bluuebunny/crossref_metadata_2025 huggingface dataset:
Circulating Proteoglycan Endocan Mediates EGFR-Driven Progression of Non–Small Cell Lung Cancer
Authors: Yang Yi-Chieh , Pan Ke-Fan , Lee Wei-Jiunn , Chang Jer-Hwa , Tan Peng , Gu Chia-Chi , Chang Wei-Min , Yang Shun-Fa , Hsiao Michael , Hua Kuo-Tai , Chien Ming-Hsien
Published: June 2020

Although new generations of EGFR-tyrosine kinase inhibitors (EGFR-TKI) have been developed for the treatment of patients with non–small cell lung cancer (NSCLC) with EGFR-mutant tumors, TKI resistance often returns as a result of additional EGFR mutations. In addition to seeking for next-generation EGFR-TKI, developing novel EGFR-targeting strategies may hold the key to overcome the vicious cycle of TKI resistance. Endocan is known as a receptor tyrosine kinase ligand enhancer in tumorigenesis, but the impact of endocan on EGFR-driven NSCLC progression remains unknown. In this study, higher endocan levels were found in lung tumors compared with cancer-free tissues and correlated with poor prognosis in patients with NSCLC harboring mutant EGFR; circulating endocan levels were also significantly higher in patients with mutant EGFR. Endocan facilitated EGFR signaling via direct binding and enhancing of the EGF–EGFR interaction and supported the growth of tumors driven by mutated EGFR. Activated EGFR in turn upregulated expression of endocan via JAK/STAT3 and ERK/ELK cascades, thus forming a positive regulatory loop of endocan-EGFR signaling. On the basis of the binding region between endocan and EGFR, we designed therapeutic peptides and demonstrated promising therapeutic effects in xenografts harboring EGFR mutations including TKI-resistant T790M. Together, our findings highlight the novel interaction between endocan and EGFR and new opportunities to effectively target endocan-EGFR regulatory axis in patients with TKI-resistant NSCLC.

Significance:

Endocan is a novel and critical regulator of EGF/EGFR signaling and serves as an alternative target of EGFR-TKI resistance in NSCLC.
Pharmacokinetic Profiles Determine Optimal Combination Treatment Schedules in Computational Models of Drug Resistance
Authors: Irurzun-Arana Itziar , McDonald Thomas O. , Trocóniz Iñaki F. , Michor Franziska
Published: June 2020

Identification of optimal schedules for combination drug administration relies on accurately estimating the correct pharmacokinetics, pharmacodynamics, and drug interaction effects. Misspecification of pharmacokinetics can lead to wrongly predicted timing or order of treatments, leading to schedules recommended on the basis of incorrect assumptions about absorption and elimination of a drug and its effect on tumor growth. Here, we developed a computational modeling platform and software package for combination treatment strategies with flexible pharmacokinetic profiles and multidrug interaction curves that are estimated from data. The software can be used to compare prespecified schedules on the basis of the number of resistant cells where drug interactions and pharmacokinetic curves can be estimated from user-provided data or models. We applied our approach to publicly available in vitro data of treatment with different tyrosine kinase inhibitors of BT-20 triple-negative breast cancer cells and of treatment with erlotinib of PC-9 non–small cell lung cancer cells. Our approach is publicly available in the form of an R package called ACESO (https://github.com/Michorlab/aceso) and can be used to investigate optimum dosing for any combination treatment.

Significance:

These findings introduce a computational modeling platform and software package for combination treatment strategies with flexible pharmacokinetic profiles and multidrug interaction curves that are estimated from data.
Prognostic Value of EndoPredict in Women with Hormone Receptor–Positive, HER2-Negative Invasive Lobular Breast Cancer
Authors: Sestak Ivana , Filipits Martin , Buus Richard , Rudas Margaretha , Balic Marija , Knauer Michael , Kronenwett Ralf , Fitzal Florian , Cuzick Jack , Gnant Michael , Greil Richard , Dowsett Mitch , Dubsky Peter
Published: June 2020

Purpose:

Invasive lobular carcinoma (ILC) accounts for approximately 5%–15% of all invasive breast cancer cases. Most of the correlations between multigene assays and patient outcome were derived from studies based on patients with invasive ductal carcinoma (IDC) or without distinction between the subtypes. Here, we investigate the prognostic value of EndoPredict (EPclin) in a large cohort of ILCs pooled from three phase III randomized trials (ABCSG-6, ABCSG-8, TransATAC).

Experimental Design:

The primary objective of this analysis was to determine the prognostic value of EPclin for distant recurrence (DR) in years 0–10 in postmenopausal women with ILC. The primary outcome was DR.

Results:

470 women (17.9%) presented with ILC, 1,944 (73.9%) with IDC, and 216 (8.2%) with other histologic types. EPclin was highly prognostic in women with ILC [HR = 3.32 (2.54–4.34)] and provided more prognostic value than the Clinical Treatment Score [CTS; HR = 2.17 (1.73–2.72)]. 63.4% of women were categorized into the low EPclin risk group and they had a 10-year DR of 4.8% (2.7–8.4) compared with 36.6% of women in the high-risk group with a 10-year DR risk of 26.6% (20.0–35.0). EPclin also provided highly prognostic information in women with node-negative disease [HR = 2.56 (1.63–4.02)] and node-positive disease [HR = 3.70 (2.49–5.50)].

