bluuebunny/crossref_metadata_2025 huggingface dataset:
Resolution of unexpected pregnancy‐related findings in a rat embryofetal development and toxicokinetic study of monoclonal antibodies specific for hCMV
Authors: Katavolos Paula , Prell Rodney , Zane Doris , Deng Rong , Halpern Wendy
Published: November 2018

Background

Developmental and reproductive toxicity testing is not uniformly warranted for biopharmaceuticals that lack relevant targets in test species. However, RG7667, consisting of two monoclonal antibodies specific for human cytomegalovirus (hCMV), was intended for administration to pregnant women to prevent transmission of CMV to the developing fetus.

Methods

Considering the target indication, a Pilot Embryo Fetal Development/Toxicokinetic study was conducted to assess toxicokinetics in the dam and fetuses and general tolerability.

Results

RG7667 administered intravenously to presumed pregnant Sprague–Dawley rats was well tolerated with no clinical signs in any dam and comparable litter sizes and viability across groups. However, at cesarean section, hepatic necrosis and pancreatic edema were identified in two dams administered RG7667, with no clear dose relationship. Investigation of total protein, albumin, and transaminase activity in residual serum from TK samples demonstrated striking hypoproteinemia and elevated transaminases limited to these two dams. Overall, these pathology findings in dams were considered of uncertain relationship to RG7667; therefore, a subsequent Pivotal EFD study was conducted, which did not repeat the liver or pancreatic findings.

Conclusions

The results of the Pivotal study confirmed the lack of overt toxicity, teratogenicity, or effects on litter size and viability when human or humanized monoclonal antibodies that lack an endogenous target are administered IV to rats during pregnancy. With these additional data, we concluded that the unexpected pathology findings in the Pilot study were not specific to RG7667, but rather highlight some clinical pathology and macroscopic/microscopic findings that can occur during pregnancy in rats.
Quantitative imaging of cancer in the postgenomic era: Radio(geno)mics, deep learning, and habitats
Authors: Napel Sandy , Mu Wei , Jardim‐Perassi Bruna V. , Aerts Hugo J. W. L. , Gillies Robert J.
Published: November 2018

Although cancer often is referred to as “a disease of the genes,” it is indisputable that the (epi)genetic properties of individual cancer cells are highly variable, even within the same tumor. Hence, preexisting resistant clones will emerge and proliferate after therapeutic selection that targets sensitive clones. Herein, the authors propose that quantitative image analytics, known as “radiomics,” can be used to quantify and characterize this heterogeneity. Virtually every patient with cancer is imaged radiologically. Radiomics is predicated on the beliefs that these images reflect underlying pathophysiologies, and that they can be converted into mineable data for improved diagnosis, prognosis, prediction, and therapy monitoring. In the last decade, the radiomics of cancer has grown from a few laboratories to a worldwide enterprise. During this growth, radiomics has established a convention, wherein a large set of annotated image features (1‐2000 features) are extracted from segmented regions of interest and used to build classifier models to separate individual patients into their appropriate class (eg, indolent vs aggressive disease). An extension of this conventional radiomics is the application of “deep learning,” wherein convolutional neural networks can be used to detect the most informative regions and features without human intervention. A further extension of radiomics involves automatically segmenting informative subregions (“habitats”) within tumors, which can be linked to underlying tumor pathophysiology. The goal of the radiomics enterprise is to provide informed decision support for the practice of precision oncology.
Should chemotherapy plus immune checkpoint inhibition be the standard front‐line therapy for patients with metastatic non–small cell lung cancer?
Authors: Goldberg Sarah B. , Herbst Roy S.
Published: November 2018

Recent trials have demonstrated that the addition of a programmed cell death protein 1 inhibitor to chemotherapy in the first‐line setting in patients with metastatic squamous or nonsquamous non–small cell lung cancer improves survival compared with chemotherapy alone. These findings provide a new treatment option for patients with newly diagnosed, advanced non–small cell lung cancer, regardless of tumor histology or programmed death‐ligand 1 expression, thereby representing a major advancement in the field.
ABOUND.2L+: A randomized phase 2 study of nanoparticle albumin‐bound paclitaxel with or without CC‐486 as second‐line treatment for advanced nonsquamous non‐small cell lung cancer (NSCLC)
Authors: Morgensztern Daniel , Cobo Manuel , Ponce Aix Santiago , Postmus Pieter E. , Lewanski Conrad R. , Bennouna Jaafar , Fischer Jürgen R. , Juan‐Vidal Oscar , Stewart David J. , Fasola Gianpiero , Ardizzoni Andrea , Bhore Rafia , Wolfsteiner Marianne , Talbot Denis C. , Jin Ong Teng , Govindan Ramaswamy , on behalf of the ABOUND.2L+ Investigators
Published: November 2018

Background

This randomized phase 2 trial compared the efficacy and safety of second‐line nanoparticle albumin‐bound paclitaxel (nab‐paclitaxel) with or without the addition of CC‐486 (an oral formulation of 5‐azacytidine) in patients with advanced‐stage, nonsquamous non‐small cell lung cancer.

Methods

Patients were randomized to receive either nab‐paclitaxel 100 mg/m2 on days 8 and 15 plus CC‐486 200 mg daily on days 1 to 14 or single‐agent nab‐paclitaxel 100 mg/m2 on days 1 and 8, with both regimens administered every 21 days until tumor progression or unacceptable toxicity. The primary endpoint was progression‐free survival. Secondary endpoints included the overall response rate, the disease control rate, and overall survival.

