowl‐like) and negative (saddle‐like) Gaussian curvatures and adopts an overall quasi‐monkey saddle‐type of geometry. In terms of properties, the non‐planar surface exhibits a high electron affinity that was measured by cyclic voltammetry, with electrolysis and in situ UV/vis spectroscopy experiments indicating that the one‐electron reduced state displays a long lifetime in solution. Overall, these results indicate the future potential of mechanochemistry in accessing synthetically challenging and functional curved π‐systems.
Physico‐mechanical, rheological and gas barrier properties of organoclay and inorganic phyllosilicate reinforced thermoplastic films
Authors: Ghosh Suman Kumar , Das Tushar Kanti , Ghosh Sabyasachi , Ganguly Sayan , Nath Krishnendu , Das Narayan Chandra
Published: August 2020

Insertion of 2:1 organo‐modified phyllosilicate tactoids into rheologically tough thermoplastics has extraordinary potential candidate in oxygen permeability and microstructural toughening. Herein, two commercially abundant clays have been taken for improvement of the thermoplastic's gas barrier property in reasonably low loading. The cause of low loading has been accounted to the usage of maleated polyethylene (MA‐g‐PE) during the melt mixing tenure. The optimized nanocomposite compression molded film has been tested against uniaxial stretching, which showed a negligible change in the residual permanent set with sacrificing the elongation at break feature. Moreover, nanoindentation was also performed to get the hardness of the sample surface. The flow behavior of the nanocomposites showed thixotropic likely with increasing the frequency. Oxygen transmission rate (OTR) has significantly decreased for tallow amine‐modified nanoclay system (cloisite 15A) in comparison to cloisite Na+ providing 'tortoise path' formation inside the matrix. Thus, hitherto, the work could demonstrate and provide the information of comparative studies between organo‐clay and simple phyllosilicates, which could be remediation of the loopholes in mechanical toughening and gas barrier lineaments.
Novel semi‐interpenetrated networks based on collagen‐polyurethane‐polysaccharides in hydrogel state for biomedical applications
Authors: Claudio‐Rizo Jesús A. , Hernandez‐Hernandez Nalleli G. , Cano‐Salazar Lucia F. , Flores‐Guía Tirso E. , de la Cruz‐Durán Fabiola N. , Cabrera‐Munguía Denis A. , Becerra‐Rodríguez Juan J.
Published: August 2020

The development of collagen hydrogels with tailored properties for improved applications in biomedicine represents an area of opportunity for materials science. The collagen can form semi‐interpenetrated networks (semi‐IPN) with various natural and/or synthetic polymers. This work aims the preparation of novel hydrogels generated from a collagen matrix cross‐linked with polyurethane (PU), and the subsequent inclusion of polysaccharide chains to form semi‐IPN systems with improved properties. The choice of polysaccharides for this purpose is related to their ability to modulate the biocompatibility and the antibacterial capacity in various biomedical strategies. The work contemplates to study the effect of the chemical structure of polysaccharide (hydroxyethylcellulose (HEC), hydroxypropylmethylcellulose (HPMC) or starch (Alm)) on the properties of these novel hydrogels. The results indicate that the semi‐IPN hydrogels that include Alm exhibit the formation of stronger intermolecular interactions promoted by hydrogen bonds than HEC and HPMC, significantly improving the mechanical properties and their degradation rate in acidic, alkaline, and proteolytic media; also showing high capacity to inhibit the growth of E. colli. The semi‐IPN hydrogels based on HEC and HPMC exhibit excellent improvement in both thermal and proteolytic degradation, compared with the collagen‐PU matrix. On the other hand, this semi‐IPN system does not present cytotoxic character for monocytes and fibroblasts growing for up to 48 h of culture. Therefore, these innovative 3D matrices will be excellent candidates with potential application in biomedical strategies such as wound healing dressings.
Self‐healable and reprocessible liquid crystalline elastomer and its highly thermal conductive composites by incorporating graphene via in‐situ polymerization
Authors: Zhang Qian , Chen Guokang , Wu Kun , Shi Jun , Liang Liyan , Lu Mangeng
Published: August 2020

