bluuebunny/crossref_metadata_2025 huggingface dataset:
Demography of evergreen and deciduous oaks in a mixed oak savanna: insights from a long‐term experiment
Authors: Davis Frank W. , Tyler Claudia M. , Mahall Bruce E.
Published: January 2019

The co‐existence of evergreen and deciduous oaks in Mediterranean‐climate savannas has motivated comparative studies on species’ physiological adaptations to light and drought, establishment niche differences in acorn production, dispersal and seedling herbivory, and differential sapling tolerance of ungulate browsing. Understanding how species’ differences collectively affect co‐occurrence or segregation requires long‐term studies that consider multiple life stages. We compare survival, height growth, and modeled population growth rate of the evergreen sclerophyll, Quercus agrifolia, to those of the winter‐deciduous, broadleaved Q. lobata in southern California savanna sites where the species naturally co‐occur. We evaluate species’ performances after 8.7 yr for four cohorts sown as acorns in 1997, 1998, 2000, and 2001 under four different levels of protection from cattle, deer, and rodents. Survival curves for the two species were closely similar, with large differences between cohorts associated with precipitation in the year acorns were sown. Survival and growth rates of Q. agrifolia seedlings and saplings were slightly lower, and were more reduced by ungulates and rodents, than those of Q. lobata. No Q. agrifolia plants (0/1431) exposed to ungulates (cattle and/or deer) and rodents survived to the end of the experiment. Of 1421 Q. lobata acorns planted in these treatments, only 19 plants (1.3%) survived 8.7 yr and none of these plants progressed out of the ungulate browse layer. However, when protected from both ungulates and rodents, survival rates increased significantly for both species, and Q. agrifolia increased height faster than Q. lobata. Simulated population growth rates increased slightly for plants protected from ungulates, and 95% confidence intervals spanned the stable population growth rate of 1. With exclusion of ungulates and rodents, sapling and small tree recruitment rates for both species far exceeded those needed to offset the rate of recent adult mortality, with modeled population growth rates of 1.07–1.11. Our results underscore the essential role of occasional high rainfall years for initial establishment, plus the key role of consumers in limiting early survival and growth of both evergreen and deciduous oaks in mixed oak savannas.
Characterization of Olive Oils from Superintensive Crops with Different Ripening Degree, Irrigation Management, and Cultivar: (Arbequina, Koroneiki, and Arbosana)
Authors: Vidal Alfonso M. , Alcalá Sonia , de Torres Antonia , Moya Manuel , Espínola Francisco
Published: January 2019

Olive fruit maturation depends directly on the moment of olive harvest. In addition, the composition of extra virgin olive oil changes depending on the ripening degree of the fruit harvested. Likewise, using different olive cultivars in the extraction, the olive oil obtained has different quality and composition. Superintensive crops own special characteristics such as more trees per hectare than traditional crops. This improves the production of olives by surface; being superintensive more profitable than the traditional cultivar. Three different olive cultivars: Arbequina, Koroneiki, and Arbosana, and from superintensive crops with different irrigation management are used for the extraction. Olive oils are extracted at the laboratory with the Abencor system. Monounsaturated fatty acid (MUFA) content is increased by increasing the maturity index. The highest content of phenolic compounds is obtained from rainfed Koroneiki, with approximately 1 g kg−1. The maximum quantity of total lipoxygenase pathway volatile compounds is 28 mg kg−1, obtained in irrigated Arbequina olives. According to the results obtained, the optimum time of harvest is with a maturity index of approximately 2, when the content of oil, phenols, and MUFA reach their maximum. In addition, higher contents of minor components are obtained for rainfed than irrigated crops.

Practical Applications: Determining the optimal stage for harvest the fruit of the olive tree is the main practical application or potential use. Additionally, to predict, approximately, the composition of an olive oil that may have according to some agronomic factors, such as the cultivar used, irrigation management, or the stage of maturation of the olive fruit.

Different ripening degrees of the olive fruit, with different irrigation management and with different cultivar of olive trees, from superintensive crops are used to produce an extra virgin olive oil.
Synthesis of 7‐Allylated Benzofuran Derivatives from o‐Allyloxyethynylbenzene via Claisen Rearrangement and TBAF‐Catalyzed Annulation
Authors: Watanabe Kohei , Mino Takashi , Masuda Chihiro , Yoshida Yasushi , Sakamoto Masami
Published: January 2019

The 7‐allylated benzofuran derivatives were synthesized via a continuous reaction of Claisen rearrangement and annulation using o‐allyloxyetynylbenzene as starting material. In addition, it was observed that annulation of o‐alkynylphenol proceeded under mild conditions when carried out in the presence of a catalytic amount of TBAF. Furthermore, these continuous reactions could be achieved in a one‐pot reaction and afforded not only 7‐allylbenzofurans but also 7‐alkenylbenzofurans by controlling the reaction temperature and time of the annulation. Finally, we demonstrated that 7‐allylbenzofuran and 7‐alkenylbenzofuran could be converted into 7‐(2‐formylvinyl)benzofuran and 7‐formylbenzofuran derivatives, respectively. Therefore, various 7‐substituted benzofuran derivatives could be synthesized according to this synthetic strategy.
Effect of Silicon Crystallite Size on Its Electrochemical Performance for Lithium‐Ion Batteries
Authors: Domi Yasuhiro , Usui Hiroyuki , Sugimoto Kai , Sakaguchi Hiroki
Published: January 2019