Results

Between January 2015 and August 2016, 161 patients were randomized (81 to the combination arm and 80 to the single‐agent nab‐paclitaxel arm). There was no benefit from the addition of CC‐486 to nab‐paclitaxel. The median progression‐free survival was 3.2 months for the combination and 4.2 months for single‐agent nab‐paclitaxel (hazard ratio, 1.3; 95% confidence interval, 0.9‐1.9). The median overall survival was 8.1 months in the combination arm and 17 months in the single‐agent nab‐paclitaxel arms (hazard ratio, 1.7; 95% confidence interval, 1.08‐2.57). Grade 3 or greater treatment‐related, emergent adverse events were reported by 40.5% of patients in the combination arm and by 31.6% of those in the single‐agent nab‐paclitaxel arm.

Conclusions

Single‐agent nab‐paclitaxel was associated with promising outcomes and a tolerable safety profile as second‐line treatment for patients with advanced‐stage, nonsquamous non‐small cell lung cancer. There was no benefit from the addition of CC‐486 to nab‐paclitaxel.
Estimating child mortality associated with maternal mortality from breast and cervical cancer
Authors: Mailhot Vega Raymond B. , Balogun Onyinye D. , Ishaq Omar F. , Bray Freddie , Ginsburg Ophira , Formenti Silvia C.
Published: November 2018

Background

Large‐scale population studies demonstrate an association between mothers’ deaths and child mortality in both lower and higher income countries. The authors estimated children’s deaths in association with mothers’ deaths from breast or cervical cancer, 2 common cancers in low‐income and middle‐income countries affecting women of reproductive age, to develop a comprehensive assessment of the death burden of these cancers.

Methods

A Monte Carlo simulation model was devised whereby women were at risk of dying from breast cancer, cervical cancer, or another cause. Compared with children who have living mothers, children of women who die before they reached age 10 years have an elevated risk of death from all causes. Therefore, simulations were conducted, and the impact of mothers’ deaths from cervical and breast cancer on associated child mortality was quantified for Bangladesh, Burkina Faso, and Denmark (benchmark analysis), then the analyses were extended to all African countries.

Results

Benchmark estimates of child deaths associated with mothers’ deaths from breast and cervical cancer resulted in an increment in cancer‐related mortality of approximately 2% in Bangladesh, 14% in Burkina Faso, and less than 1% in Denmark. The model predicted an increment in comprehensive cancer deaths when including child death estimates by as high as 30% in certain African countries.

Conclusions

To the authors’ knowledge, this is the first study to estimate the impact of a mother’s death from cancer on child mortality. The model’s estimates call for further investigation into this correlation and underscore the relevance of adequate access to prevention and treatment among women of childbearing age.
2H and 13C NMR‐Based Enantiodetection Using Polyacetylene versus Polypeptide Aligning Media: Versatile and Complementary Tools for Chemists
Authors: Lesot Philippe , Berdagué Philippe , Meddour Abdelkrim , Kreiter Alexander , Noll Markus , Reggelin Michael
Published: November 2018

In this work, the practical/analytical potential of an L‐valine‐derived polyacetylene (PLA) lyotropic liquid crystal (LLC) is examined to spectrally discriminate enantiomers (racemic mixture) or enantiotopic directions of a large collection (23) of (pro)chiral model compounds (from rigid to flexible and polar to apolar ones), thus covering various important aspects of enantiomorphism. Experimental 2H‐{1H} (deuterated analytes and at natural abundance level) and 13C‐{1H} NMR results are discussed in terms of the difference of 2H‐RQCs or 13C‐RCSAs and compared to those obtained in polypeptide‐type LLCs (PBLG). The analysis of the NMR results provides an overview of the enantiodifferentiation capabilities of PLA and gives useful/practical hints for the chemist to select the most appropriate chiral oriented system. Astonishing NAD NMR results were obtained in the case of one of the simplest, chiral alkanes, 3‐methylhexane. From a theoretical viewpoint, the data collected highlight the key molecular factors involved in orientation/discrimination processes, as a basis for optimizing computational prediction (molecular dynamics simulation), as well as designing novel helically chiral polymers as new enantiodiscriminating aligning media. In addition, a new, robust and efficient protocol to synthesize PLA and its enantiomer (PDA) on a large scale and with small polydispersities is proposed.
Design, synthesis, and biological evaluation of Helicobacter pylori inosine 5′‐monophosphate dehydrogenase (HpIMPDH) inhibitors
Authors: Sahu Niteshkumar U. , Purushothaman Gayathri , Thiruvenkatam Vijay , Kharkar Prashant S.
Published: November 2018

Inosine 5′‐monophosphate dehydrogenase (IMPDH) catalyzes a crucial step in the biosynthesis of guanine nucleotides. Being a validated target for immunosuppressive, antiviral, and anticancer drug development, lately it has been exploited as a promising target for antimicrobial therapy. Extending our previous work on Mycobacterium tuberculosis IMPDH, GuaB2, inhibitor development, we screened a set of 23 new chemical entities (NCEs) with substituted flavone (Series 1) and 1,2,3‐triazole (Series 2) core structures for their in vitro Helicobacter pylori IMPDH (HpIMPDH) and human IMPDH2 (hIMPDH2) inhibitory activities. All the NCEs possessed acceptable molecular, physicochemical, and toxicity property profiles. The ranges for HpIMPDH and hIMPDH2 inhibition were 9–99.9% and 16–57%, respectively, at 10 μM concentration. The most potent HpIMPDH inhibitor, 25c, exhibited IC50 value of 1.27 μM with no hIMPDH2 inhibitory activity. The moderately potent, structurally novel hit molecule, 25c, may serve as a lead for further design and development of highly potent HpIMPDH inhibitors.
The first complete mitochondrial genome of the Mariana Trench Freyastera benthophila (Asteroidea: Brisingida: Brisingidae) allows insights into the deep‐sea adaptive evolution of Brisingida
Authors: Mu Wendan , Liu Jun , Zhang Haibin
Published: November 2018

