bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial distribution of soil salinity and potential implications for soil management in the Manas River watershed, China
Authors: Wang Jianyong , Liu Yingxia , Wang Shaoming , Liu Huiming , Fu Guangqiang , Xiong Youcai
Published: August 2019

Understanding the watershed‐scale spatial distribution of soil salinity and its compositions is important for soil management. Here, we present the first study on the Manas River watershed in northwest China. In this study, we took soil samples in upper 20 cm of soil from 186 locations across the watershed and measured total salt concentration (TSC), salt ion composition and soil particle size distribution (PSD). We found that on average topsoil TSC tended to increase, from 3.55 g kg−1 in upstream regions to 19.40 g kg−1 in downstream regions. The stoichiometric analysis showed that the equivalence ratio of soil Cl‐ to SO42− increased from 0.53 in upstream regions to 2.12 in midstream regions, and further to 3.76 in downstream regions; thus, the soil types were classified into chloride–sulfate, sulfate–chloride and chloride soils types, respectively. Additionally, proportions of small (<2 μm in diameter) and large (>2,000 μm) soil particles increased, while that of medium sizes (2–50 μm) decreased from upstream to downstream, with an increasing coefficient of variance (CV) in PSD. Taken together, watershed‐scale topsoil salinity may be horizontally characterized by increased TSC and Na+ & Cl− proportions, greater equivalence ratio of Cl− vs. SO42− and more balanced distribution of PSD along with surface water flow. Results demonstrated that soil salinity and its ions compositions showed a great variation across the watershed scale, suggesting that soil management may consider the spatial heterogeneity of saline–alkaline soil types, and our results provided scientific guidance for local soil management and restoration.
An Investigation on Learning Climate at Sport High Schools
Authors: Şentürk Halil Evren , Mutlu T. Osman
Published: August 2019

Sport High Schools that activate in Turkey and where students who are skilled at sports have their secondary education are found to be suitable place to study on. In this study, it is aimed to study perception of teachers working and students studying in these institutions regarding learning climate. 342 teachers and 557 students that participated in the study voluntarily are considered to be the best universe taking part in the study in daily basis. In terms of data collection tool, Camur’s “Learning Climate Scale” with its Turkish adaptation in the year 2006 is used by considering its sub-dimensions. The participants are reached through sharing prepared research form in on-line social media sport high school groups. In order to find out learning climate perception of both teachers and students, determining statistics is used where, t-test and one-way variance analysis is used for comparing independent samples based on demographic features, and in order to find the relationships in the study, Pearson r relationship analysis is applied. In the end of the analyses made, it is found out that physical education and sports teachers have negative impression about learning climate in sport high schools (n=120, mean=3,304). Teachers of other fields working at sport high schools displayed highly negative impression (n=222, mean=2,828). Students studying at these institutions on the other hand displayed lesser levels of negative impression when compared to teachers (n=557, mean=3,637). As a result, when sport high schools are investigated based on learning climate, it is concluded that; both teachers and students do not meet at an appropriate education environment due to current status in those schools.
Comparative study and characterization of atomic layer deposition Al2O3 films as metal-insulator-metal capacitor dielectric for GaAs hetero-junction bipolar transistor technology
Authors: Yota Jiro , Janani Mehran , Banbrook Hal M. , Rabinzohn Patrick , Bosund Markus
Published: August 2019