Conclusions:

EPclin provided highly significant prognostic value and significant risk stratification for women with ILC. Ten-year DR risk in the EPclin low-risk groups were similar between ILC and IDC. Our results show that EPclin is informative in women with ILC and suggest that it is equally valid in both histologic subtypes.
The Long Noncoding RNANEAT1Promotes Sarcoma Metastasis by Regulating RNA Splicing Pathways
Authors: Huang Jianguo , Sachdeva Mohit , Xu Eric , Robinson Timothy J. , Luo Lixia , Ma Yan , Williams Nerissa T. , Lopez Omar , Cervia Lisa D. , Yuan Fan , Qin Xiaodi , Zhang Dadong , Owzar Kouros , Gokgoz Nalan , Seto Andrew , Okada Tomoyo , Singer Samuel , Andrulis Irene L. , Wunder Jay S. , Lazar Alexander J. , Rubin Brian P. , Pipho Krista , Mello Stephano S. , Giudice Jimena , Kirsch David G.
Published: June 2020

Soft-tissue sarcomas (STS) are rare malignancies showing lineage differentiation toward diverse mesenchymal tissues. Half of all high-grade STSs develop lung metastasis with a median survival of 15 months. Here, we used a genetically engineered mouse model that mimics undifferentiated pleomorphic sarcoma (UPS) to study the molecular mechanisms driving metastasis. High-grade sarcomas were generated with Cre recombinase technology using mice with conditional mutations in Kras and Trp53 (KP) genes. After amputation of the limb bearing the primary tumor, mice were followed for the development of lung metastasis. Using RNA-sequencing of matched primary KP tumors and lung metastases, we found that the long noncoding RNA (lncRNA) Nuclear Enriched Abundant Transcript 1 (Neat1) is significantly upregulated in lung metastases. Furthermore, NEAT1 RNA ISH of human UPS showed that NEAT1 is upregulated within a subset of lung metastases compared with paired primary UPS. Remarkably, CRISPR/Cas9-mediated knockout of Neat1 suppressed the ability of KP tumor cells to colonize the lungs. To gain insight into the underlying mechanisms by which the lncRNA Neat1 promotes sarcoma metastasis, we pulled down Neat1 RNA and used mass spectrometry to identify interacting proteins. Interestingly, most Neat1 interacting proteins are involved in RNA splicing regulation. In particular, KH-Type Splicing Regulatory Protein (KHSRP) interacts with Neat1 and is associated with poor prognosis of human STS. Moreover, depletion of KHSRP suppressed the ability of KP tumor cells to colonize the lungs. Collectively, these results suggest that Neat1 and its interacting proteins, which regulate RNA splicing, are involved in mediating sarcoma metastasis.

Implications:

Understanding that lncRNA NEAT1 promotes sarcoma metastasis, at least in part, through interacting with the RNA splicing regulator KHSRP may translate into new therapeutic approaches for sarcoma.
Endoscopic History and Provider Characteristics Influence Gastric Cancer Survival in Asian Americans
Authors: Jeon Christie Y. , Lin Yu-Chen , Klempner Samuel J. , Wu Bechien U. , Kim Sungjin , Waters Kevin M. , Haile Robert W.
Published: June 2020

Gastric carcinoma (GC) disproportionately affects Asian Americans. We examined whether history of upper gastrointestinal (GI) endoscopy was associated with lower stage at GC diagnosis among Asian Americans and whether origin of providers influenced referral for endoscopy. We employed Surveillance Epidemiology and End Results–Medicare data on Asian Americans diagnosed with GC in 2004–2013 (n = 1,554). Stage distribution, GI conditions at diagnosis, and history of endoscopy were compared between Asian ethnic groups. Multivariate logistic regression adjusting for age, sex, poverty level, tumor location, and histology was used to examine the association of ethnicity and endoscopic history with stage I disease at diagnosis of GC. Koreans were more likely to be diagnosed with stage I, T1a GC and have prior history of endoscopy, compared with other Asian ethnicities (24% vs. 8% for stage I, T1a; 40% vs. 15% for endoscopy). Patients with primary care providers of concordant ethnic origin were more likely to have history of endoscopy. Asian American patients with GC with history of endoscopy were more likely to be diagnosed with GC at stage I disease (adjusted OR, 3.07; 95% confidence interval, 2.34–4.02). Compared with other Asian Americans, Koreans were diagnosed with GC at earlier stages owing to common history of endoscopy, which was more often undergone by patients with primary care providers of concordant ethnic origin. Overall, upper GI endoscopy was associated with early detection of GC in Asian Americans. Novelty and Impact. It is well-established that Asian Americans in the United States are disproportionately affected by gastric cancer. In our study we found that Asian American patients treated by physicians of similar ethnic background are more likely to undergo upper GI endoscopy in the United States, leading to early detection of gastric cancer and longer survival. Given this, targeted endoscopic screening in Asian Americans should be considered for early detection of GC.
Lineage Reversion Drives WNT Independence in Intestinal Cancer
Authors: Han Teng , Goswami Sukanya , Hu Yang , Tang Fanying , Zafra Maria Paz , Murphy Charles , Cao Zhen , Poirier John T. , Khurana Ekta , Elemento Olivier , Hechtman Jaclyn F. , Ganesh Karuna , Yaeger Rona , Dow Lukas E.
Published: June 2020

The WNT pathway is a fundamental regulator of intestinal homeostasis, and hyperactivation of WNT signaling is the major oncogenic driver in colorectal cancer. To date, there are no described mechanisms that bypass WNT dependence in intestinal tumors. Here, we show that although WNT suppression blocks tumor growth in most organoid and in vivo colorectal cancer models, the accumulation of colorectal cancer–associated genetic alterations enables drug resistance and WNT-independent growth. In intestinal epithelial cells harboring mutations in KRAS or BRAF, together with disruption of TP53 and SMAD4, transient TGFβ exposure drives YAP/TAZ-dependent transcriptional reprogramming and lineage reversion. Acquisition of embryonic intestinal identity is accompanied by a permanent loss of adult intestinal lineages, and long-term WNT-independent growth. This work identifies genetic and microenvironmental factors that drive WNT inhibitor resistance, defines a new mechanism for WNT-independent colorectal cancer growth, and reveals how integration of associated genetic alterations and extracellular signals can overcome lineage-dependent oncogenic programs.