Starfish (phylum Echinodermata) are ecologically important and diverse members of marine ecosystems in all of the world's oceans, from the shallow water to the hadal zone. The deep sea is recognized as an extremely harsh environment on earth. In this study, we present the mitochondrial genome sequence of Mariana Trench starfish Freyastera benthophila, and this study is the first to explore in detail the mitochondrial genome of a deep‐sea member of the order Brisingida. Similar to other starfish, it contained 13 protein‐coding genes, two ribosomal RNA genes, and 22 transfer RNA genes (duplication of two tRNAs: trnL and trnS). Twenty‐two of these genes are encoded on the positive strand, while the other 15 are encoded on the negative strand. The gene arrangement was identical to those of sequenced starfish. Phylogenetic analysis showed the deep‐sea Brisingida as a sister taxon to the traditional members of the Asteriidae. Positive selection analysis indicated that five residues (8 N and 16 I in atp8, 47 D and 196 V in nad2, 599 N in nad5) were positively selected sites with high posterior probabilities. Compared these features with shallow sea starfish, we predict that variation specifically in atp8, nad2, and nad5 may play an important role in F. benthophila's adaptation to deep‐sea environment.
Investigation of Malonic Acid in Superacidic Solutions
Authors: Schickinger Manuel , Zischka Florian , Stierstorfer Karin , Kornath Andreas
Published: November 2018

Malonic acid reacts with the superacidic solutions XF/MF5 (X = H, D; M = As, Sb) to form their corresponding salts [(OH)2CCH2C(O)OH][MF6] and [(OH)2CCH2C(OH)2][MF6]2. The hexafluoridometalates of the mono‐ and diprotonated malonic acid have been characterized by vibrational spectroscopy and single‐crystal X‐ray structure analyses. Monoprotonated malonic acid, [(OH)2CCH2C(O)OH][AsF6], crystallizes in the orthorhombic space group Pbca with eight formula units per unit cell: a = 9.6739(4) Å, b = 11.8355(5) Å, c = 13.9826(6) Å, and diprotonated malonic acid, [(OH)2CCH2C(OH)2][AsF6]2, crystallizes in the monoclinic space group P21/n with four formula units per unit cell: a = 7.3348(2) Å, b = 9.8437(3) Å, c = 16.6903(6) Å, β = 97.818(3)°. The experimental data are compared to quantum chemical calculations at the MP2/aug‐cc‐pVTZ‐level of theory for the free cations [(OH)2CCH2C(O)OH]+ and [(OH)2CCH2C(OH)2]2+. A six‐membered ring‐like structure containing an intramolecular hydrogen bond was found for the monoprotonated species of malonic acid.
Hyperbolic normal stochastic volatility model
Authors: Choi Jaehyuk , Liu Chenru , Seo Byoung Ki
Published: November 2018

For option pricing models and heavy‐tailed distributions, this study proposes a continuous‐time stochastic volatility model based on an arithmetic Brownian motion: a one‐parameter extension of the normal stochastic alpha‐beta‐rho (SABR) model. Using two generalized Bougerol's identities in the literature, the study shows that our model has a closed‐form Monte Carlo simulation scheme and that the transition probability for one special case follows Johnson's distribution—a popular heavy‐tailed distribution originally proposed without stochastic process. It is argued that the distribution serves as an analytically superior alternative to the normal SABR model because the two distributions are empirically similar.
Cancer diagnosis and immunotherapy in the age of CRISPR
Authors: Cook Peter J. , Ventura Andrea
Published: November 2018

The explosion in genome editing technologies that has occurred in the past decade has revolutionized cancer research and promises to improve cancer diagnosis and therapy. Ongoing efforts include engineering of chimeric antigen receptor‐T cells using clustered regularly interspaced short palindromic repeats (CRISPR) to generate a safer, more effective therapy with improved performance in immunologically “cold” tumors, as well as clever adaptations of CRISPR enzymes to allow fast, simple, and sensitive detection of specific nucleotide sequences. While still in their infancy, CRISPR‐based cancer therapeutics and diagnostics are developing at an impressive speed and it is likely they will soon impact clinical practice. Here, we summarize their history and the most recent developments.
Smoking and Hepatitis B Virus–Related Hepatocellular Carcinoma Risk: The Mediating Roles of Viral Load and Alanine Aminotransferase
Authors: Wang Ya‐Hui , Chuang Ya‐Hui , Wu Chih‐Feng , Jan Meng‐Chin , Wu Wan‐Jung , Lin Chih‐Lin , Liu Chun‐Jen , Yang Ya‐Chien , Chen Pei‐Jer , Lin Shi‐Ming , Tsai Mong‐Hsun , Huang Yi‐Wen , Yu Ming‐Whei
Published: November 2018

Smoking interacts with hepatitis B virus (HBV) to increase the risk of hepatocellular carcinoma (HCC), which might be explained by its role in antiviral immunity. We evaluated the potential mediating role of viral load and/or alanine aminotransferase (ALT) in the relation of smoking with HBV‐associated HCC risk. Using multiple mediation analyses to analyze data from 209 HCC cases and 1,256 controls nested within a cohort of 4,841 male HBV carriers, we found that the effect of smoking on the risk of subsequent HCC was substantially mediated through viral load (percent mediated, 31.7%; P = 0.0054), and a significant mediation effect by both viral load and ALT was also evidenced. Among the 1,143 subjects with repeated measures of viral load and ALT over periods of up to 16 years, we further observed that a higher number of pack‐years of smoking was associated with higher viral load, maintenance of a high viral load (>4.39 log copies/mL), more severe hepatotoxicity grade, and increased likelihood of ALT ≥80 U/L (odds ratio, 3.14; 95% confidence interval, 1.03‐9.64; odds ratio, 6.06; 95% confidence interval, 1.10‐33.25, respectively, for 10‐19 and ≥20 pack‐years versus nonsmokers) during follow‐up. Furthermore, plasma interferon‐γ levels were reduced in smokers compared with nonsmokers (interferon‐γ‐positive rate, 14.9% versus 28.7%; P < 0.0001) at baseline. Smoking was also associated with a reduced natural killer (NK) cell frequency in peripheral blood, characterized by reduced NK function through a systems immunology approach, after long‐term follow‐up in a subsample (n = 171). The combination of smoking and reduced NK cell frequency further increased viral load and the likelihood of ALT ≥80 U/L. Conclusion: The data highlight a role of smoking in HBV viral load, underlining the importance of smoking prevention and cessation in hepatitis B management.
A Pathophysiologic Approach Combining Genetics and Insulin Resistance to Predict the Severity of Nonalcoholic Fatty Liver Disease
Authors: Danford Christopher J. , Connelly Margery A. , Shalaurova Irina , Kim Misung , Herman Mark A. , Nasser Imad , Otvos James D. , Afdhal Nezam H. , Jiang Z. Gordon , Lai Michelle
Published: November 2018