It is reported that silicon (Si) anodes with a smaller crystallite size show better electrochemical performance in lithium‐ion batteries (LIBs); Si particles with different diameters are also used. However, it is yet to be clarified whether the better performance is attributed to crystallite size or particle diameter. The effect of Si crystallite size on its anode performance using Si particles having the same diameter and different crystallite sizes is investigated. Longer cycle life is obtained for smaller crystallite size, due to the small amount of the amorphous Li‐rich Li—Si phase formed during charging. The phase is likely to form in a greater amount in Si particles with larger crystallite size, leading to degradation of the Si electrode at an early stage. Furthermore, Si electrodes with larger crystallite size show superior rate performance because of the high Li diffusion rate into the broader grain boundary; on the other hand, Si with smaller crystallite size should limit Li diffusion due to the narrower grain boundary. Therefore, smaller crystallite size helps improve the cycle life but deteriorates the rate performance of LIBs.
Modeling the Influence of Mixing Strategies on Microstructural Properties of All‐Solid‐State Electrodes
Authors: Laue Vincent , Wolff Nicolas , Röder Fridolin , Krewer Ulrike
Published: January 2019

All‐solid‐state batteries currently have the disadvantage of low conductivity of the solid electrolytes (SEs) at room temperature and have issues with nonutilized active material (AM) and high reaction overpotentials due to a low SE/AM interface area. These limitations are partially due to the material properties because of the complex, yet nonoptimal production process. Therefore, a model‐based investigation of the influence of microstructural properties on the electronic and ionic conductivities of all‐solid‐state electrodes is conducted. The objective of this work is to highlight the optimization potential of the mixing and premixing of AM, SE, and conducting additive. The results show that the premixing of AM and conducting additives increases the effective electronic conductivity compared with that of the nonpremixed electrodes. It allows a significantly lower additive volume fraction as the percolation threshold of the conducting additive network reaches earlier. Conducting additives are shown to decrease the effective ionic conductivity by increasing the tortuosity of the microstructures, an effect which can be reduced by premixing the conducting additive and SE.
Nanostructured Polypyrrole Composite Aerogels for a Rechargeable Flexible Aqueous Zn‐Ion Battery with High Rate Capabilities
Authors: Li Xianwei , Xie Xiuli , Lv Ruihua , Na Bing , Wang Bin , He Yan
Published: January 2019

Aqueous Zn‐ion batteries usually suffer from an inferior rate capability because of high internal resistance. Herein, nanostructured polypyrrole (PPy) composite aerogels are fabricated as the flexible cathode of an aqueous Zn‐ion battery. Highly porous composite aerogels enable easy ion diffusion toward nanostructured PPy and a low internal resistance of 1.5 Ω cm−2. A high power density of 11.7 kW kg−1 is thus achieved for the aqueous Zn‐ion battery at a satisfactory energy density of 64.0 Wh kg−1, superior to other aqueous batteries and supercapacitors. The Zn‐ion battery exhibits good flexibility, as illustrated by high‐capacity retention of 80.3% after 1000 bending cycles. The flexible Zn‐ion battery with high rate capabilities could find practical applications in wearable electronics requiring rapid charge.
Effects of vortex finder shapes on the performance of cyclone separators
Authors: Wu Xiaoming , Chen Xiaobo
Published: January 2019

Researches on vortex finders of cyclone mostly focus on the diameter of the cylinder‐shaped vortex finder and the length of its internal section, while the shape of the internal section has significant effect on cyclone's performance. This article establishes, based on the Stairmand cyclone, five different cyclone models, including ones with diameter variation, and ones with internally contracted and expanded shapes. The collection efficiency and pressure drop are calculated by means of computational fluid dynamics and the relations of performances between different models are discussed. The collection efficiency improves significantly with the decrease of the vortex finder diameter; however it is accompanied with sharp increases of pressure drop. Two objectives of cyclone optimization, improving the collection efficiency and reducing the pressure drop, are seemingly contradictory. According to the result in this study, based on the standard Stairmand cyclone, the vortex finder design as contracted and expanded internal section can achieve smaller change in the collection efficiency and pressure drop. This provides a reference for vortex finder design to meet the demands of reduction of pressure drop but not decrease collection efficiency largely or vice versa. © 2019 American Institute of Chemical Engineers Environ Prog, 38:e13146, 2019
Indirect genetic effects clarify how traits can evolve even when fitness does not
Authors: Fisher David N. , McAdam Andrew G.
Published: January 2019

There are many situations in nature where we expect traits to evolve but not necessarily for mean fitness to increase. However, these scenarios are hard to reconcile simultaneously with Fisher's fundamental theorem of natural selection (FTNS) and the Price identity (PI). The consideration of indirect genetic effects (IGEs) on fitness reconciles these fundamental theorems with the observation that traits sometimes evolve without any adaptation by explicitly considering the correlated evolution of the social environment, which is a form of transmission bias. Although environmental change is often assumed to be absent when using the PI, here we show that explicitly considering IGEs as change in the social environment with implications for fitness has several benefits: (1) it makes clear how traits can evolve while mean fitness remains stationary, (2) it reconciles the FTNS with the evolution of maladaptation, (3) it explicitly includes density-dependent fitness through negative social effects that depend on the number of interacting conspecifics, and (4) it allows mean fitness to evolve even when direct genetic variance in fitness is zero, if related individuals interact and/or if there is multilevel selection. In summary, considering fitness in the context of IGEs aligns important theorems of natural selection with many situations observed in nature and provides a useful lens through which we might better understand evolution and adaptation.
Effects of ammonium polyphosphate and triphenyl phosphate on the flame retardancy, thermal, and mechanical properties of glass fiber–reinforced PLA/PC composites
Authors: Hazer Seda , Coban Meral , Aytac Ayse
Published: January 2019