Significance:

Colorectal and intestinal cancers are driven by mutations in the WNT pathway, and drugs aimed at suppressing WNT signaling are in active clinical development. Our study identifies a mechanism of acquired resistance to WNT inhibition and highlights a potential strategy to target those drug-resistant cells.

This article is highlighted in the In This Issue feature, p. 1426
Soil and Seed: Coconspirators in Therapy-Induced Myeloid Neoplasms
Authors: Shannon Kevin , Link Daniel C.
Published: June 2020

In this issue of Blood Cancer Discovery, Stoddart and colleagues describe cooperative effects of exposing both the bone marrow microenvironment of recipient mice and donor hematopoietic stem and progenitor cells (HSPC) to an alkylating agent in a genetically accurate model of therapy-induced myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) characterized by chromosome 5q deletions. The authors further implicate senescence of alkylator-treated mesenchymal stem cells (MSC) as contributing to the microenvironmental damage and subsequent therapy-induced myeloid neoplasms (tMN). Loss of Trp53 function and somatic mutations in other DNA damage response (DDR) genes were associated with overt AML in this model. Together, these studies shed new light on the complex pathogenesis of tMN and establish a robust model for biologic and preclinical investigation.

See related article by Stoddart et al., p. 32.
Brain Fuel Utilization in the Developing Brain
Authors: Steiner Pascal
Published: June 2020

During pregnancy and infancy, the human brain is growing extremely fast; the brain volume increases significantly, reaching 36, 72, and 83% of the volume of adults at 2–4 weeks, 1 year, and 2 years of age, respectively, which is essential to establish the neuronal networks and capacity for the development of cognitive, motor, social, and emotional skills that will be continually refined throughout childhood and adulthood. Such dramatic changes in brain structure and function are associated with very large energetic demands exceeding by far those of other organs of the body. It has been estimated that during childhood the brain may account for up to 60% of the body basal energetic requirements. While the main source of energy for the adult brain is glucose, it appears that it is not sufficient to sustain the dramatic metabolic demands of the brain during its development. Recently, it has been proposed that this energetic challenge is solved by the ability of the brain to use ketone bodies (KBs), produced from fatty acid oxidation, as a complement source of energy. Here, we first describe the main cellular and physiological processes that drive brain development along time and how different brain metabolic pathways are engaged to support them. It has been assumed that the majority of energetic substrates are used to support neuronal activity and signal transmission. We discuss how glucose and KBs are metabolized to provide the carbon backbones used to synthesize lipids, nucleic acid, and cholesterol, which are indispensable building blocks of neuronal cell proliferation and are also used to establish and refine brain connectivity through synapse formation/elimination and myelination. We conclude that glucose and KBs are not only important to support the energy needs of the brain under development, but they are also essential substrates for the biosynthesis of macromolecules underlying structural brain growth and reorganization. We emphasize that glucose and fatty acids supporting the production of KBs are provided in complex food matrices, such as breast milk, and understanding how their availability impacts the brain will be key to promote adequate nutrition to support brain metabolism and, therefore, optimal brain development.
A Comparison of Subconjunctival Wound Healing between Different Methods of Dissecting Subconjunctival Tissues
Authors: Gong Ruowen , Zuo Chengguo , Wu Keling , Zhang Simin , Qin Xi , Li Yangyang , Gao Xinbo , Huang Danping , Lin Mingkai
Published: June 2020

Objective: To compare different methods for dissecting subconjunctival tissues by developing subconjunctival wound healing models. Methods: New Zealand white rabbits were separated into 3 groups based on the method by which the rabbit subconjunctival wound healing model was generated: subconjunctival tissues were dissected episclerally (EPI) or subepithelially (SUB), with a corresponding blank control (CON). All the cases in the experimental groups were surgically prepared with conjunctival flaps, and they were sacrificed on the third postoperative day. At the surgical sites, the protein levels of hypoxia-inducible factor-1 (HIF-1)-α, vascular endothelial growth factor (VEGF)-A, and matrix metalloproteinase (MMP)-2 were detected by Western blot, morphological vascularity was measured by Adobe Photoshop, and subconjunctival fibrosis was assessed by histology. Results: Compared with the CON group, both the EPI and SUB groups showed significantly upregulated protein levels of HIF-1α, VEGF-A, and MMP-2. In addition, the protein levels of HIF-1α, VEGF-A, and MMP-2 were higher in the EPI group than in the SUB group. Morphological vascularity was significantly elevated in the EPI group compared with the SUB and CON groups. Collagen content was markedly increased in the EPI group compared with the SUB and CON groups. Conclusions: Dissecting subconjunctival tissues subepithelially inhibits subconjunctival fibrosis, which may be instructive in tenonectomy in filtration surgery.
Prognostic Value of Dynamic Changes in Pulmonary Congestion During Exercise Stress Echocardiography in Heart Failure With Preserved Ejection Fraction
Authors: Coiro Stefano , Simonovic Dejan , Deljanin-Ilic Marina , Duarte Kevin , Carluccio Erberto , Cattadori Gaia , Girerd Nicolas , Ambrosio Giuseppe
Published: June 2020