Nonalcoholic fatty liver disease (NAFLD) is a complex disease dictated by both genetic and environmental factors. While insulin resistance (IR) is a key pathogenic driver, two common genetic variants in patatin‐like phospholipase domain containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) also impart significant risk for disease progression. Traditional approaches to NAFLD risk stratification rely on biomarkers of fibrosis, an end result of disease progression. We hypothesized that by combining genetics and a novel measurement for IR we could predict disease progression by the NAFLD activity score (NAS) and histologic presence of significant fibrosis. A total of 177 patients with biopsy‐proven NAFLD were enrolled in this cross‐sectional study. PNPLA3 I148M and TM6SF2 E167K genotypes were determined by TaqMan assays. The enhanced lipoprotein IR index (eLP‐IR) was calculated from serum biomarkers using nuclear magnetic resonance (NMR) spectroscopy. Multivariate regression models were used to study the relationships between genetics, IR, and histologic features of NAFLD. In the multivariate analysis, the eLP‐IR was strongly associated with histologic features of NAFLD activity and hepatic fibrosis (P < 0.001 to 0.02) after adjustment for potential confounders. PNPLA3 148M and TM6SF2 E167K genotypes were significantly associated with steatosis (P = 0.003 and P = 0.02, respectively). A combination of the eLP‐IR and genetic score was able to predict the presence of NAS ≥3 with an area under the receiver operating characteristic curve (AUROC) of 0.74. Adding age to this model predicted stages 3‐4 liver fibrosis with an AUROC of 0.82. Conclusion: This proof‐of‐concept study supports the hypothesis that genetics and IR are major determinants of NAFLD severity and demonstrates the feasibility of a new risk stratification paradigm using exclusively pathogenic factors.
Patient‐specific determination of change in ocular spherical aberration to improve near and intermediate visual acuity of presbyopic eyes
Authors: Shetty Naren , Kochar Shruti , Paritekar Prajakta , Artal Pablo , Shetty Rohit , Nuijts Rudy M. M. A. , Webers Carroll A. B. , Sinha Roy Abhijit
Published: November 2018

The purpose was to determine the optimum negative spherical aberration induction required to improve near and intermediate visual acuity (VA) of presbyopic eyes. A total of 174 normal and diabetic (no retinopathy) presbyopic eyes (age ≥ 40 years) were measured with visual adaptive optics simulator (Voptica, Spain). First, baseline uncorrected VA and aberrations were measured. VA at 40 cm (near), 80 cm (intermediate) and distance was measured. Then, a negative spherical aberration (SA) was added to baseline ocular SA, and VA at all targets was reassessed after correction of distance refractive error. Clinically, baseline SA and root mean square of higher order aberrations were similar between the normal and diabetic presbyopic eyes. Baseline VA of the diabetic eyes at near and intermediate was better than the same of normal eyes (P = 0.001). After SA change, VA at near and intermediate of both normal and diabetic presbyopic eyes improved. However, fewer diabetic eyes needed higher SA change than normal eyes (P = 0.03). The corresponding trends with change in VA at near and intermediate were also similar between the normal and diabetic eyes. Patient‐specific modulation of ocular SA to improve near and intermediate VA in a large cohort of eyes was successful in improving VA, sometimes even distance VA.
Long noncoding RNA DLEU1 aggravates pancreatic ductal adenocarcinoma carcinogenesis via the miR‐381/CXCR4 axis
Authors: Gao Song , Cai Yunyun , Zhang Hu , Hu Fei , Hou Lengchen , Xu Qing
Published: November 2018

Recent evidence has highlighted that long noncoding RNAs (lncRNA) are associated with many diseases, particularly cancer. However, current understanding of the lncRNA deleted in lymphocytic leukemia 1 (DLEU1) in pancreatic ductal adenocarcinoma (PDAC) remains limited. Our studies indicated that the DLEU1 expression level was upregulated in PDAC tissue samples compared with adjacent normal tissue. Moreover, the aberrant overexpression of DLEU1 indicated poor prognosis of patients with PDAC. Loss‐of‐function experiments revealed that DLEU1 knockdown inhibited the proliferation, migration, and invasion of PDAC cells in vitro and decreased tumor growth in vivo. Bioinformatics analysis predicted that miR‐381 potentially targeted the DLEU1 3′‐untranslated region (UTR), suggesting an interaction between miR‐381 and DLEU1. Furthermore, miR‐381 also targeted the chemokine receptor‐4 (CXCR4) messenger RNA 3′‐UTR, which was validated by luciferase reporter assay. Taken together, our study demonstrated the oncogenic role of DLEU1 in clinical PDAC specimens and cellular experiments, showing the potential involvement of DLEU1/miR‐381/CXCR4 pathway. These results provide novel insight into PDAC tumorigenesis.
OCT4&SOX2‐specific cytotoxic T lymphocytes plus programmed cell death protein 1 inhibitor presented with synergistic effect on killing lung cancer stem‐like cells in vitro and treating drug‐resistant lung cancer mice in vivo
Authors: Zhang Xueyan , Hu Fang , Li Changhui , Zheng Xiaoxuan , Zhang Bo , Wang Huimin , Tao Guangyu , Xu Jianlin , Zhang Yanwei , Han Baohui
Published: November 2018