The booming of modern electronic devices featuring increasing power and multi‐functionalization demands novel high thermal conductive materials with various functions, such as self‐healing property and high deformability, while traditional polymer‐based or metallic‐based materials could hardly provide. Therefore, we report a high thermal conductive and disulfide‐based self‐healable and reprocessible liquid crystalline elastomer (SHLCE) composite by incorporating graphene nanoplates (GNPs) fillers. The obtained GNPs/SHLCE composites exhibited desired thermal conductivity (5.08 Wm−1K−1) when the content of GNPs was 20 wt% to the composites. Moreover, the GNPs/SHLCE composites showed intriguing recycled performance (Tensile strength after recycle could maintain over 93% compared with that of original composites). Furthermore, we concluded that the improved thermal conductivity of GNPs/SHLCE composites was beneficial to the thermal induced reprocessible and shelf‐healable systems.
Molecular weight influence on shape memory effect of shape memory polymer blend (poly(caprolactone)/styrene‐butadiene‐styrene)
Authors: Ben Abdallah Abir , Gamaoun Fehmi , Kallel Achraf , Tcharkhtchi Abbas
Published: August 2020

The shape memory effect (SME) does not only concern the macroscopic structure. It concerns also the polymer structure at morphological, macromolecular, and molecular scales. This effect may depend on different physicochemical properties like morphology heterogeneity, chain rigidity, steric hindrance, chain polarity, free volume, cross‐linking or entanglement density, molecular shape and weight, and so on. Hence, finding the relationship between the SME and these properties is very important. This can help to obtain the knowledge about the phenomenon origin and mechanism. One of the basic polymer properties, which can have direct SME, may be the molecular weight (Mw). The question here is: If the Mw of a shape memory polymer (SMP) changes, for different reasons like degradation, what will be the effect of this change on its SME. In order to answer to this question, the investigation is focused on an SMP blend of 40% poly(ɛ‐caprolactone) (PCL) and 60% styrene‐butadiene‐styrene (SBS). Then, enzymatic hydrolysis is performed on this blend to change its Mw. It is shown that this change is only related to the variation in the Mw of PCL. After that, different samples with a distinct average Mw are prepared and characterized by various experimental methods. Shape memory tests are performed on these blends, and the recovery rate (Rr) for each of them is determined. It is found that when Mw of PCL decreases, its degree of crystallinity, its glass transition, and its melting temperatures, corresponding to the PCL phase, increase. However, the elongation at break of the blend declines with the reduction in Mw. The tests show that the alteration in the blend's Mw influences its SME. Indeed, Rr of the (PCL/SBS) mixture drops with the decrease in Mw of PCL.
Association of a Serum Protein Signature With Rheumatoid Arthritis Development
Authors: O’Neil Liam J. , Spicer Victor , Smolik Irene , Meng Xiaobo , Goel Rishi R. , Anaparti Vidyanand , Wilkins John , El‐Gabalawy Hani S.
Published: August 2020

Objective

The pathophysiologic events that precede the onset of rheumatoid arthritis (RA) remain incompletely understood. This study was undertaken to identify changes in the serum proteome that precede the onset of RA, with the aim of providing new insights into the pathogenic mechanisms that lead to its development.

Methods

In a cohort of first‐degree relatives of Indigenous North American RA patients, the SomaScan proteomics platform was used to determine the levels of 1,307 proteins in multiple longitudinal serum samples from 17 individuals who were followed up prospectively to the time of disease onset. Proteomic signatures from this group of individuals (designated the progressor group) were compared to those in a group of individuals who were considered at risk of developing RA, stratified as either positive (n = 63) or negative (n = 47) for anti–citrullinated protein antibodies (ACPAs) (designated the at‐risk group). Machine learning was used to identify a protein signature that could accurately classify those individuals at highest risk of future RA development.