The purpose of this study is to increase of the flammability properties of the glass fiber (GF)–reinforced poly (lactic acid)/polycarbonate (PLA/PC) composites. Ammonium polyphosphate (APP) and triphenyl phosphate (TPP) were used as flame retardants that are including the organic phosphor to increase flame retardancy of GF‐reinforced composites. APP, TPP, and APP‐TPP mixture flame retardant including composites were prepared by using extrusion and injection molding methods. The properties of the composites were determined by the tensile test, limiting oxygen index (LOI), differential scanning calorimetry (DSC), and heat release rate (HRR) test. The minimum Tg value was observed for the TPP including PLA/PC composites in DSC analysis. The highest tensile strength was observed in GF‐reinforced PLA/PC composites. In the LOI test, GF including composite was burned with the lowest concentration of oxygen, and burning time was the longest of this composite. However, the shortest burning time was obtained by using the mixture flame retardant system. The flame retardancy properties of GF‐reinforced PLA/PC composite was improved by using mixture flame retardant. When analyzed the results of HRR, time to ignition (TTI), and mass loss rate together, the best value was obtained for the composite including APP.
Sturgeon and Paddlefish Migration: Evidence to Support the Need for Interjurisdictional Management
Authors: Tripp Sara J , Phelps Quinton E , Hupfeld Ryan N , Herzog David P , Ostendorf David E , Moore Travis L , Brooks Ron C , Garvey James E
Published: January 2019

Paddlefish Polyodon spathula and three sturgeon species are present in the upper Mississippi River; of these four species, two are commercially and recreationally important (Paddlefish and Shovelnose Sturgeon Scaphirhynchus platorynchus), and two are protected under federal or state endangered species laws (Pallid Sturgeon S. albus and Lake Sturgeon Acipenser fulvescens). Before management strategies can be implemented, quantification of movement patterns is necessary to determine the appropriate spatial scale for management. To increase the available relevant information, we investigated broad-scale movement patterns of the above species in the upper Mississippi River by using telemetry. All four species were capable of long-range (>300-km) movements, and these movements were cued by the changing river stages and water temperature. Ultimately, our data suggest that sturgeon and Paddlefish movement patterns are highly variable, with fish moving freely among rivers (e.g., the Mississippi, Missouri, Illinois, Ohio, and Des Moines rivers) across many political boundaries and encompassing multiple regulatory agencies. This migratory nature can lead to portions of the population being subject to harvest in multiple management units, affecting population dynamics, biology, harvest, and management/recovery in both the natal area and in the harvest areas. To effectively manage or recover these highly mobile fish populations, interjurisdictional collaboration will be necessary.
Heat stability of the in vitro inhibitory effect of spices on lipase, amylase, and glucosidase enzymes
Authors: Fernando Irushika T. , Perera Kumudu I. , Athauda Senarath B. P. , Sivakanesan Ramiah , Kumar Nimal Savitri , Jayasinghe Lalith
Published: January 2019

This study investigated the effect of boiling on the inhibitory action of spices on digestive enzymes. Unboiled extracts of Trigonella foenum‐graecum (seed) (25.42%), Myristica fragrans (seed) (22.70%), and Cuminum cyminum (seed) (19.17%) showed significantly (p < 0.05) a higher lipase inhibitory activity than their respective boiled extracts (20.23%, 15.74%, and 12.57%). Unboiled extracts of Cinnamomum zeylanicum (stem bark) (−16.98%) and Foeniculum officinale (seed) (−16.05%) showed an activation of lipase enzyme, and boiling significantly (p < 0.05) changed the activity into lipase inhibition as 8.47% and 9.54%, respectively. Unboiled extracts of Coriandrm sativum (seed), C. cyminum, and Elettaria cardamomum (seed) showed an activation of amylase enzyme, and boiling these extracts significantly reduced the enzyme activation. The other unboiled extracts showed a higher amylase inhibition than the boiled extracts, whereas the boiled extracts of C.longa (rhizome) and Syzygium aromaticum (flower) exhibited significantly (p < 0.05) lower values. Unboiled extracts of C. zeylanicum, M. fragrans, and S. aromaticum showed an insignificantly higher glucosidase inhibitory activity than the boiled extracts. Inhibition of digestive enzymes by nutritional intervention is one avenue to be considered in treating diet‐induced obesity and in the management of postprandial hyperglycemia. Spices, used as food additives, could be a potential source of digestive enzyme inhibitors. The current study revealed that unboiled extracts of T. foenum‐graecum (seed), C. cyminum (seed), and M. fragrans (seed) are more effective than the boiled extracts as an antiobesity therapy. Moreover, it endorses the use of infusion of T. foenum‐graecum seeds as an antiobesity therapy.
Characterization of γ‐glutamyltranspeptidases from dormant garlic and onion bulbs
Authors: Sun Yuee , Hu Jing , Wang Weidong , Zhang Bin , Shen Yingbin
Published: January 2019