This study aimed to investigate the synergistic effect of octamer‐binding transcription factor 4 and sex determining region Y‐box 2 (OCT4&SOX2)‐specific cytotoxic T lymphocytes (CTLs) and programmed cell death protein 1 (PD‐1) inhibitor on killing lung cancer stem‐like cells (LCSCs) and their efficacy in treating drug‐resistant lung cancer (DRLC) mice. OCT4&SOX2‐specific CTLs and PD‐1 inhibitor with differed doses were applied to treat PC9 cells and PC9 LCSCs. Cell counting kit‐8 (CCK8) assay and flow cytometry (FCM) assay with carboxyfluorescein diacetate/succinimidyl ester staining target cells before treatment and propidium iodide (PI) staining dead cells after treatment were conducted to detect the cytotoxic activity. DRLC mice were constructed by injection of PC9 LCSCs suspension and Matrigel into left lung of SD mice. DRLC mice were randomly divided into five groups: control group, cytomegalovirus (CMV) pp65 CTLs group, OCT4&SOX2 CTLs group, PD‐1 inhibitor group, and OCT4&SOX2 CTLs + PD‐1 inhibitor group. In vitro, both CCK8 assay and FCM assay disclosed that OCT4&SOX2‐specific CTLs plus PD‐1 inhibitor presented with elevated cytotoxic activity on PC9 cells and PC9 LCSCs. In vivo, tumor volume and tumor weight were decreased, while tumor necrosis and tumor apoptosis were increased in OCT4&SOX2 CTLs group than CMV pp65 CTLs group and control group, and in OCT4&SOX2 CTLs + PD‐1 inhibitor group than OCT4&SOX2 CTLs group and PD‐1 inhibitor group. In addition, CD8 expression was increased while OCT4&SOX2 expressions were decreased in OCT4&SOX2 CTLs + PD‐1 inhibitor group than OCT4&SOX2 CTLs group and PD‐1 inhibitor group. In conclusion, OCT4&SOX2‐specific CTLs and PD‐1 inhibitor presented with the synergistic effect on killing LCSCs in vitro and treating DRLC mice in vivo.
Gas phase reaction between chromones and solvent in an electrospray ionization source
Authors: Liu Zhen , Shao Yunlong , Zhu Guizhen , Wang Xiayan , Chai Yunfeng , Wang Lin
Published: November 2018

Chromones were measured by using electrospray ionization mass spectrometry in negative mode. Interestingly, in addition to the deprotonated ion ([M − H]−), unexpected [M + 17]− and [M + 31]− ions were observed in high intensity when water and methanol were used as the solvent. Chromones with different substitutes were tested. Compared with the deprotonated ion, [M + 17]− and [M + 31]− ions were observed with higher abundances when the C‐3 site of chromones was substituted by electron withdrawing groups. Based on high performance liquid chromatography‐mass spectrometry (LC‐MS), deuterium‐labeling and collisional‐induced dissociation experiments, a covalent gas‐phase nucleophilic addition reaction between chromone and water, and the formation of a noncovalent complex between chromone and methanol were proposed as the mechanism for the observed [M + 17]− and [M + 31]− ions, respectively. Understanding and using these unique gas phase reactions can avoid misannotation when analyzing chromones and their metabolites.
The influence of ethnicity on disease outcome in patients with chronic hepatitis B infection
Authors: Koc Özgür M. , Robaeys Geert , Yildirim Beytullah , Posthouwer Dirk , Hens Niel , Koek Ger H.
Published: November 2018

Since the cultural diversity in Western Europe is growing, this study assessed whether foreign‐born chronic hepatitis B (CHB) patients have more cirrhosis than Dutch‐ or Belgian‐born patients, with a main focus on the Turkish population. Baseline characteristics (eg, socioeconomic status [SES]), biological characteristics, and disease outcome (eg, cirrhosis) were collected for all patients. Between December 2009 and January 2015, 269 CHB patients participated from the outpatient departments of three hospitals in the Netherlands, Belgium, and Turkey. Out of the 269 CHB patients, 210 were foreign‐born and 59 were Dutch‐ or Belgian‐born. Compared with Dutch‐ or Belgian‐born patients, foreign‐born patients had a higher prevalence of low SES (58% vs 31%; P = 0.001) and cirrhosis (27% vs 10%; P = 0.007). Among the Turkish population, there were no significant differences regarding the prevalence of low SES (73% vs 61%; P = 0.170), alcohol abuse (1% vs 5%; P = 0.120), anti‐hepatitis C virus positivity (4% vs 0%; P = 0.344), anti‐hepatitis D virus positivity (1% vs 6%; P = 0.297), and cirrhosis (37% vs 27%; P = 0.262) between patients (n = 102) living in Turkey (local) and Turkish CHB (n = 38) patients living in the Netherlands or Belgium (immigrant). In multivariate analysis, low SES (odds ratio, 5.7; 95% confidence interval, 2.3‐14.5; P < 0.001) was associated with cirrhosis. In this study, foreign‐born CHB patients were associated with more advanced HBV‐related liver disease with 27% having cirrhosis. However, ethnicity was not associated with cirrhosis when SES was included in the multivariate analysis. The similar prevalence of cirrhosis in local Turkish compared to immigrant Turkish CHB patients is novel and warrants further investigation.
Sci‐Hub: The new and ultimate disruptor? View from the front
Authors: Nicholas David , Boukacem‐Zeghmouri Chérifa , Xu Jie , Herman Eti , Clark David , Abrizah Abdullah , Rodríguez‐Bravo Blanca , Świgoń Marzena
Published: November 2018