Results

A preclinical proteomic signature that differentiated RA progressors from at‐risk individuals, irrespective of ACPA status, was identified (area under the curve 0.913, accuracy 91.2%). Importantly, the predictive preclinical proteomic signature was present not only in serum samples obtained close to the onset of RA, but also in serum samples obtained a median of 30.9 months prior to onset. Network analysis implicated the activation of Toll‐like receptor 2 and production of tumor necrosis factor and interleukin‐1 as key events that precede RA progression.

Conclusion

Alterations in the serum proteome in the preclinical phase of RA can emerge years prior to the onset of disease. Our findings suggest that the serum proteome provides a rich source of proteins serving both to classify at‐risk individuals and to identify molecular pathways involved in the development of clinically detectable RA.
B(C6F5)3‐Catalyzed Tandem Friedel‐Crafts and C−H/C−O Coupling Reactions of Dialkylanilines
Authors: Zhai Gaowen , Liu Xueting , Ma Wentao , Wang Guoqiang , Yang Liu , Li Shuhua , Wu Youting , Hu Xingbang
Published: August 2020

Tandem Friedel‐Crafts (FC) and C−H/C−O coupling reactions catalyzed by tris(pentafluorophenyl) borane (B(C6F5)3) were achieved without using any other additive in the absence of solvent. This process can be used for the reactions between a series of dialkylanilines and vinyl ethers with good isolated yields of bis(4‐dialkylaminophenyl) compounds. Based on combined theoretical and experimental studies, the possible reaction mechanism was proposed. B(C6F5)3 can activate the C=C and C−O bond for FC and C−H/C−O coupling reactions respectively. The FC reaction is slow, which is followed by a fast C−H/C−O coupling.
Engineered Live Biotherapeutics: Progress and Challenges
Authors: Tan Yang , Shen Juntao , Si Tong , Ho Chun Loong , Li Yinqing , Dai Lei
Published: August 2020

The human microbiome plays an important role in human health, from metabolism to immunity. In the last few decades, advances in synthetic biology have enabled scientists to design and engineer live microorganisms for therapeutic purposes. In this review, major strategies for manipulating the microbiome are outlined, which include three emerging areas with promising therapeutic applications: engineered commensal bacteria, synthetic microbial consortia, and targeted modulation by phages. Furthermore, the applications of engineered live biotherapeutics in treating a variety of human diseases, including pathogenic infections, metabolic disorders, inflammatory bowel disease, and colorectal cancer, are highlighted. Finally, an overview of the challenges and opportunities in the future development of engineered live biotherapeutics is provided.
Metabolically engineered Caldicellulosiruptor bescii as a platform for producing acetone and hydrogen from lignocellulose
Authors: Straub Christopher T. , Bing Ryan G. , Otten Jonathan K. , Keller Lisa M. , Zeldes Benjamin M. , Adams Michael W. W. , Kelly Robert M.
Published: August 2020

The production of volatile industrial chemicals utilizing metabolically engineered extreme thermophiles offers the potential for processes with simultaneous fermentation and product separation. An excellent target chemical for such a process is acetone (Tb = 56°C), ideally produced from lignocellulosic biomass. Caldicellulosiruptor bescii (Topt 78°C), an extremely thermophilic fermentative bacterium naturally capable of deconstructing and fermenting lignocellulose, was metabolically engineered to produce acetone. When the acetone pathway construct was integrated into a parent strain containing the bifunctional alcohol dehydrogenase from Clostridium thermocellum, acetone was produced at 9.1 mM (0.53 g/L), in addition to minimal ethanol 3.3 mM (0.15 g/L), along with net acetate consumption. This demonstrates that C. bescii can be engineered with balanced pathways in which renewable carbohydrate sources are converted to useful metabolites, primarily acetone and H2, without net production of its native fermentation products, acetate and lactate.
An in situ collagen‐HA hydrogel system promotes survival and preserves the proangiogenic secretion of hiPSC‐derived vascular smooth muscle cells
Authors: Dash Biraja C. , Duan Kaiti , Xing Hao , Kyriakides Themis R. , Hsia Henry C.
Published: August 2020