Atomic layer deposition (ALD) aluminum oxide (Al2O3) films have been deposited using trimethyl aluminum (TMA) and H2O, and using TMA and H2O with O3 as precursors, and were characterized and evaluated as a metal-insulator-metal (MIM) capacitor dielectric in GaAs hetero-junction bipolar transistor (HBT) technology. The results show that the capacitor with 60 nm of ALD Al2O3 capacitor dielectric films deposited using TMA and H2O and deposited using TMA, H2O, and O3 resulted in a capacitance density of 1.36 × 10−15–1.37 × 10−15 F/μm2, and a dielectric constant of 9.2–9.3. The capacitance density of the capacitor using these films increased by 2.3%–3.0%, when the temperature was increased from 25 to 125 °C. No significant change in capacitance density of these ALD films was observed when the applied voltage was varied from −5 to +5 V. However, the 60 nm ALD aluminum oxide film deposited using the TMA, H2O, and O3 has significantly higher breakdown voltage (46 V) compared to the ALD aluminum oxide film deposited using TMA and H2O only (38.4 V). Furthermore, the leakage current density of the ALD Al2O3 from TMA, H2O, and O3 is significantly lower compared to that of ALD Al2O3 from TMA and H2O (5.6 × 10−8 A/cm2 vs 8.9 × 10−6 A/cm2 at 5 MV/cm). As the temperature was increased from 25 to 125 °C, the breakdown voltage of both films decreased, while the leakage current marginally increased. Additionally, as the capacitor area is increased, the leakage current also increased, while no change in breakdown voltage is observed.
Forty years of reform and opening up: China’s progress toward a sustainable path
Authors: Lu Yonglong , Zhang Yueqing , Cao Xianghui , Wang Chenchen , Wang Yichao , Zhang Meng , Ferrier Robert C. , Jenkins Alan , Yuan Jingjing , Bailey Mark J. , Chen Deliang , Tian Hanqin , Li Hong , von Weizsäcker Ernst Ulrich , Zhang Zhongxiang
Published: August 2019

China is experiencing a decoupling of economic growth and environmental impacts.
Dynamic tuning of FRET in a green fluorescent protein biosensor
Authors: Trigo-Mourino Pablo , Thestrup Thomas , Griesbeck Oliver , Griesinger Christian , Becker Stefan
Published: August 2019

The dynamic nature of FRET sensor Twitch-2B, as probed by x-ray, NMR, and modeling, reveals key information on how to tune FRET.
Cell cycle progression in confining microenvironments is regulated by a growth-responsive TRPV4-PI3K/Akt-p27
Kip1
signaling axis
Authors: Nam Sungmin , Gupta Vivek Kumar , Lee Hong-pyo , Lee Joanna Y. , Wisdom Katrina M. , Varma Sushama , Flaum Eliott Marie , Davis Ciara , West Robert B. , Chaudhuri Ovijit
Published: August 2019

A growth-responsive TRPV4-PI3K-p27 pathway regulates cell cycle progression for cancer cells in confining 3D microenvironments.
Decreased conformational stability in the oncogenic N92I mutant of Ras-related C3 botulinum toxin substrate 1
Authors: Toyama Yuki , Kontani Kenji , Katada Toshiaki , Shimada Ichio
Published: August 2019

We demonstrate that the decrease in conformational stability underlies the oncogenic activity of the N92I mutant of Rac1.
Solving a new R2lox protein structure by microcrystal electron diffraction
Authors: Xu Hongyi , Lebrette Hugo , Clabbers Max T. B. , Zhao Jingjing , Griese Julia J. , Zou Xiaodong , Högbom Martin
Published: August 2019

We used 3D microcrystal electron diffraction (MicroED) to solve a new protein structure.
Lysozyme elicits pain during nerve injury by neuronal Toll-like receptor 4 activation and has therapeutic potential in neuropathic pain
Authors: Yadav Saurabh , Surolia Avadhesha
Published: August 2019

Neuronal Toll-like receptor 4 activation by lysozyme enhances pain perception during nerve injury and emerges as neuron intrinsic axis to treat it.
Toxoplasma gondii Oocyst Infectivity Assessed Using a Sporocyst-Based Cell Culture Assay Combined with Quantitative PCR for Environmental Applications
Authors: Rousseau Angélique , Escotte-Binet Sandie , La Carbona Stéphanie , Dumètre Aurélien , Chagneau Sophie , Favennec Loïc , Kubina Sophie , Dubey Jitender P. , Majou Didier , Bigot-Clivot Aurélie , Villena Isabelle , Aubert Dominique
Published: August 2019