The Harbinger project was a 3‐year‐long international study of the changing attitudes and behaviours of early career researchers (ECRs). One of the aims of the project was to discover if ECRs were adopting disrupting platforms that, legitimately or illegitimately, promote openness and sharing. It has been alleged that such an adoption appeals to them as Millennials. More than 100 ECRs from seven countries were questioned annually, and questions about Sc‐Hub were raised as part of discussions about discovery and access. Interview data were supplemented by desk research and Google Trends statistics. It was found that Sci‐Hub use was increasing and that a quarter of the ECRs now use it, with French ECRs being the biggest users. However, Sci‐Hub is making little headway with ECRs from the UK, USA, Malaysia, and China, although in China's case, this can be explained by it being banned and the country having its own equivalent, www.91lib.com. Sci‐Hub is used as much for convenience as necessity; use is not connected to the strength of library provision and and it has been suggested that it represents a bigger threat to publishers than ResearchGate, whose star might be waning.
Virulence behavior of uropathogenic Escherichia coli strains in the host model Caenorhabditis elegans
Authors: Schifano Emily , Marazzato Massimiliano , Ammendolia Maria Grazia , Zanni Elena , Ricci Marta , Comanducci Antonella , Goldoni Paola , Conte Maria Pia , Uccelletti Daniela , Longhi Catia
Published: November 2018

Urinary tract infections (UTIs) are among the most common bacterial infections in humans. Although a number of bacteria can cause UTIs, most cases are due to infection by uropathogenic Escherichia coli (UPEC). UPEC are a genetically heterogeneous group that exhibit several virulence factors associated with colonization and persistence of bacteria in the urinary tract. Caenorhabditis elegans is a tiny, free‐living nematode found worldwide. Because many biological pathways are conserved in C. elegans and humans, the nematode has been increasingly used as a model organism to study virulence mechanisms of microbial infections and innate immunity. The virulence of UPEC strains, characterized for antimicrobial resistance, pathogenicity‐related genes associated with virulence and phylogenetic group belonging was evaluated by measuring the survival of C. elegans exposed to pure cultures of these strains. Our results showed that urinary strains can kill the nematode and that the clinical isolate ECP110 was able to efficiently colonize the gut and to inhibit the host oxidative response to infection. Our data support that C. elegans, a free‐living nematode found worldwide, could serve as an in vivo model to distinguish, among uropathogenic E. coli, different virulence behavior.
Pigmented Rice‐Derived Phenolic Compounds Reduce Biomarkers of Oxidative Stress and Inflammation in Human Umbilical Vein Endothelial Cells
Authors: Callcott Esther T. , Blanchard Christopher L. , Oli Prakash , Santhakumar Abishek B.
Published: November 2018

Scope

Endothelial dysfunction pathogenesis is significantly associated with increased oxidative stress (OS) and inflammation. Rice‐derived phenolic compounds have been demonstrated to have antioxidant and anti‐inflammatory potential. This study aims to determine if phenolic extracts (PE) from pigmented rice varieties (Purple, Yunlu29–red, and Reiziq–brown) at varying concentrations modulate biomarkers of OS and inflammation in human umbilical vein endothelial cells under induced OS conditions.

Methods and results

2,7‐dichlorofluorescein diacetate and superoxide dismutase‐1 (SOD‐1) enzyme‐linked immuno‐sorbent assay quantification demonstrate that Purple PE significantly decreases reactive oxygen species and increases SOD‐1 by 27% and 226%, respectively. Yunlu29 PE (50 µg mL−1) is the most effective in reducing (p < 0.0001) interleukin‐8 (61%) and interleukin‐6 (57.2%). Yunlu29 (50 µg mL−1) reduces intracellular‐adhesion molecule‐1 (p < 0.0001) expression by 34%, followed by Reiziq (31.9%) and Purple (30.2%). Flow cytometric analysis demonstrates that vascular cell‐adhesion molecule‐1 expression is reduced (p < 0.0001) by 53.5% by Yunlu29 followed by Purple (46.8%) and Reiziq (46.7%). Yunlu29 is the most effective in reducing nuclear factor kappa‐B expression by 50.1%, followed by purple (48.8%) and Reiziq (38.6%).

Conclusion

This study indicates that colored rice PE may potentially target OS and inflammatory pathways associated with the pathogenesis of endothelial dysfunction.
Assessment of intracoronary stent location and extension in intravascular ultrasound sequences
Authors: Balocco Simone , Ciompi Francesco , Rigla Juan , Carrillo Xavier , Mauri Josepa , Radeva Petia
Published: November 2018

Purpose

An intraluminal coronary stent is a metal scaffold deployed in a stenotic artery during percutaneous coronary intervention (PCI). In order to have an effective deployment, a stent should be optimally placed with regard to anatomical structures such as bifurcations and stenoses. Intravascular ultrasound (IVUS) is a catheter‐based imaging technique generally used for PCI guiding and assessing the correct placement of the stent. A novel approach that automatically detects the boundaries and the position of the stent along the IVUS pullback is presented. Such a technique aims at optimizing the stent deployment.

Methods

The method requires the identification of the stable frames of the sequence and the reliable detection of stent struts. Using these data, a measure of likelihood for a frame to contain a stent is computed. Then, a robust binary representation of the presence of the stent in the pullback is obtained applying an iterative and multiscale quantization of the signal to symbols using the Symbolic Aggregate approXimation algorithm.