Background:

Patients with heart failure (HF) with preserved ejection fraction (HFpEF) typically develop dyspnea and pulmonary congestion upon exercise. Lung ultrasound is a simple diagnostic tool, providing semiquantitative assessment of extravascular lung water through B-lines. It has been shown that patients with HFpEF develop B-lines upon submaximal exercise stress echocardiography; however, whether exercise-induced pulmonary congestion carries prognostic implications is unknown. This study aimed at evaluating the prognostic value of B-line assessment during exercise in patients with HFpEF.

Methods:

Sixty-one New York Heart Association class I to II patients with HFpEF underwent standard echocardiography, lung ultrasound (28-scanning point method), and BNP (B-type natriuretic peptide) assessment during supine exercise echocardiography (baseline and peak exercise). The primary end point was a composite of cardiovascular death or HF hospitalization at 1 year.

Results:

B-lines, E/e′, and BNP significantly increased during exercise (
P
<0.001 for all). By multivariable analysis, both peak (hazard ratio, 1.50 [95% CI, 1.21–1.85],
P
<0.001), and change (hazard ratio 1.34 [95% CI, 1.12–1.62],
P
=0.002) B-lines were retained as independent predictors of outcome (hazard ratios per 1 B-line increment), along with BNP and E/e′ ratio. Importantly, adding peak B-line on top of a clinical model significantly improved prognostic accuracy (C-index increase, 0.157 [0.056–0.258],
P
=0.002) and net reclassification (continuous net reclassification improvement, 0.51 [0.09–0.74],
P
=0.016), with similar results for B-line change.

Conclusions:

Detection of exercise-induced pulmonary congestion by lung ultrasound is an independent predictor of outcome in patients with HFpEF; its use may help refining the routine risk stratification of these patients on top of well-established clinical variables.
Risk of Ischemic Stroke Increases Over the Spectrum of Metabolic Syndrome Severity
Authors: DeBoer Mark D. , Filipp Stephanie L. , Sims Mario , Musani Solomon K. , Gurka Matthew J.
Published: June 2020

Background and Purpose:

Ischemic stroke is associated with the metabolic syndrome (MetS) as diagnosed using dichotomous criteria; however, these criteria exhibit racial/ethnic discrepancies. Our goal was to assess whether ischemic stroke risk extended over the spectrum of worsening MetS severity using a sex- and race/ethnicity-specific MetS-severity
Z
score.

Methods:

We used Cox-proportional hazards models to assess the relationship between baseline MetS-
Z
score and incident ischemic stroke among participants of the Atherosclerosis Risk in Communities study and Jackson Heart Study who were free from diabetes, coronary heart disease or stroke at baseline, evaluating 13 141 white and black individuals with mean follow-up of 18.6 years.

Results:

We found that risk of ischemic stroke increased consistently with MetS severity, with a hazard ratio of 1.75 (95% CI, 1.35–2.27) for those >75th percentile compared to those <25th percentile. This risk was highest for white females (hazard ratio, 2.63 [CI, 1.70–4.07]) though without significant interaction by sex and race. Relationships between stroke and all the individual components of MetS were only noted for white females, though again without sex-race interactions. Hazard ratio’s for systolic blood pressure and stroke were significant among all sex/racial subgroups.

Conclusions:

Ischemic stroke risk increased over the spectrum of MetS severity in the absence of baseline diabetes mellitus, further implicating potential etiologic risks from processes underlying MetS. Individuals with elevated MetS severity should be counselled toward lifestyle modification to lower ischemic stroke risk.
Recent distribution of Eurytemora velox (Lilljeborg, 1853) (Copepoda, Calanoida) in brackish and fresh waters of Ukraine
Authors: Samchyshyna Larysa , Gromova Yulia , Zorina-Sakharova Kateryna
Published: June 2020

The brackish water calanoid copepod Eurytemora velox has become a widespread species in inland fresh waters of Ukraine. Nowadays it is one of the dominant crustacean species in the littoral zooplankton of the main Ukrainian rivers: Dnieper, Danube and Pivdenny Buh. We present a survey on E. velox localities in, mainly, fresh waters of Ukraine, data on some quite isolated populations of E. velox in the Carpathian region, as well as new records of the species in the upper parts of some rivers. These data will provide a more complete view of the inland distribution of E. velox in Ukraine.
Representatives of the genus Eurytemora Giesbrecht, 1881 (Calanoida, Temoridae) in aquatic ecosystems of Belarus
Authors: Vezhnavets Vasil V. , Litvinova Anastasiya G.
Published: June 2020

The main biological features of two species of the genus Eurytemora have been studied: the relict E. lacustris (Poppe, 1887) and the alien E. velox (Lilljeborg, 1853), which can be found in natural environments on the territory of the Republic of Belarus.

The relict species E. lacustris has been found only in two mesotrophic dimictic lakes belonging to the Baltic Sea basin: Volchin (maximum depth 32.9 m) and Vecheliye (35.9 m). E. velox has now colonized the main rivers of the south of Belarus and their accessory reservoirs belonging to the basins of the Baltic and Black seas.