The ubiquitous protozoanToxoplasma gondiiis the subject of renewed interest due to the spread of oocysts in water and food causing endemic and epidemic outbreaks of toxoplasmosis in humans and animals worldwide. Displaying a sensitivity close to animal models, cell culture represents a real alternative to assess the infectivity of oocysts in water and in biological sentinel mussels. This method opens interesting perspectives for evaluating human exposure to infectiousT. gondiioocysts in the environment, where oocyst amounts are considered to be very small.
Draft Genome Sequence of
Massilia
sp. Strain ONC3, a Novel Bacterial Species of the
Oxalobacteraceae
Family Isolated from Garden Soil
Authors: Peta Vincent , Raths Rachel , Bücking Heike
Published: August 2019

From garden soil, we isolated and sequenced
Massilia
sp. strain ONC3, a new member of the
Oxalobacteraceae
within the
Massilia
genus. Sequence analysis showed an assembled genome size of 5,622,601 bp, with a predicted total of 5,104 protein-coding sequences, 3,194 functionally assigned genes, 2 rRNA operons, and 56 tRNAs.
octoFLU: Automated Classification for the Evolutionary Origin of Influenza A Virus Gene Sequences Detected in U.S. Swine
Authors: Chang Jennifer , Anderson Tavis K. , Zeller Michael A. , Gauger Phillip C. , Vincent Amy L.
Published: August 2019

The diversity of the 8 genes of influenza A viruses (IAV) in swine reflects introductions from nonswine hosts and subsequent antigenic drift and shift. Here, we curated a data set and present a pipeline that assigns evolutionary lineage and genetic clade to query gene segments.
Complete Genome Sequences of Three Star-Shaped Bacteria, Stella humosa, Stella vacuolata, and Stella Species ATCC 35155
Authors: Shibai Atsushi , Maeda Tomoya , Kawada Masako , Kotani Hazuki , Sakata Natsue , Furusawa Chikara
Published: August 2019

Stella
species are unique star-shaped alphaproteobacteria found in various environments. We report the complete genome sequences of three
Stella
strains,
Stella humosa
ATCC 43930,
Stella vacuolata
ATCC 43931, and
Stella
species ATCC 35155. These are the first complete genome sequences of members of the genus
Stella
.
PEPtalk2: results of a pilot randomised controlled trial to compare VZIG and aciclovir as postexposure prophylaxis (PEP) against chickenpox in children with cancer
Authors: Bate Jessica , Baker Stephen , Breuer Judith , Chisholm Julia C , Gray Juliet , Hambleton Sophie , Houlton Aimee , Jit Mark , Lowis Stephen , Makin Guy , O’Sullivan Catherine , Patel Soonie R , Phillips Robert , Ransinghe Neil , Ramsay Mary Elizabeth , Skinner Roderick , Wheatley Keith , Heath Paul T
Published: August 2019

Objective

To determine the likely rate of patient randomisation and to facilitate sample size calculation for a full-scale phase III trial of varicella zoster immunoglobulin (VZIG) and aciclovir as postexposure prophylaxis against chickenpox in children with cancer.

Design

Multicentre pilot randomised controlled trial of VZIG and oral aciclovir.

Setting

England, UK.

Patients

Children under 16 years of age with a diagnosis of cancer: currently or within 6 months of receiving cancer treatment and with negative varicella zoster virus (VZV) serostatus at diagnosis or within the last 3 months.

Interventions

Study participants who have a significant VZV exposure were randomised to receive PEP in the form of VZIG or aciclovir after the exposure.

Main outcome measures

Number of patients registered and randomised within 12 months of the trial opening to recruitment and incidence of breakthrough varicella.

Results

The study opened in six sites over a 13-month period. 482 patients were screened for eligibility, 32 patients were registered and 3 patients were randomised following VZV exposure. All three were randomised to receive aciclovir and there were no cases of breakthrough varicella.