Results

The technique was extensively validated on a set of 103 IVUS of sequences of in vivo coronary arteries containing metallic and bioabsorbable stents acquired through an international multicentric collaboration across five clinical centers. The method was able to detect the stent position with an overall F‐measure of 86.4%, a Jaccard index score of 75% and a mean distance of 2.5 mm from manually annotated stent boundaries, and in bioabsorbable stents with an overall F‐measure of 88.6%, a Jaccard score of 77.7 and a mean distance of 1.5 mm from manually annotated stent boundaries. Additionally, a map indicating the distance between the lumen and the stent along the pullback is created in order to show the angular sectors of the sequence in which the malapposition is present.

Conclusions

Results obtained comparing the automatic results vs the manual annotation of two observers shows that the method approaches the interobserver variability. Similar performances are obtained on both metallic and bioabsorbable stents, showing the flexibility and robustness of the method.
Changes in the uterine metabolome of the cow during the first 7 days after estrus
Authors: Tríbulo Paula , Balzano‐Nogueira Leandro , Conesa Ana , Siqueira Luiz G. , Hansen Peter J.
Published: November 2018

The uterine microenvironment during the first 7 days after ovulation accommodates and facilitates sperm transit to the oviduct and constitutes the sole source of nutrients required for the development of preimplantation embryos. Knowledge of the composition of uterine fluid is largely incomplete. Using untargeted mass spectrometry, we characterized the uterine metabolome during the first 7 days of the estrous cycle. Bovine uteri were collected on Days 0 (N = 4), 3 (N = 4), 5 (N = 3), and 7 (N = 4) relative to ovulation and flushed with Dulbecco’s phosphate‐buffered saline. A total of 1,993 molecular features were detected of which 184 peaks with putative identification represent 147 unique metabolites, including amino acids, benzoic acids, lipid molecules, carbohydrates, purines, pyrimidines, vitamins, and other intermediate and secondary metabolites. Results revealed changes in the uterine metabolome as the cow transitions from ovulation to Day 7 of the estrous cycle. The majority of metabolites that changed with day reached maximum intensity on either Day 5 or 7 relative to ovulation. Moreover, several metabolites found in the uterine fluid have signaling capabilities and some have been shown to affect preimplantation embryonic development. In conclusion, the metabolome of the bovine uterus changes during early stages of the estrous cycle and is likely to participate in the regulation of preimplantation embryonic development. Data reported here will serve as the basis for future studies aiming to evaluate maternal regulation of preimplantation embryonic development and optimal conditions for the culture of embryos.
Formabhängige Eigenschaften und kooperative Effekte
Authors: Polarz Sebastian , Boldt Klaus
Published: November 2018

In Materialien aus anisotropen Nanoteilchen lassen sich richtungsabhängige Eigenschaften durch das Zusammenwirken der einzelnen Partikel bestimmen, etwa der Ladungsransport in CdSe‐Netzwerken oder Magnetismus in EuO‐Röhren. Dafür ist die Partikelform entscheidend. Sie lässt sich durch Additive wie Phosphonsäuren kontrollieren.
15 Sekunden ‐‐ die kanadische Wissenschaftsjournalistin Sarah Everts im Porträt
Authors: Zbikowski Frauke
Published: November 2018

Die Biochemikerin und Journalistin Sarah Everts ging im Jahr 2007 von Washington nach Berlin, um für US‐Leser über europäische Wissenschaft zu berichten. Nun verlässt sie Europa. Ein Rückblick auf Geschichten aus dem 20. Jahrhundert, über den ehemaligen Ostblock und deutsche Umgangsformen.
Nikotin geht ins Blut
Authors: Frank Hartmut , Engewald Werner
Published: November 2018

Gaschromatographie galt noch Ende der 1950er Jahre als ungeeignet für die Bioanalytik. Marjorie G. Horning und ihr Mann Evan entwickelten sie in den 1960er Jahren weiter und etablierten sie als eine leistungsfähige Methode für die biomedizinische Forschung. Marjorie Groothuis Horning, die im August ihren 101. Geburtstag feierte, untersuchte damit Stoffwechselprodukte und Arzneimittel im menschlichen Körper.
Eine Zahl für den Stellenwert von Forschung
Authors: Langhals Heinz
Published: November 2018

Das wissenschaftliche Echo auf Forschungsergebnisse im Lauf der Zeit lässt sich als Maß für die gesellschaftliche Bedeutung eines Forschungsgebiets auffassen. Dies zeigen die Beispiele des Wirkstoffs Azulen, des Farbstoffs Perylen und Fulleren, für welche die Datenbank Chemical Abstracts sowohl Folgepublikationen als auch Zitate erfasst. Ein Denkansatz ist, anhand dieser Daten ein Relevanzkriterium zu entwickeln.
Medizintechnik: Gen abschalten und gesunden
Authors: Bulmahn Maren
Published: November 2018

Das erste RNAi‐Medikament beruht auf einer Technik, die am Göttinger Max‐Planck‐Institut für biophysikalische Chemie entwickelt wurde.
Gründen, finanzieren, vernetzen
Authors: Köster Hendrik
Published: November 2018

Jede Idee verdient eine Chance. Denn sie stärkt die Wettbewerbsfähigkeit der Wirtschaft. Beispiele dafür sind neue Materialien.
Nobelpreise 2018: Frances H. Arnold
Authors: Rentmeister Andrea
Published: November 2018

Für die gerichtete Evolution von Enzymen erhält Frances H. Arnold die Hälfte des Chemienobelpreises. Die zweite Hälfte des Preises teilen sich George P. Smith und Gregory Winter.
Synthese im Blickpunkt: Durch aktive Template zu verzahnten Molekülen
Authors: Pairault Noel , Niemeyer Jochen
Published: November 2018

Rotaxane und Catenane lassen sich inzwischen in guten Ausbeuten herstellen – auch wegen neuer Synthesestrategien wie der Active‐Template‐Methode. Diese nutzt Metalle wie Kupfer(I), und zwar nicht nur als Templatbildner, sondern auch als Katalysator.
Bioökonomie: Signal an die Chemieindustrie
Authors: Bengs Holger
Published: November 2018