This study investigated the characteristics of γ‐glutamyltranspeptidases (GGTs) isolated from dormant garlic (Allium sativum L.) and onion (Allium cepa L. var. agrogatum Don) bulbs. GGTs were isolated using (NH4)2SO4 precipitation and hydrophobic interaction chromatography (phenyl‐Sepharose column). The optimal temperature, optimal pH of extraction, and the effects of metal ions and organic compounds on the activity of GGTs were investigated. The optimal pH of the GGTs of garlic and onion was 5 and 7, respectively; the optimal temperatures were 70 and 50°C, respectively. Garlic's GGT had a major band at 53 kDa, whereas onion's GGT had two bands at 55 and 22 kDa. Cu2+, Mn2+, Fe2+, Mg2+, glucose, aspartic acid, and cysteine significantly enhanced the activity of garlic's GGT. Lysine and proline remarkably promoted the activity of onion's GGT, whereas Cu2+, glucose, and aspartic acid repress its activity. These results may deepen our understanding of allium GGTs and promote the commercial production of bioactive allium compounds.
Paleolithic artifact deposits at Wadi Dabsa, Saudi Arabia: A multiscalar geoarchaeological approach to building an interpretative framework
Authors: Inglis Robyn H. , Fanning Patricia C. , Stone Abi , Barfod Dan N. , Sinclair Anthony , Chang Hsing‐Chung , Alsharekh Abdullah M. , Bailey Geoff
Published: January 2019

Surface artifacts dominate the archaeological record of arid landscapes, particularly the Saharo‐Arabian belt, a pivotal region in dispersals out of Africa. Discarded by hominins, these artifacts are key to understanding past landscape use and dispersals, yet behavioral interpretation of present‐day artifact distributions cannot be carried out without understanding how geomorphological processes have controlled, and continue to control, artifact preservation, exposure and visibility at multiple scales. We employ a geoarchaeological approach to unraveling the formation of a surface assemblage of 2,970 Palaeolithic and later lithic artifacts at Wadi Dabsa, Saudi Arabia, the richest locality recorded to date in the southwestern Red Sea coastal region. Wadi Dabsa basin, within the volcanic Harrat Al Birk, contains extensive tufa deposits formed during wetter conditions. We employ regional landscape mapping and automatic classification of surface conditions using satellite imagery, field observations, local landform mapping, archaeological survey, excavation, and sedimentological analyses to develop a multiscalar model of landscape evolution and geomorphological controls acting on artifact distributions in the basin. The main artifact assemblage is identified as a palimpsest of activity, actively forming on a deflating surface, a model with significant implications for future study and interpretation of this, and other, surface artifact assemblages.
Neural mechanisms of training an auditory event‐related potential task in a brain–computer interface context
Authors: Halder Sebastian , Leinfelder Teresa , Schulz Stefan M. , Kübler Andrea
Published: January 2019

Effective use of brain–computer interfaces (BCIs) typically requires training. Improved understanding of the neural mechanisms underlying BCI training will facilitate optimisation of BCIs. The current study examined the neural mechanisms related to training for electroencephalography (EEG)‐based communication with an auditory event‐related potential (ERP) BCI. Neural mechanisms of training in 10 healthy volunteers were assessed with functional magnetic resonance imaging (fMRI) during an auditory ERP‐based BCI task before (t1) and after (t5) three ERP‐BCI training sessions outside the fMRI scanner (t2, t3, and t4). Attended stimuli were contrasted with ignored stimuli in the first‐level fMRI data analysis (t1 and t5); the training effect was verified using the EEG data (t2‐t4); and brain activation was contrasted before and after training in the second‐level fMRI data analysis (t1 vs. t5). Training increased the communication speed from 2.9 bits/min (t2) to 4 bits/min (t4). Strong activation was found in the putamen, supplementary motor area (SMA), and superior temporal gyrus (STG) associated with attention to the stimuli. Training led to decreased activation in the superior frontal gyrus and stronger haemodynamic rebound in the STG and supramarginal gyrus. The neural mechanisms of ERP‐BCI training indicate improved stimulus perception and reduced mental workload. The ERP task used in the current study showed overlapping activations with a motor imagery based BCI task from a previous study on the neural mechanisms of BCI training in the SMA and putamen. This suggests commonalities between the neural mechanisms of training for both BCI paradigms.
Government doctor absenteeism and its effects on consumer demand in rural north India
Authors: Iles Richard A.
Published: January 2019

Government doctor absenteeism from their public posts is a sizable problem across developing economies. The consumer demand estimation for outpatient fever treatment presented in this paper investigates the interrelationship between government doctor absenteeism and the large informal healthcare sector. Using a counterfactual framework, this paper estimates treatment effect of eliminating government doctor absenteeism. The effects are measured by changes to the market share of government Bachelor of Medicine and Bachelor of Surgery (MBBS) providers and resulting own‐price elasticities of demand for government MBBS providers and unqualified providers. Modelling incorporates patients expected health outcomes by provider via the use of a qualitative measure of word‐of‐mouth recommendations. Results indicate that eliminating government MBBS provider absenteeism in North India would increase utilisation of government outpatient fever treatments from 18% to 50%.
Prognostic factors and treatment outcomes of advanced maxillary gingival squamous cell carcinoma treated by intra‐arterial infusion chemotherapy concurrent with radiotherapy
Authors: Hayashi Yuichiro , Osawa Kohei , Nakakaji Rina , Minamiyama Shuhei , Ohashi Nobuhide , Ohya Takashi , Iida Masaki , Iwai Toshinori , Ozawa Tomomichi , Oguri Senri , Koizumi Toshiyuki , Hirota Makoto , Kioi Mitomu , Hata Masaharu , Mitsudo Kenji
Published: January 2019

Background

The aim of this study was to evaluate the prognostic factors and treatment outcomes of advanced maxillary gingival squamous cell carcinoma (SCC) treated with intra‐arterial infusion chemotherapy concurrent with radiotherapy.