Conclusions

Given the limited recruitment to the PEPtalk2 pilot, it is unlikely that the necessary sample size would be achievable using this strategy in a full-scale trial. The study identified factors that could be used to modify the design of a definitive trial but other options for defining the best means to protect such children against VZV should be explored.

Trial registration number

ISRCTN48257441, EudraCT number: 2013-001332-22, sponsor: University of Birmingham.
Qualitative study: patients’ and parents’ views on brain tumour MRIs
Authors: Tyldesley-Marshall Natalie , Greenfield Sheila , Neilson Susan , English Martin , Adamski Jenny , Peet Andrew
Published: August 2019

Background

MRI is essential to the clinical management of children and young people with brain tumours. Advances in technology have made images more complicated to interpret, yet more easily available digitally. It is common practice to show these to patients and families, but how they emotionally respond to, understand and value, seeing brain tumour MRIs has not been formally studied.

Methods

Qualitative semi-structured interviews were undertaken with 14 families (8 patients, 15 parents) purposively sampled from paediatric patients (0 to 18 years) attending a large UK children’s hospital for treatment or monitoring of a brain tumour. Transcripts were analysed thematically using the Framework Method.

Results

Four themes were identified: Receiving results (waiting for results, getting results back, preferences to see images), Emotional responses to MRIs, Understanding of images (what they can show, what they cannot show, confusion) and Value of MRIs (aesthetics, aiding understanding, contextualised knowledge/emotional benefits, enhanced control, enhanced working relationships, no value). All families found value in seeing MRIs, including reassurance, hope, improved understanding and enhanced feeling of control over the condition. However emotional responses varied enormously.

Conclusions

Clinical teams should always explain MRIs after ‘framing’ the information. This should minimise participant confusion around meaning, periodically evident even after many years. Patient and parent preferences for being shown MRIs varied, and often changed over time, therefore clinicians should identify, record and update these preferences. Time between scanning and receiving the result was stressful causing ‘scanxiety’, but most prioritised accuracy over speed of receiving results.
Unilateral remote temperature monitoring to predict future ulceration for the diabetic foot in remission
Authors: Lavery Lawrence A , Petersen Brian J , Linders David R , Bloom Jonathan D , Rothenberg Gary M , Armstrong David G
Published: August 2019

Objective

Daily remote foot temperature monitoring is an evidence-based preventive practice for patients at risk for diabetic foot complications. Unfortunately, the conventional approach requires comparison of temperatures between contralaterally matched anatomy, limiting practice in high-risk cohorts such as patients with a wound to one foot and those with proximal lower extremity amputation (LEA). We developed and assessed a novel approach for monitoring of a single foot for the prevention and early detection of diabetic foot complications. The purpose of this study was to assess the sensitivity, specificity, and lead time associated with unilateral diabetic foot temperature monitoring.

Research design and methods

We used comparisons among ipsilateral foot temperatures and between foot temperatures and ambient temperature as a marker of inflammation. We analyzed data collected from a 129-participant longitudinal study to evaluate the predictive accuracy of our approach. To evaluate classification accuracy, we constructed a receiver operator characteristic curve and reported sensitivity, specificity, and lead time for four different monitoring settings.

Results

Using this approach, monitoring a single foot was found to predict 91% of impending non-acute plantar foot ulcers on average 41 days before clinical presentation with a resultant mean 4.2 alerts per participant-year. By adjusting the threshold temperature setting, the specificity could be increased to 78% with corresponding reduced sensitivity of 53%, lead time of 33 days, and 2.2 alerts per participant-year.