Human‐induced pluripotent stem cell‐derived vascular smooth muscle cells (hiPSC‐VSMCs) with proangiogenic properties have huge therapeutic potential. While hiPSC‐VSMCs have already been utilized for wound healing using a biomimetic collagen scaffold, an in situ forming hydrogel mimicking the native environment of skin offers the promise of hiPSC‐VSMC mediated repair and regeneration. Herein, the impact of a collagen type‐I‐hyaluronic acid (HA) in situ hydrogel cross‐linked using a polyethylene glycol‐based cross‐linker on hiPSC‐VSMCs viability and proangiogenic paracrine secretion was investigated. Our study demonstrated increases in cell viability, maintenance of phenotype and proangiogenic growth factor secretion, and proangiogenic activity in response to the conditioned medium. The optimally cross‐linked and functionalized collagen type‐I/HA hydrogel system developed in this study shows promise as an in situ hiPSC‐VSMC carrier system for wound regeneration.
Irisin ameliorates high glucose‐induced cardiomyocytes injury via AMPK/mTOR signal pathway
Authors: Deng Jingyu , Zhang Ning , Chen Feng , Yang Chao , Ning Hongjuan , Xiao Chun , Sun Ke , Liu Yongfei , Yang Ming , Hu Taohong , Zhang Zheng , Jiang Wei
Published: August 2020

High glucose (HG)‐induced cardiomyocytes (CMs) injury is a leading cause of diabetic cardiomyopathy with little treatment options. Irisin, a new myokine, which is cleaved from its precursor fibronectin type III domain‐containing protein 5 (FNDC5), has aroused great attention as an essential cardioprotective factor and glucose metabolism regulator but little was known on diabetic cardiomyopathy yet. Here, we aim to clarify the role of irisin in the HG‐induced CMs injury. Neonatal Sprague–Dawley rat CMs were cultured in a normal or HG medium for 12, 24, and 48 hr, respectively before exposing to irisin. The apoptosis level was determined by terminal‐deoxynucleotidyl transferase‐mediated‐dUTP nick end‐labeling assay. Cell viability was measured with the conventional methyl thiazolyl tetrazolium assay. Moreover, reactive oxygen species production was evaluated by dihydroethidium staining. Inflammatory factors, namely tumor necrosis factor‐α, interleukin‐6, interleukin‐1β were determined by enzyme‐linked immunosorbent assay kits. Furthermore, protein and messenger RNA (mRNA) expressions were measured by western blot and quantitative real‐time polymerase chain reaction, respectively. HG increases the apoptosis of CMs and activated the inflammatory responses and oxidative stress in CMs. Meanwhile, the mRNA and protein expressions of FNDC5 are decreased after HG exposure. Nevertheless, the increased apoptosis is alleviated by irisin treatment. Notably, irisin suppresses the inflammatory responses and oxidative stress in injured CMs. Mechanically, after the administration of Compound C, AMP‐activated protein kinase (AMPK) inhibitor, these cardioprotective effects resulting from irisin are reversed. Irisin plays a significant role in antiapoptosis, anti‐inflammation, antioxidative stress in HG‐induced CMs via AMPK/mammalian target of the rapamycin signaling pathway.
MAPRE1 promotes cell cycle progression of hepatocellular carcinoma cells by interacting with CDK2
Authors: Liang Xing‐hua , Feng Zheng‐ping , Liu Fo‐qiu , Yan Rong , Yin Liang‐yu , Shen Hao , Lu Hai‐lin
Published: August 2020