Das erste World Bioeconomy Forum mit Teilnehmern von vier Kontinenten spezialisierte sich auf Holz. Weitere Themen sind notwendig und Vertreter der Chemiewirtschaft gefordert.
Chemiedidaktik: Enzymkinetik mit dem Blutzuckermessgerät
Authors: Heinzerling Peter
Published: November 2018

Die Kinetik enzymatischer Reaktionen wird überwiegend mit photometrischen Messmethoden untersucht. Einfacher geht es mit Geräten für die medizinische Diagnostik, wie sie für insulinpflichtige Patienten zum Alltag gehört. Enzyme für solche Untersuchungen finden sich in Nahrungsergänzungsmitteln.
LONGEVITY‐RELATED OPTIONS FOR SOCIAL SECURITY: A MICROSIMULATION APPROACH TO RETIREMENT AGE AND MORTALITY ADJUSTMENTS
Authors: Reznik Gayle L. , Couch Kenneth A. , Tamborini Christopher R. , Iams Howard M.
Published: November 2018

We consider the distributional implications of Social Security policy changes in the context of increases in life expectancy and differential mortality. Using a robust microsimulation model, we examine how several options for raising the retirement age, including a scenario that applies a mortality adjustment in combination with such policies, affect different types of individuals and households. Policy changes are simulated for Social Security beneficiaries in 2030 using the Modeling Income in the Near Term (MINT) microsimulation model. The analysis shows that increasing either the age at which individuals receive their full retirement benefit alone or the early eligibility and full retirement ages together result in across‐the‐board reductions in benefit levels. The policies are projected to result in slightly higher poverty, but the expected rise is sharper among groups known to experience higher rates of mortality, as well as many disadvantaged groups. Analysis of a hypothetical adjustment to offset the historical impacts of differential mortality by lifetime earnings on lifetime benefit receipt, when combined with these retirement age increases, shows varied results. While some groups of individuals experience sharper reductions in median monthly benefits, the adjustment has an offsetting and protective effect for the benefits of disadvantaged groups when combined with options that would raise the retirement age. This combined package of policies, as well as simulations that incorporate a behavioral adjustment in benefit claiming ages, result in an increase of less than one percentage point in the average poverty rate.
Tumor cell heterogeneity and resistance; report from the 2018 Coffey‐Holden Prostate Cancer Academy Meeting
Authors: Miyahira Andrea K. , Den Robert B. , Carlo Maria I. , de Leeuw Renée , Hope Thomas A. , Karzai Fatima , McKay Rana R. , Salami Simpa S. , Simons Jonathan W. , Pienta Kenneth J. , Soule Howard R.
Published: November 2018

Introduction

The 2018 Coffey‐Holden Prostate Cancer Academy (CHPCA) Meeting, “Tumor Cell Heterogeneity and Resistance,” was held in Los Angeles, California from June 21 to 24, 2018.

Methods

The CHPCA Meeting is a unique, discussion‐oriented scientific conference convened annually by the Prostate Cancer Foundation (PCF), which focuses on the most critical topics in need of further study to advance the treatment of lethal prostate cancer. The 6th Annual CHPCA Meeting was attended by 70 investigators and concentrated on prostate cancer heterogeneity and treatment resistance.

Results

The meeting focused on topics including: recognition of tumor heterogeneity, molecular drivers of heterogeneity, the role of the tumor microenvironment, the role of heterogeneity in disease progression, metastasis and treatment resistance, clinical trials designed to target resistance and tumor heterogeneity, and immunotherapeutic approaches to target and overcome tumor heterogeneity.

Discussion

This review article summarizes the presentations and discussions from the 2018 CHPCA Meeting in order to share this knowledge with the scientific community and encourage new studies that will lead to improved treatments and outcomes for men with prostate cancer.
Coaching on Borrowed Time: Balancing the Roles of the Literacy Professional
Authors: Pletcher Bethanie C. , Hudson Alida K. , John Lini , Scott Alison
Published: November 2018

Serving both teachers and students in a hybrid literacy professional role requires thoughtful planning and reflection. In this article, the authors reflect on their work over the course of one school year to determine how to manage time effectively to combine the job descriptions of reading specialist and literacy coach. Strategies are presented for each of the following topics that emerged as a result of these reflections: sticking to a schedule while remaining flexible, seeking topic choices that balance different needs, starting small by coaching a few teachers at a time, using expert teachers, holding brief but effective coaching conversations, and seeking support for coaching.
Exploiting wind profiler information
Authors: Hisscott Alan
Published: November 2018

There exists a network of wind profilers at locations across the British Isles and Europe which continuously provide wind information throughout the lower atmosphere, primarily for assimilation into numerical forecast models. However, the algorithms used for processing the profiler signals also provide secondary data: the virtual vertical velocity and signal‐to‐noise ratio. One of the UK Met Office profilers is installed close to the Isle of Man Met Office at Ronaldsway Airport. The primary and secondary data from this profiler have been used to analyse several meteorological phenomena that occurred around the Isle of Man.
Critical Dialogue to Open Doors for Leadership
Authors: Blom Andrew , Johnson Matthew R.
Published: November 2018

This chapter explores how the high‐impact practice of critical, intergroup dialogue connects leadership with the broader learning objectives in the liberal arts. Based on experiences with building partnerships for leadership learning at their own university, the authors offer lessons for fostering cross‐unit collaboration.
Courses for International Leadership
Authors: Widner‐Edberg Tara
Published: November 2018

This chapter advocates that building capacity for international leadership should be the goal of leadership educators in course‐based experiences. It also recommends a model of global leadership that is consistent with this view and discusses an example of the model in action.