Methods

A total of 46 patients were reviewed retrospectively in this study. The treatment schedule comprised intra‐arterial chemotherapy (total, 60 mg/m2 docetaxel and 150 mg/m2 cisplatin) and three‐dimensional computed tomography based, daily conventional radiotherapy (total, 60 Gy/30 fr) for 6 weeks.

Results

The median follow‐up period was 40 months (range, 3‐110 months). The 3‐year overall survival and locoregional control rates for all patients were 64.3% and 84.3%, respectively. The OS rate of the patients with N0‐1 was significantly higher than that of the patients with N ≥ 2 (P < .05). No grade 5 toxicities were observed.

Conclusions

Intra‐arterial infusion chemotherapy concurrent with radiotherapy was effective for advanced maxillary gingival SCC.
JNJ‐4178 (AL‐335, Odalasvir, and Simeprevir) for 6 or 8 Weeks in Hepatitis C Virus‐Infected Patients Without Cirrhosis: OMEGA‐1
Authors: Zeuzem Stefan , Bourgeois Stefan , Greenbloom Susan , Buti Maria , Aghemo Alessio , Lampertico Pietro , Janczewska Ewa , Lim Seng Gee , Moreno Christophe , Buggisch Peter , Tam Edward , Corbett Chris , Willems Wouter , Vijgen Leen , Fevery Bart , Ouwerkerk‐Mahadevan Sivi , Ackaert Oliver , Beumont Maria , Kalmeijer Ronald , Sinha Rekha , Biermer Michael ,   on behalf of the OMEGA‐1 study team
Published: January 2019

The combination of three direct‐acting antiviral agents (AL‐335, odalasvir, and simeprevir: JNJ‐4178 regimen) for 6 or 8 weeks demonstrated good efficacy and safety in a phase IIa study in chronic hepatitis C virus (HCV) genotype (GT)‐1‐infected patients without cirrhosis and has now been evaluated in a larger phase IIb study, OMEGA‐1. This multicenter, randomized, open‐label study (NCT02765490) enrolled treatment‐naïve and interferon (±ribavirin) treatment‐experienced patients with HCV GT1, 2, 4, 5, or 6 infection. Patients with HCV GT3 infection and/or liver cirrhosis were excluded. Patients received AL‐335 800 mg, odalasvir 25 mg, and simeprevir 75 mg once daily for 6 or 8 weeks. The primary endpoint was sustained virologic response 12 weeks after the end of treatment (SVR12). In total, 365 patients (GT1a, 29.3%; GT1b, 42.5%; GT2, 12.3%; GT4, 14.2%; GT5, 1.4%; GT6, 0%) were randomized to receive 6 weeks (n = 183) or 8 weeks (n = 182) of treatment. SVR12 rates after 6 weeks (98.9%) or 8 weeks (97.8%) of treatment were noninferior to a historical control (98%). Viral relapse occurred in 5 patients (1.4%; 4 with HCV GT2c; 1 with GT1a). With the exception of 4 patients in the 8‐week group, including 3 patients with missing data at the SVR24 timepoint, all patients who achieved SVR12 also achieved SVR24. One GT1a‐infected patient experienced late viral relapse after achieving SVR18. Most adverse events (AEs) were mild with no treatment‐related serious AEs. All randomized patients completed treatment. Conclusion: In HCV‐infected patients, 6 and 8 weeks of treatment with JNJ‐4178 resulted in SVR12 rates of 98.9% and 97.8%, respectively, and was well tolerated.
An Efficient Combination Immunotherapy for Primary Liver Cancer by Harmonized Activation of Innate and Adaptive Immunity in Mice
Authors: Wen Liang , Xin Bing , Wu Panyisha , Lin Chia‐Hao , Peng Chuanhui , Wang Gaowei , Lee Jin , Lu Li‐Fan , Feng Gen‐Sheng
Published: January 2019

Immunotherapy with checkpoint inhibitors for liver cancer, while active in many clinical trials worldwide, may have uncertain outcomes due to the unique immunotolerant microenvironment of the liver. In previous experiments, we unexpectedly identified a robust liver tumor‐preventive effect of a synthetic double‐stranded RNA, polyinosinic‐polycytidylic acid (polyIC), in mice. Herein we further demonstrate that polyIC given at the precancer stage effectively prevented liver tumorigenesis by activating natural killer cells, macrophages, and some T‐cell subsets; no inhibitory effect was observed on tumor progression if injected after tumor initiation. Nevertheless, polyIC administration potently induced programmed death ligand 1 (PD‐L1) expression in liver sinusoid endothelial cells, which prompted us to test a combined treatment of polyIC and PD‐L1 antibody (Ab). Although injecting PD‐L1 Ab alone did not show any therapeutic effect, injection of polyIC sensitized the hepatic response to PD‐L1 blockade. Combination of polyIC and PD‐L1 Ab resulted in sustained accumulation of active cluster of differentiation 8 cytotoxic T cells and robust liver tumor suppression and conferred a survival advantage in mice. These preclinical data in animal models suggest that, despite the low efficacy of PD‐L1/PD‐1 blockade alone, careful design of mechanism‐based combinatorial immunotherapeutic protocols may shift the paradigm in liver cancer treatment by coordinating maximal activation of multiple innate and adaptive immune functions. Conclusion: We provide proof of principle for the development of an efficient prevention strategy of liver tumorigenesis and a powerful combination immunotherapy for primary liver cancer.
Lynch‐like syndrome is as frequent as Lynch syndrome in early‐onset nonfamilial nonpolyposis colorectal cancer
Authors: Antelo Marina , Golubicki Mariano , Roca Enrique , Mendez Guillermo , Carballido Marcela , Iseas Soledad , Cuatrecasas Miriam , Moreira Leticia , Sanchez A , Carballal S , Castells Antoni , Boland Clement R. , Goel Ajay , Balaguer Francesc
Published: January 2019