Targeting cyclin‐dependent kinases (CDKs) is a promising method of therapy for cancer. Unfortunately, the efficacy of CDK inhibitors in hepatocellular carcinoma (HCC) is limited, due in part to incomplete understanding of cell cycle progression and a lack of specific biomarkers to adequately identify which patients may be responsive to CDK inhibitors. In the present study, we report that microtubule‐associated protein RP/EB family member 1 (MAPRE1), a gene involved in cell cycle and microtubule regulation, is significantly increased in HCC tissue, promotes HCC cell proliferation, enhances in vitro tumorigenesis, and associates with poor prognosis of HCC. We demonstrate that MAPRE1 binds with CDK2, resulting in the hyperphosphorylation of the CDK2 Thr161 residue in HCC cells. Our findings reveal that targeting MAPRE1 might be an effective therapeutic strategy in HCC, and suggest that MAPRE1 expression might provide a promising biomarker to stratify patients with HCC who may benefit from treatment with CDK inhibitors.
A Modified Four‐Probe Method to Separate Ionic Conductance from Composite Conductors
Authors: Fu Xudong , Xia Zhangxun , Liu Qingting , Wang Suli , Sun Gongquan
Published: August 2020

As one of the most important phenomena in electrochemistry and biosystems, ion transport often suffers from the difficulty of effective measurement in electron‐/ion‐conductive composite components. Hence, by modifying the testing probes with an ion‐conductive polymer, a new four‐probe method is invented to separate ion transport within composite materials. By adopting this method, the ionic conductance of the electronic conductors could be precisely measured and the ion migration behaviors in various environments could also be investigated.
Nucleation of Tiny Silver Nanoparticles by Using a Tetrafacial Organic Molecular Barrel: Potential Use in Visible‐Light‐Triggered Photocatalysis
Authors: Mondal Bijnaneswar , Bhandari Pallab , Mukherjee Partha Sarathi
Published: August 2020

Coordination‐driven self‐assembly of discrete molecular architectures of diverse shapes and sizes has been well studied in the last three decades. Use of dynamic imine bonds for designing analogous metal‐free architectures has become a growing challenge recently. This article reports an organic molecular barrel (OB4R) as a potential template for nucleation and stabilization of very tiny (<1.5 nm) Ag nanoparticles (AgNPs). Imine bond condensation of a rigid tetra‐aldehyde with a flexible diamine followed by imine‐bond reduction yielded the discrete tetragonal organic barrel (OB4R). The presence of a molecular pocket ornamented with eight diamine moieties gives the potential for encapsulation of silver(I). The organic barrel was finally used as a molecular vessel for the controlled nucleation of silver nanoparticles (AgNPs) with fine size tuning through binding of AgI ions in the confined space of the barrel followed by reduction. Transmission electron microscopy (TEM) analysis of the Ag0@OB4R composite revealed that the mean particle size is 1.44±0.16 nm. The composite material has approximately 52 wt % silver loading. The barrel‐supported ultrafine AgNPs [Ag0@OB4R] are found to be an efficient photocatalyst for facile Ullmann‐type aryl‐amination coupling of haloarenes at ambient temperature without using any additives. The catalyst was stable for several cycles of reuse without any agglomeration. The new composite Ag0@OB4R represents the first example of discrete organic barrel‐supported AgNPs employed as a photocatalyst in Ullmann‐type coupling reactions at room temperature.
Low participation rates and disparities in participation in interventional clinical trials for myelodysplastic syndromes
Authors: Brierley Charlotte K. , Zabor Emily C. , Komrokji Rami S. , DeZern Amy E. , Roboz Gail J. , Brunner Andrew M. , Stone Richard M. , Sekeres Mikkael A. , Steensma David P.
Published: August 2020

Background

The development of novel therapies for the myelodysplastic syndromes (MDS) is hampered by inadequate trial recruitment. Factors contributing to low trial accrual are incompletely understood.

Methods

This study analyzed a pooled patient database from institutions of the US MDS Clinical Research Consortium to compare the characteristics of participants in interventional trials with those of patients who did not enroll in a trial.