E. lacustris is characterized by an uneven distribution in the water column and location in deep water layers with temperatures below 13°C. Seasonal and daily vertical migrations have been established for E. lacustris. With age, the amplitude of migrations increases, reaching values of more than 10 m of depth for adults. E. velox is recorded in the coastal biotopes of watercourses and shallow water bodies.

In the recent two years, the average density of E. lacustris in Lake Vecheliye has been established as about 2000 ind./m3, while their percentage in the zooplankton was 6%. In Lake Volchin, its density has been 2-5 times lower in the same period, and there this species’ percentage in the plankton did not exceed 2%. The density of E. velox varies from 20 to 12 000 ind./m3, their average density is 1631 ind./m3, and their percentual share in the zooplankton does not exceed 1%.

For E. lacustris, the body length at all stages of development has been determined. It has been established that males have a greater body length in comparison with females, due to the relatively longer male abdomen, which is not typical for other species of freshwater planktonic copepods.

In Belarus, E. lacustris is a bicyclic species, whereas E. velox is polycyclic.
Can women benefit from war? Women’s agency in conflict and post-conflict societies
Authors: Yadav Punam
Published: June 2020

Women’s agency in Peace and Conflict Studies has received increased policy attention since the formulation of UN Security Council Resolution in 2000. Academic attention regarding this question has, as a result, also increased dramatically in the intervening period. Women today, as a consequence, are not just seen as victims of conflict, but also as agents of change. Despite their vulnerabilities in the situations created by conflict, women may be exposed to new knowledge and opportunities, which may have positive impacts on their lives. Therefore, it is important to recognize the lived realities and the multiple stories of postwar societies to address the new needs of people and build a sustainable peace. This article examines the everyday lives of women in post-conflict Nepal to demonstrate the significant transformations that have taken place since the war. It specifically investigates conflict-induced social and structural changes through the lived experiences of women tempo drivers, war widows, women ex-combatants and women politicians. This article is based on the analysis of 200 interviews and six focus group discussions (FGDs) carried out over a period of 12 years in seven districts of Nepal.
What’s going on next door? Irregular leader change in neighboring countries, uncertainty, and civil war
Authors: Sakstrup Casper
Published: June 2020

Uncertainty about capabilities or resolve is a prominent explanation for war between states. However, we know comparatively little about uncertainty as a cause of armed conflict between domestic actors. This article proposes that irregular leader change in a neighboring country generates uncertainty about third-party resolve and thus increases the likelihood of intrastate armed conflict. I argue that domestic actors take potential third parties’ capabilities and resolve into account when bargaining, that neighboring countries are important potential third parties, and that irregular leader change among these potential third parties results in uncertainty because there is an increased risk of foreign policy change combined with limited access to information. With uncertain estimates of third-party resolve, the risk of bargaining failure and armed conflict increases. Global spatial analyses spanning 1946–2014 corroborate the argument. As expected, I find that irregular leader change in one or more neighboring countries increases the probability of intrastate armed conflict onset. The results are robust across three different distance thresholds for neighboring countries, using time and country fixed effects and several alternative model specifications. Overall, this article advances our knowledge about uncertainty as a cause of civil war and sheds new light on the adverse consequences of irregular leader change.
“We talked about our hookups”: A diary study of sexual communication among U.S. college women
Authors: Pariera Katrina L. , Abraham Brianna
Published: June 2020

For many young women, college is a time of major changes in sexual behavior and attitudes, driven in part by their social environment. Yet little is known about how young women actually talk about sex day-to-day. To understand daily sexual communication, 96 U.S. college students who identify as women kept a sexual communication diary for 7 days, generating 1,211 records. A content analysis revealed that women talked about sex an average of 13 times per week. Most conversations were with friends, face-to-face, and mostly about previous sexual encounters, dating, and potential sexual activity. The underlying function of most conversations was exchanging opinions, recapping, and gossiping. Sex appears to be a somewhat regularly discussed topic for college women and a way of socializing and exploring attitudes. The results have important implications for health promotion efforts targeted at college women.
Starchitects in Bohemia: An Exploration of Cultural Cities from the “Top-Down” and “Bottom-Up”
Authors: Jeong Hyesun , Patterson Matt
Published: June 2020

Urban scholars have devoted significant attention to the “cultural city,” but less attention has been paid to how different forms of culture relate to each other and to the larger urban environment. In this article, we compare two quintessential forms of culture-led urbanization that represent opposite ends on a spectrum: iconic architecture and neo-bohemia. While iconic architecture is a “top-down” approach to culture involving large budgets, elite “starchitects,” and powerful clients, neo-bohemia tends to be a “bottom-up” phenomenon formed as individual artists gravitate toward particular neighborhoods, establishing arts scenes. Using a combination of neighborhood case studies and national-level quantitative analysis, we investigate the ecological relationship between these two phenomena. In doing so, we provide new insights into the geographic and social structure of the cultural city.
Telehealth and hospital performance: Does it matter?
Authors: Zhao Mei , Hamadi Hanadi , Xu Jing , Haley D Rob , Park Sinyoung , White-Williams Cynthia
Published: June 2020

Introduction

Previous studies indicated that telehealth services may improve hospital performance. However, the extent to which these telehealth provisions would improve hospital total performance score under the hospital value-based purchasing (HVBP) programme is not clear. The aim of this study is to examine the association between telehealth provision and hospital performance.

Methods

We performed a retrospective analysis of the association between the provision of telehealth services and 2699 hospital’s total performance score (TPS) on the 2018 HVBP programme and its four domains. Multivariate regression models were used to analyse TPS and hospital performance on each domain. Telehealth services offered by a hospital was categorically operationalized as hospitals with no telehealth services, with one to two telehealth services, and with three or more telehealth services.