Early‐onset (<50 years‐old) nonpolyposis nonfamilial colorectal cancer (EO NP NF CRC) is a common clinical challenge. Although Lynch syndrome (LS) is associated with EO CRC, the frequency of this syndrome in the EO NF cases remains unknown. Besides, mismatch repair deficient (MMRd) CRCs with negative MMR gene testing have recently been described in up to 60% of cases and termed “Lynch‐like syndrome” (LLS). Management and counseling decisions of these patients are complicated because of unconfirmed suspicions of hereditary cancer. To define the prevalence of MMR deficient CRCs, LS and LLS in patients with EO NP NF CRC, we recruited 102 patients with a first diagnosis of NP NF CRC ≤ 50 years old during 2003–2009 who underwent genetic counseling at our institution in Argentina. Tumor immunohistochemical (IHC) MMR for protein expression and microsatellite instability (MSI) status were evaluated, and in those with loss of MLH1 expression by IHC, somatic BRAF V600E mutation and both somatic and germline MLH1 methylation levels were studied. Tumors characterized as MMRd without somatic BRAF mutation nor MLH1 methylation were sent for germline analysis. Twenty one (20.6%) tumors were MMRd. Fourteen of 16 putative LS cases underwent germline testing: 6 pathogenic mutations were identified and 8 cases had no identifiable pathogenic mutations. The prevalence of LS and LLS in this cohort was 5.8% (6/102) and 7.8% (8/102), respectively. As a conclusion we found that 20% of patients with EO NP NF CRC have MMRd tumors, and at least half of these are likely to have LLS.
Evaluation of soluble carbonic anhydrase IX as predictive marker for efficacy of bevacizumab: A biomarker analysis from the geparquinto phase III neoadjuvant breast cancer trial
Authors: Janning Melanie , Müller Volkmar , Vettorazzi Eik , Cubas‐Cordova Miguel , Gensch Victoria , Ben‐Batalla Isabel , zu Eulenburg Christine , Schem Christian , Fasching Peter A. , Schnappauf Benjamin , Karn Thomas , Fehm Tanja , Just Marianne , Kühn Thorsten , Holms Frank , Overkamp Friedrich , Krabisch Petra , Rack Brigitte , Denkert Carsten , Untch Michael , Tesch Hans , Rezai Mahdi , Kittel Kornelia , Pantel Klaus , Bokemeyer Carsten , Loibl Sibylle , von Minckwitz Gunter , Loges Sonja
Published: January 2019

We analyzed the predictive potential of pretreatment soluble carbonic anhydrase IX levels (sCAIX) for the efficacy of bevacizumab in the phase III neoadjuvant GeparQuinto trial. sCAIX was determined by enzyme‐linked immunosorbent assay (ELISA). Correlations between sCAIX and pathological complete response (pCR), disease‐free and overall survival (DFS, OS) were assessed with logistic and Cox proportional hazard regression models using bootstrapping for robust estimates and internal validation. 1,160 HER2‐negative patient sera were analyzed, of whom 577 received bevacizumab. Patients with low pretreatment sCAIX had decreased pCR rates (12.1 vs. 20.1%, p = 0.012) and poorer DFS (adjusted 5‐year DFS 71.4 vs. 80.5 months, p = 0.010) compared to patients with high sCAIX when treated with neoadjuvant chemotherapy (NCT). For patients with low sCAIX, pCR rates significantly improved upon addition of bevacizumab to NCT (12.1 vs. 20.4%; p = 0.017), which was not the case in patients with high sCAIX (20.1% for NCT vs. 17.0% for NCT‐B, p = 0.913). When analyzing DFS we found that bevacizumab improved 5‐year DFS for patients with low sCAIX numerically but not significantly (71.4 vs. 78.5 months; log rank 0.234). In contrast, addition of bevacizumab worsened 5‐year DFS for patients with high sCAIX (81 vs. 73.6 months, log‐rank 0.025). By assessing sCAIX levels we identified a patient cohort in breast cancer that is potentially undertreated with NCT alone. Bevacizumab improved pCR rates in this group, suggesting sCAIX is a predictive biomarker for bevacizumab with regards to treatment response. Our data also show that bevacizumab is not beneficial in patients with high sCAIX.
Screen‐detected and interval colorectal cancers in England: Associations with lifestyle and other factors in women in a large UK prospective cohort
Authors: Blanks Roger , Burón Pust Andrea , Alison Rupert , He Emily , Barnes Isobel , Patnick Julietta , Reeves Gillian K , Floud Sarah , Beral Valerie , Green Jane
Published: January 2019