Results

Data were identified for 1919 patients with MDS, and 449 of these patients (23%) participated in an interventional clinical trial. The median age of all patients was 68 years, and 64% were male. Patients who participated in trials were significantly younger than nonparticipants (P = .014), and men were more likely to participate in a trial (71% of trial participants were male, whereas 61% of nonparticipants were; P < .001). Race and ethnicity were not associated with trial enrollment. Patients in more affluent ZIP codes had a higher participation rate (P < .001). Patients with intermediate‐ and high‐risk disease according to the revised International Prognostic Scoring System were overrepresented (P = .004), and trial participants less frequently had treatment‐related disease (P < .001). In multivariable analyses, participation in a clinical trial was associated with a reduced hazard of death (P = .004). Even at large referral centers, only a minority of patients with MDS enrolled in interventional trials.

Conclusions

Restrictive trial eligibility criteria that exclude patients with MDS on account of age, comorbidities, or a history of another cancer are limit enrollment of MDS patients to clinical trials. Gaining insight into the barriers to trial accrual may help investigators and study sponsors to design trials that will accrue more rapidly and augment treatment options for patients with MDS.
Efficacy and Safety of Ticagrelor vs. Clopidogrel in East Asian Patients with Acute Myocardial Infarction: A Nationwide Cohort Study
Authors: Chang Chi‐Jen , Tung Ying‐Chang , Liu Jia‐Rou , Chang Shu‐Hao , Kuo Chi‐Tai , See Lai‐Chu
Published: August 2020

Ticagrelor improves clinical outcomes in patients with acute myocardial infarction (AMI). This study aimed to compare the efficacy and safety of ticagrelor vs. clopidogrel in East Asian patients with AMI. Between July 2013 and December 2015, patients with AMI prescribed dual antiplatelet therapy were identified from the National Health Insurance Research Database of Taiwan. Using propensity score weighting, ticagrelor was compared with clopidogrel for the primary efficacy end point (a composite of all‐cause death, myocardial infarction (MI), and stroke) and bleeding. A total of 32,442 patients with AMI (ticagrelor: 10,057; clopidogrel: 22,385) were eligible for analysis. After propensity score weighting, ticagrelor was comparable to clopidogrel in the incidence rate of the primary efficacy end point (23.6 vs. 22.76/100 patient‐years; hazard ratio (HR) 0.97; 95% confidence interval (CI) 0.89–1.06; P = 0.513). Ticagrelor was associated with a lower risk of stroke (1.78 vs. 2.66/100 patient‐years; HR 0.64; 95% CI 0.49–0.85; P = 0.002) and higher risks of overall (21.59 vs. 18.35/100 patient‐years; HR 1.16; 95% CI 1.06–1.27; P = 0.002) and Bleeding Academic Research Consortium (BARC) type 2 bleeding (18.67 vs. 15.08/100 patient‐years; HR 1.22; 95% CI 1.11–1.36; P < 0.001). The risks of death, MI, and BARC 3 or 5 bleeding were comparable between ticagrelor and clopidogrel. In the present study, ticagrelor was comparable to clopidogrel in the composite of death, MI, and stroke, but had an increased risk of BARC type 2 bleeding. Ticagrelor may be beneficial in preventing post‐MI stroke in East Asian patients.
Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C19 and Proton Pump Inhibitor Dosing
Authors: Lima John J. , Thomas Cameron D. , Barbarino Julia , Desta Zeruesenay , Van Driest Sara L. , El Rouby Nihal , Johnson Julie A. , Cavallari Larisa H. , Shakhnovich Valentina , Thacker David L. , Scott Stuart A. , Schwab Matthias , Uppugunduri Chakradhara Rao S. , Formea Christine M. , Franciosi James P. , Sangkuhl Katrin , Gaedigk Andrea , Klein Teri E. , Gammal Roseann S. , Furuta Takahisa
Published: August 2020