Results

Hospitals with one to two telehealth services have TPS (ß coefficient = 1.50; 95% confident intervals (CI): 0.28, 2.73; p < 0.05) and hospitals with three or more telehealth services have higher efficiency and cost reduction (ß = 1.10; 95% CI: 0.32, 1.87; p < 0.01) domain scores. However, the impact of telehealth on clinical care, person and community engagement, and safety domain scores was not significant.

Discussion

The expansion of hospital telehealth service provision can improve not only the efficiency of care, but also the total performance of the hospital. Since total performance is directly associated with hospital payments from the government, these findings have significant practice and policy implications. In addition, the effect of telehealth on other quality measures such as clinical care and safety needs further investigation.
Fast intrinsic optical signal correlates with activation phase of phototransduction in retinal photoreceptors
Authors: Yao Xincheng , Kim Tae-Hoon
Published: June 2020

Quantitative assessment of physiological condition of retinal photoreceptors is desirable for better detection and treatment evaluation of eye diseases that can cause photoreceptor dysfunctions. Functional intrinsic optical signal (IOS) imaging, also termed as optoretinography (ORG) or optophysiology, has been proposed as a high-resolution method for objective assessment of retinal physiology. Fast IOS in retinal photoreceptors shows a time course earlier than that of electroretinography a-wave, promising an objective marker for noninvasive ORG of early phototransduction process in retinal photoreceptors. In this article, recent observations of fast photoreceptor-IOS in animal and human retinas are summarized, and the correlation of fast photoreceptor-IOS to five steps of phototransduction process is discussed. Transient outer segment conformational change, due to inter-disc space shrinkage correlated with activation phase of phototransduction, has been disclosed as a primary source of the fast photoreceptor-IOS.

Impact statement

As the center of phototransduction, retinal photoreceptors are responsible for capturing and converting photon energy to bioelectric signals for following visual information processing in the retina. This article summarizes experimental observation and discusses biophysical mechanism of fast photoreceptor-intrinsic optical signal (IOS) correlated with early phase of phototransduction. Quantitative imaging of fast photoreceptor-IOS may provide objective optoretinography to advance the study and diagnosis of age-related macular degeneration, retinitis pigmentosa, diabetic retinopathy, and other eye diseases that can cause photoreceptor dysfunctions.
heap: A command for fitting discrete outcome variable models in the presence of heaping at known points
Authors: Yan Zizhong , Arulampalam Wiji , Corradi Valentina , Gutknecht Daniel
Published: June 2020

Self-reported survey data are often plagued by the presence of heaping. Accounting for this measurement error is crucial for the identification and consistent estimation of the underlying model (parameters) from such data. In this article, we introduce two commands. The first command, heapmph, estimates the parameters of a discrete-time mixed proportional hazard model with gammaunobserved heterogeneity, allowing for fixed and individual-specific censoring and different-sized heap points. The second command, heapop, extends the framework to ordered choice outcomes, subject to heaping. We also provide suitable specification tests.
MIMO-OFDM/OCDM low-complexity equalization under a doubly dispersive channel in wireless sensor networks
Authors: Solyman Ahmad AA , Attar Hani , Khosravi Mohammad R , Koyuncu Baki
Published: June 2020

In this article, three novel systems for wireless sensor networks based on Alamouti decoding were investigated and then compared, which are Alamouti space–time block coding multiple-input single-output/multiple-input multiple-output multicarrier modulation (MCM) system, extended orthogonal space–time block coding multiple-input single-output MCM system, and multiple-input multiple-output system. Moreover, the proposed work is applied over multiple-input multiple-output systems rather than the conventional single-antenna orthogonal chirp division multiplexing systems, based on the discrete fractional cosine transform orthogonal chirp division multiplexing system to mitigate the effect of frequency-selective and time-varying channels, using low-complexity equalizers, specifically by ignoring the intercarrier interference coming from faraway subcarriers and using the LSMR iteration algorithm to decrease the equalization complexity, mainly with long orthogonal chirp division multiplexing symbols, such as the TV symbols. The block diagrams for the proposed systems are provided to simplify the theoretical analysis by making it easier to follow. Simulation results confirm that the proposed multiple-input multiple-output and multiple-input single-output orthogonal chirp division multiplexing systems outperform the conventional multiple-input multiple-output and multiple-input single-output orthogonal frequency division multiplexing systems. Finally, the results show that orthogonal chirp division multiplexing exhibited a better channel energy behavior than classical orthogonal frequency division multiplexing, thus improving the system performance and allowing the system to decrease the equalization complexity.
Silver ion release from Ag/PET hollow fibers: Mathematical model and its application to food packing
Authors: Lin Ling , Yao Shao-Wen , Li Huigai
Published: June 2020

A food packing system requires an antimicrobial environment with high air permeability to guarantee absolutely both food safety and long and reliable durability. A hollow fiber membrane containing silver ions is the best candidate for this purpose. However, a safe and controllable release process has become a pressing issue in the practical application. Here, we use the predator–prey model to predict the antimicrobial activity of silver ions released from a hollow fiber, and Staphylococcus aureus was applied to the antibacterial experiment. Both theoretical and experimental results show that there are an optimal concentration of the silver ions and an optimal release time. This article sheds a bright light on the design of a new kind of food packing systems using the hollow fiber membrane.
Factor XII and kininogen asymmetric assembly with gC1qR/C1QBP/P32 is governed by allostery
Authors: Kaira Bubacarr G , Slater Alexandre , McCrae Keith R , Dreveny Ingrid , Sumya Um-May , Mutch Nicola J , Searle Mark , Emsley Jonas
Published: June 2020