Faecal occult blood (FOB) ‐ based screening programmes for colorectal cancer detect about half of all cancers. Little is known about individual health behavioural characteristics which may be associated with screen‐detected and interval cancers. Electronic linkage between the UK National Health Service Bowel Cancer Screening Programme (BCSP) in England, cancer registration and other national health records, and a large on‐going UK cohort, the Million Women Study, provided data on 628,976 women screened using a guaiac‐FOB test (gFOBt) between 2006 and 2012. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated by logistic and Cox regression for associations between individual lifestyle factors and risk of colorectal tumours. Among screened women, 766 were diagnosed with screen‐detected colorectal cancer registered within 2 years after a positive gFOBt result, and 749 with interval colorectal cancers registered within 2 years after a negative gFOBt result. Current smoking was significantly associated with risk of interval cancer (RR 1.64, 95%CI 1.35–1.99) but not with risk of screen‐detected cancer (RR 1.03, 0.84–1.28), and was the only factor of eight examined to show a significant difference in risk between interval and screen‐detected cancers (p for difference, 0.003). Compared to screen‐detected cancers, interval cancers tended to be sited in the proximal colon or rectum, to be of non‐adenocarcinoma morphology, and to be of higher stage.
Genome‐wide association study of peripheral blood DNA methylation and conventional mammographic density measures
Authors: Li Shuai , Dugué Pierre‐Antoine , Baglietto Laura , Severi Gianluca , Wong Ee Ming , Nguyen Tuong L. , Stone Jennifer , English Dallas R. , Southey Melissa C. , Giles Graham G. , Hopper John L. , Milne Roger L.
Published: January 2019

Age‐ and body mass index (BMI)‐adjusted mammographic density is one of the strongest breast cancer risk factors. DNA methylation is a molecular mechanism that could underlie inter‐individual variation in mammographic density. We aimed to investigate the association between breast cancer risk‐predicting mammographic density measures and blood DNA methylation. For 436 women from the Australian Mammographic Density Twins and Sisters Study and 591 women from the Melbourne Collaborative Cohort Study, mammographic density (dense area, nondense area and percentage dense area) defined by the conventional brightness threshold was measured using the CUMULUS software, and peripheral blood DNA methylation was measured using the HumanMethylation450 (HM450) BeadChip assay. Associations between DNA methylation at >400,000 sites and mammographic density measures adjusted for age and BMI were assessed within each cohort and pooled using fixed‐effect meta‐analysis. Associations with methylation at genetic loci known to be associated with mammographic density were also examined. We found no genome‐wide significant (p < 10−7) association for any mammographic density measure from the meta‐analysis, or from the cohort‐specific analyses. None of the 299 methylation sites located at genetic loci associated with mammographic density was associated with any mammographic density measure after adjusting for multiple testing (all p > 0.05/299 = 1.7 × 10−4). In summary, our study did not find evidence for associations between blood DNA methylation, as measured by the HM450 assay, and conventional mammographic density measures that predict breast cancer risk.
High response rates for T‐VEC in early metastatic melanoma (stage IIIB/C‐IVM1a)
Authors: Franke Viola , Berger Danique M.S. , Klop W. Martin C. , van der Hiel Bernies , van de Wiel Bart A. , ter Meulen Sylvia , Wouters Michel W.J.M. , van Houdt Winan J. , van Akkooi Alexander C.J.
Published: January 2019

Talimogene laherparepvec (T‐VEC) is a modified herpes simplex virus, type 1 (HSV‐1), which can be administered intralesionally in patients with stage IIIB/C‐IVM1a unresectable melanoma (EMA label). The phase 3 OPTiM registration study showed an overall response rate (ORR) of 26%. Since December 2016, 48 eligible patients started treatment at the Netherlands Cancer Institute. We included 26 patients in this study with a follow up time ≥6 months, reporting Overall Response Rate (ORR), Disease Control Rate (DCR), Adverse Events (AE), prior treatment for melanoma and baseline characteristics, documented in a prospectively maintained database. In house developed treatment protocol consists of clinical evaluation, periodic PET‐CT and histological biopsies for response evaluation. Median follow‐up was 12.5 months. Of 26 patients, 16 (61.5%) had a Complete Response (CR) as their best response. Seven (26.9%) patients had a Partial Response (PR) as their best response, 1 (3.8%) patient Stable Disease (SD) and 2 (7.7%) patients Progressive Disease (PD). Best ORR was 88.5%. DCR was 92.3%. Grade 1–2 AEs occurred in all patients. Mostly, these consisted of fatigue, influenza‐like symptoms and injection site erythema. All patients underwent prior treatment. Prior treatment did not influence response or toxicity of T‐VEC. Best ORR for T‐VEC monotherapy at our institute was 88.5% with 61.5% achieving a CR. This prospective study for T‐VEC in early metastatic (stage IIIB/C‐IVM1a) melanoma demonstrated superior results to the phase 3 OPTiM study and confirms the role of oncolytic immunotherapy for melanoma.
Information privacy practices in e‐government in an African least developing country, Rwanda
Authors: Mutimukwe Chantal , Kolkowska Ella , Grönlund Åke
Published: January 2019