Proton pump inhibitors (PPIs) are widely used for acid suppression in the treatment and prevention of many conditions, including gastroesophageal reflux disease, gastric and duodenal ulcers, erosive esophagitis, Helicobacter pylori infection, and pathological hypersecretory conditions. Most PPIs are metabolized primarily by cytochrome P450 2C19 (CYP2C19) into inactive metabolites, and CYP2C19 genotype has been linked to PPI exposure, efficacy, and adverse effects. We summarize the evidence from the literature and provide therapeutic recommendations for PPI prescribing based on CYP2C19 genotype (updates at www.cpicpgx.org). The potential benefits of using CYP2C19 genotype data to guide PPI therapy include (i) identifying patients with genotypes predictive of lower plasma exposure and prescribing them a higher dose that will increase the likelihood of efficacy, and (ii) identifying patients on chronic therapy with genotypes predictive of higher plasma exposure and prescribing them a decreased dose to minimize the risk of toxicity that is associated with long‐term PPI use, particularly at higher plasma concentrations.
Cannabidivarin for HIV‐Associated Neuropathic Pain: A Randomized, Blinded, Controlled Clinical Trial
Authors: Eibach Luca , Scheffel Simone , Cardebring Madeleine , Lettau Marie , Özgür Celik M. , Morguet Andreas , Roehle Robert , Stein Christoph
Published: August 2020

HIV remains a major burden to the health care system and neuropathic pain is the most common neurological complication of HIV infection. Because current treatment strategies often lack satisfying pain relief, cannabinoids (CBs) are discussed as a new option. We investigated cannabidivarin (CBDV) as treatment for HIV‐associated neuropathic pain. We conducted a randomized, double‐blind, placebo‐controlled crossover study. Patients underwent two successive treatment phases (4 weeks each) and were treated with CBDV (400 mg/day) or placebo in a randomized order. A 3‐week washout phase was designed to eliminate potential carry‐over effects. Patients were followed up for 3 weeks after the end of the second treatment phase. The primary end point was pain intensity on an 11‐point numeric rating scale, recorded in a diary. Secondary end points were additional pain medication, pain characteristics, and quality of life. We included 32 patients. The mean pain intensity under CBDV was 0.62 points higher compared with placebo (P = 0.16, 95% confidence interval −0.27 to 1.51). CBDV did not influence the amount of additional pain medication, pain characteristics, or quality of life. The incidence of adverse events was similar during both treatments. No suspected unexpected adverse reactions occurred during either treatment. CBDV was safe but failed to reduce neuropathic pain in patients with HIV. This may be explained by a lack of CB receptor activation, as indicated by preclinical experiments. Although a larger patient number might be desirable, we would not expect a change in the conclusions because the present differences are far from statistical significance. Therefore, we would currently not consider CBDV as a clinically meaningful treatment option for neuropathic pain.
The use of 5‐aminolevulinic acid to reduce heat‐stress‐related damages in tall fescue
Authors: Katuwal Krishna B , Rowe Somerville , Jespersen David
Published: August 2020

Heat stress is a major abiotic stress that damages cool‐season turfgrasses, such as tall fescue (Festuca arundinacea Schreb.), during summer months. Heat stress results in oxidative damage, reductions in photosynthesis, and ultimately can cause plant death. Exogenous applications of 5‐aminolevulinic acid (ALA) have previously been demonstrated to improve abiotic stress tolerance in a number of crops by improving chlorophyll levels and reducing oxidative damage, two major indicators of heat stress in plants. Experiments were conducted in growth chamber conditions to determine the effect of ALA application on heat stress in tall fescue plants and to confirm if ALA could alleviate damage related to inhibited photosynthesis or oxidative damages associated with high temperature. A rate of 100 mg L−1 ALA was determined to be effective in eliciting positive tall fescue responses during heat stress with plants maintaining better visual characteristics. Plants treated with ALA had greater levels of chlorophyll as well as photosynthetic performance under heat stress than plants that were not treated with ALA. Additionally, ALA plants had reduced oxidative damage associated with greater antioxidant activities of the enzymes catalase (CAT), ascorbate peroxidase (APX), and glutathione reductase (GR). The use of ALA was demonstrated to be effective in reducing heat stress related damages in tall fescue.