The contact system is composed of Factor XII (FXII), prekallikrein (PK) and co-factor kininogen (HK). The globular C1q receptor (gC1qR) has been shown to interact with FXII and HK. We reveal the FXII fibronectin type II domain (FnII) binds gC1qR in a Zn2+ dependent fashion and determined the complex crystal structure. FXIIFnII binds the gC1qR trimer in an asymmetric fashion with residues Arg36 and Arg65 forming contacts with two distinct negatively charged pockets. gC1qR residues Asp185 and His187 coordinate a Zn2+ adjacent to the FXII binding site and a comparison with the ligand free gC1qR crystal structure reveals the anionic G1-loop becomes ordered upon FXIIFnII binding. Additional conformational changes in the region of the Zn2+ binding site reveal an allosteric basis for Zn2+ modulation of FXII binding. Mutagenesis coupled with SPR demonstrate the gC1qR Zn2+ site contributes to FXII binding and plasma based assays reveal gC1qR stimulates coagulation in a FXII-dependent manner. Analysis of the binding of HK domain 5 (HKD5) to gC1qR shows only one high affinity binding site per trimer. Mutagenesis studies identify a critical G3-loop located at the center of the gC1qR trimer suggesting steric occlusion as the mechanism for HKD5 asymmetric binding. Gel filtration experiments reveal that gC1qR clusters FXII and HK into a higher order 500kDa ternary complex. These results support the conclusion that extracellular gC1qR can act as a chaperone to cluster contact factors which may be a prelude for initiating the cascades which drive bradykinin generation and the intrinsic pathway of coagulation.
Immunoglobulin light chain toxicity in a mouse model of monoclonal immunoglobulin light-chain deposition disease
Authors: Bender Sébastien , Ayala Maria Victoria , Bonaud Amélie , Javaugue Vincent , Carrion Claire , Oblet Christelle , Rinsant Alexia , Kaaki Sihem , Oruc Zeliha , Boyer François , Paquet Agnes , Pons Nicolas , Herve Bastien , Ashi Mohamad Omar , Jaccard Arnaud , Delpy Laurent , Touchard Guy , Cogne Michel , Bridoux Frank , Sirac Christophe
Published: June 2020

Light chain deposition disease (LCDD) is a rare disorder characterized by glomerular and peritubular amorphous deposits of a monoclonal immunoglobulin (Ig) light chain (LC), leading to nodular glomerulosclerosis and nephrotic syndrome. We developed a transgenic model using site-directed insertion of the variable domain of a pathogenic human LC gene into the mouse Ig kappa locus, ensuring its production by all plasma cells (PCs). High free LC levels were achieved after backcrossing with mice presenting increased PC differentiation and no Ig heavy chain (HC) production. Our mouse model recapitulates the characteristic features of LCDD, including progressive glomerulosclerosis, nephrotic-range proteinuria and finally, kidney failure. The variable domain of the LC bears alone the structural properties involved in its pathogenicity. RNA sequencing conducted on PCs demonstrated that LCDD LC induces endoplasmic reticulum stress, likely accounting for the high efficiency of proteasome inhibitor-based therapy. Accordingly, reduction of circulating pathogenic LC was efficiently achieved and not only preserved renal function, but partially reversed kidney lesions. Finally, transcriptome analysis of pre-sclerotic glomeruli revealed that proliferation and extracellular matrix remodelling represented the first steps of glomerulosclerosis, paving the way for future therapeutic strategies in LCDD and other kidney diseases featuring diffuse glomerulosclerosis, particularly diabetic nephropathy.
First-line imatinib vs second- and third-generation TKIs for chronic-phase CML: a systematic review and meta-analysis
Authors: Vener Claudia , Banzi Rita , Ambrogi Federico , Ferrero Annalisa , Saglio Giuseppe , Pravettoni Gabriella , Sant Milena
Published: June 2020

Imatinib, the first tyrosine kinase inhibitor (TKI) for the treatment of chronic myeloid leukemia (CML), improves overall survival (OS), but the introduction of newer TKIs requires the definition of the optimal first-line TKI for newly diagnosed Philadelphia chromosome–positive (Ph+) chronic-phase (CP) CML. This systematic review of randomized controlled trials (RCTs) compares the efficacy and safety of imatinib vs second-generation (dasatinib, nilotinib, bosutinib) and third-generation TKIs (ponatinib) in adults with newly diagnosed Ph+ CP CML, concentrating on OS, progression-free survival (PFS), and hematological and nonhematological adverse events. The quality of the evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) method. Seven RCTs published between 1990 and 2019 (involving 3262 participants) satisfied the eligibility criteria. Two RCTs (imatinib vs nilotinib and imatinib vs dasatinib) found no difference in 5-year OS or PFS. Second- and third-generation TKIs improved 3-month major molecular responses (relative risk [RR], 4.28; 95% confidence interval [CI], 2.20-8.32) and other efficacy outcomes, decreased accelerated/blastic-phase transformations (RR, 0.44; 95% CI, 0.26-0.74), but were associated with more cases of thrombocytopenia (RR, 1.57; 95% CI, 1.20-2.05), cardiovascular events (RR, 2.54; 95% CI, 1.49-4.33), and pancreatic (RR, 2.29; 95% CI, 1.32-3.96) and hepatic effects (RR, 3.51; 95% CI 1.55-7.92). GRADE showed that the certainty of the evidence ranged from high to moderate. This study shows that, in comparison with imatinib, second- and third-generation TKIs improve clinical responses, but the safer toxicity profile of imatinib may make it a better option for patients with comorbidities.
CD4+ T-cell killing of multiple myeloma cells is mediated by resident bone marrow macrophages
Authors: Haabeth Ole Audun W. , Hennig Kjartan , Fauskanger Marte , Løset Geir Åge , Bogen Bjarne , Tveita Anders
Published: June 2020