Privacy of information is a critical issue for e‐government development as lack of it negatively influences users' trust and adoption of e‐government. To earn user trust government organizations need to provide reliable privacy assurance by implementing adequate information privacy protection (IPP) practices. African least developing countries (LDCs) today develop e‐government, but focus is on quick technical development, and the status of IPP issues is not clear. Little research has yet studied the status of IPP practices in e‐government in African LDCs. To fill this gap, we assess the status of existing IPP practices in e‐government in Rwanda, using international privacy principles as an assessment baseline. We adopt a case study approach including three cases. Data were collected by interviews and a survey. The findings call into question the efficacy of existing IPP practices and their effect in ensuring e‐government service users' privacy protection in Rwanda. The study extends existing literature by providing insights related to privacy protection from an African LDC context. For practitioners in Rwanda and other LDCs, this study contributes to the protection of information privacy in e‐government by providing recommendations to mitigate identified gaps.
An intervention using morphology to derive word meanings for English language learners
Authors: Davidson Sean J. , O'Connor Rollanda E.
Published: January 2019

Many English language learners (ELL) experience academic and reading difficulties compared to native English speakers (NES). Lack of vocabulary knowledge is a contributing factor for these difficulties. Teaching students to analyze words into their constituent morphemes (meaningful word units) in order to determine the meaning of words may be an avenue to increase vocabulary knowledge. This study investigated potential benefits of morphological instruction for learning vocabulary words and generalizing taught words to untaught words containing these morphemes. Nine fourth‐ and fifth‐grade ELL with reading difficulties participated in a multiple baseline, single‐case design study. Visual analysis of the results revealed a functional relation between the intervention and an increase in participants' vocabulary scores with 90% to 100% nonoverlapping data for eight participants. The effects of training generalized to untaught words. These findings suggest that morphological analysis is a promising approach to increase vocabulary knowledge of ELL.
The Osteocyte Transcriptome Is Extensively Dysregulated in Mouse Models of Osteogenesis Imperfecta
Authors: Zimmerman Sarah M , Dimori Milena , Heard‐Lipsmeyer Melissa E , Morello Roy
Published: January 2019

Osteocytes are long‐lived, highly interconnected, terminally differentiated osteoblasts that reside within mineralized bone matrix. They constitute about 95% of adult bone cells and play important functions including in the regulation of bone remodeling, phosphate homeostasis, and mechanical stimuli sensing and response. However, the role of osteocytes in the pathogenesis of congenital diseases of abnormal bone matrix is poorly understood. This study characterized in vivo transcriptional changes in osteocytes from CrtapKO and oim/oim mouse models of osteogenesis imperfecta (OI) compared with wild‐type (WT) control mice. To do this, RNA was extracted from osteocyte‐enriched cortical femurs and tibias, sequenced and subsequently analyzed to identify differentially expressed transcripts. These models were chosen because they mimic two types of OI with different genetic mutations that result in distinct type I collagen defects. A large number of transcripts were dysregulated in either model of OI, but 281 of them were similarly up‐ or downregulated in both compared with WT controls. Conversely, very few transcripts were differentially expressed between the CrtapKO and oim/oim mice, indicating that distinct alterations in type I collagen can lead to shared pathogenic processes and similar phenotypic outcomes. Bioinformatics analyses identified several critical hubs of dysregulation that were enriched in annotation terms such as development and differentiation, ECM and collagen fibril organization, cell adhesion, signaling, regulatory processes, pattern binding, chemotaxis, and cell projections. The data further indicated alterations in important signaling pathways such as WNT and TGF‐β but also highlighted new candidate genes to pursue in future studies. Overall, our study suggested that the osteocyte transcriptome is broadly dysregulated in OI with potential long‐term consequences at the cellular level, which deserve further investigations. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Accuracy of FRAX® in People With Multiple Sclerosis
Authors: Bisson Etienne J , Finlayson Marcia L , Ekuma Okechukwu , Marrie Ruth Ann , Leslie William D
Published: January 2019

People with multiple sclerosis (MS) have a higher risk of low bone mineral density (BMD), osteoporosis, and osteoporotic fractures than healthy adults. The Fracture Risk Assessment tool (FRAX®) has been reported to underestimate fracture risk in people with MS when BMD is unknown. We tested FRAX performance for people with MS when BMD is known, and determined if MS is a risk factor for fracture independent of FRAX score. Using population-based databases in Manitoba, Canada, we identified people with MS who underwent BMD screening after MS diagnosis (n = 744) and controls matched on age, sex, and first BMD screening date (n = 3721). We calculated FRAX 10-year probabilities at the BMD screening date, and ascertained incident major osteoporotic fractures (MOF). Using Cox proportional hazards modeling we assessed the effect of MS on the hazard of MOF, adjusting for FRAX 10-year probabilities. MS cases had a higher mean FRAX 10-year probability of MOF calculated with BMD (8.32 ± 7.53) than controls (6.98 ± 5.18; p < 0.01). MS increased the risk for MOF after controlling for FRAX 10-year probability without BMD (HR 1.67; 95% confidence interval [CI], 1.29 to 2.16), and after controlling for FRAX individual risk factors (HR 1.45; 95% CI, 1.12 to 1.89). MS remained a risk factor for MOF even when controlling for FRAX 10-year probability of MOF with BMD (HR 1.48; 95% CI, 1.14 to 1.92). The FRAX 10-year probability with and without BMD underestimated the observed 10-year MOF risk in MS cases by 3% to 5%. Calibration improved when secondary osteoporosis was used to calculate FRAX without BMD. Calibration was best when the rheumatoid arthritis input was used to calculate FRAX probability along with BMD. Using secondary osteoporosis or rheumatoid arthritis as proxies for MS improves performance of FRAX and accurately predicts MOF outcomes in those with MS. This provides clinicians with a readily available approach to improve the accuracy of fracture prediction in MS. © 2019 American Society for Bone and Mineral Research.