CD4+ T cells may induce potent antitumor immune responses through interaction with antigen-presenting cells within the tumor microenvironment. Using a murine model of multiple myeloma, we demonstrated that adoptive transfer of idiotype-specific CD4+ T cells may elicit curative responses against established multifocal myeloma in bone marrow. This finding indicates that the myeloma bone marrow niche contains antigen-presenting cells that may be rendered tumoricidal. Given the complexity of the bone marrow microenvironment, the mechanistic basis of such immunotherapeutic responses is not known. Through a functional characterization of antitumor CD4+ T-cell responses within the bone marrow microenvironment, we found that killing of myeloma cells is orchestrated by a population of bone marrow–resident CD11b+F4/80+MHC-IIHigh macrophages that have taken up and present secreted myeloma protein. The present results demonstrate the potential of resident macrophages as powerful mediators of tumor killing within the bone marrow and provide a basis for novel therapeutic strategies against multiple myeloma and other malignancies that affect the bone marrow.
Addressing chronic persistent headaches after MTBI as a neuropathic pain state
Authors: Leung Albert
Published: June 2020

An increasing number of patients with chronic persistent post-traumatic headache (PPTH) after mild traumatic brain injury (MTBI) are being referred to headache or pain specialists as conventional treatment options for primary headache disorders have not been able to adequately alleviate their debilitating headache symptoms. Evolving clinical and mechanistic evidences support the notation that chronic persistent MTBI related headaches (MTBI-HA) carry the hallmark characteristics of neuropathic pain. Thus, in addition to conventional treatment options applicable to non-traumatic primary headache disorders, other available treatment modalities for neuropathic pain should be considered. In this comprehensive review article, the author reveals the prevalence of MTBI-HA and its clinical manifestation, discusses existing clinical and mechanistic evidence supporting the classification of chronic persistent MTBI-HA as a neuropathic pain state, and explores current available treatment options and future directions of therapeutic research related to MTBI-HA.
The association between sleep duration, bedtimes, and early pubertal timing among Chinese adolescents: a cross-sectional study
Authors: Diao Hua , Wang Hong , Yang Lianjian , Li Ting
Published: June 2020

Background and objective

Early pubertal timing is associated with sleep among Western adolescents, but little is known about this association in Chinese adolescents, especially with regard to the association between bedtimes and early pubertal timing. This paper aimed to identify the association between sleep duration, bedtimes, and early pubertal timing in Chinese adolescents.

Methods

An anonymous cross-sectional survey was conducted among primary and junior middle students (grades 3 to 9) from QiJiang District, ChongQing, China. Participants were recruited by applying stratified cluster sampling. Pubertal timing, sleep duration, and bedtimes were assessed using the Pubertal Development Scale and a self-designed sleep questionnaire. We utilized multivariable logistic linear regression (MLLR) to test the association between sleep duration, bedtimes, and pubertal timing.

Results

A total of 5461 adolescents were evaluated, with mean age and BMI values of 11.41 ± 2.05 and 18.03 ± 3.03, respectively, of whom 1257 (23.02%) were in early pubertal timing. In MLLR controlling for age, BMI, family economic status, and other covariates, sufficient sleep (b = − 0.214, P = 0.032, OR = 0.808, 95% CI 0.664–0.982) was negatively related to early pubertal timing, and later bedtime (b = 0.195, P < 0.001, OR = 1.215, 95% CI 1.104–1.338) was positively associated with early pubertal timing.

Conclusion

Students with early pubertal timing had less sleep duration and later bedtimes, which may be the result of increased stress caused by physical and psychological changes. Therefore, more attention should be paid to pubertal health education for adolescents during puberty. Further longitudinal studies are needed to confirm the causality between sleep and early pubertal timing in Chinese adolescents.
Lipidome analysis of milk composition in humans, monkeys, bovids, and pigs
Authors: Mitina Aleksandra , Mazin Pavel , Vanyushkina Anna , Anikanov Nikolay , Mair Waltraud , Guo Song , Khaitovich Philipp
Published: June 2020

Background

Lipids contained in milk are an essential source of energy and structural materials for a growing neonate. Furthermore, lipids’ long-chain unsaturated fatty acid residues can directly participate in neonatal tissue formation. Here, we used untargeted mass spectrometric measurements to assess milk lipid composition in seven mammalian species: humans, two macaque species, cows, goats, yaks, and pigs.

Results

Analysis of the main milk lipid class, triacylglycerides (TAGs), revealed species-specific quantitative differences in the composition of fatty acid residues for each of seven species. Overall, differences in milk lipid composition reflect evolutionary distances among species, with each species group demonstrating specific lipidome features. Among them, human milk contained more medium and long-chain unsaturated fatty acids compared to other species, while pig milk was the most distinct, featuring the highest proportion of long-chain polyunsaturated fatty acids.

Conclusions

We show that milk lipidome composition is dynamic across mammalian species, changed extensively in pigs, and contains features particular to humans.