Conclusions

Given the high incidence of subsequent diabetic foot complications to the sound foot in patients with a history of proximal LEA and patients being treated for a wound, practice of daily temperature monitoring of a single foot has the potential to significantly improve outcomes and reduce resource utilization in this challenging high-risk population.
Tumour characteristics provide evidence for germline mismatch repair missense variant pathogenicity
Authors: Li Shuwei , Qian Dajun , Thompson Bryony A , Gutierrez Stephanie , Wu Sitao , Pesaran Tina , LaDuca Holly , Lu Hsiao-Mei , Chao Elizabeth C , Black Mary Helen
Published: August 2019

Background

Pathogenic variants in mismatch repair (MMR) genes (MLH1, MSH2,MSH6andPMS2) increase risk for Lynch syndrome and related cancers. We quantified tumour characteristics to assess variant pathogenicity for germline MMR genes.

Methods

Among 4740 patients with cancer with microsatellite instability (MSI) and immunohistochemical (IHC) results, we tested MMR pathogenic variant association with MSI/IHC status, and estimated likelihood ratios which we used to compute a tumour characteristic likelihood ratio (TCLR) for each variant. Predictive performance ofTCLRin combination within silicopredictors, and a multifactorial variant prediction (MVP) model that included allele frequency, co-occurrence, co-segregation, and clinical and family history information was assessed.

Results

Compared with non-carriers, carriers of germline pathogenic/likely pathogenic (P/LP) variants were more likely to have abnormal MSI/IHC status (p<0.0001). Among 150 classified missense variants, 73.3% were accurately predicted withTCLRalone. Models leveragingin silicoscores as prior probabilities accurately classified >76.7% variants. AddingTCLRas quantitative evidence in an MVP model (MVP +TCLRPred) increased the proportion of accurately classified variants from 88.0% (MVP alone) to 98.0% and generated optimal performance statistics among all models tested. Importantly, MVP +TCLRPredresulted in the high yield of predicted classifications for missense variants of unknown significance (VUS); among 193 VUS, 62.7% were predicted as P/PL or benign/likely benign (B/LB) when assessed according to American College of Medical Genetics and Genomics/Association for Molecular Pathology guidelines.

Conclusion

Our study demonstrates that when used separately or in conjunction with other evidence, tumour characteristics provide evidence for germline MMR missense variant assessment, which may have important implications for genetic testing and clinical management.
Design of riprap for bridge pier groups
Authors: Rashno Emad , Zarrati Amir Reza , Tabarestani Mojtaba Karimaei
Published: August 2019

Stable riprap size and optimized extension of the riprap layer around double and triple piers along the flow direction are studied experimentally. Results showed that the critical riprap failure area and stable riprap size around the first pier remain unchanged with increasing pier spacing. In addition, the largest stable riprap should always be placed in front of the first pier in comparison with the remaining downstream piers. However, by increasing the pier spacing, stable riprap size around the second and third pier increased and approached that around the first pier. A relationship was developed for designing stable riprap size in pier groups. Based on this relationship, different riprap sizes are suggested for different zones around the pier group. Experiments showed that the critical zone around the piers includes only a small area and the rest of the riprap extent area can be protected with smaller riprap stones.
Deterministic bidirectional quantum-controlled teleportation with six-qubit maximally entangled state
Authors: Zhang Wanbin
Published: August 2019

Each of three nodes in a quantum network has two qubits. The total six qubits are in a maximally entangled state [Helwig et al., Phys. Rev. A 86, 052335 (2012)]. Using such an entangled state as quantum channel, we put forward three deterministic bidirectional quantum-controlled teleportation (BQCT) schemes. To be specific, BQCT can be realized between any two nodes in a deterministic manner with another as the control. Alternatively, the BQCT capacity of such state in the given qubit distribution is thus essentially revealed by virtue of the schemes.
Fixing the number of non-sequential generations within the SU(2)L ⊗U(1)Y gauge group
Authors: Barreto Elmer Ramirez , Abad David Romero
Published: August 2019

In this work, we explore the possibility of fixing the number of new non-sequential chiral-type generations of fermions that could be added to the Standard Model by combining the condition that arise from the anomaly cancellation with the restriction in the number of flavors imposed by the QCD asymptotic freedom. We found that the maximum number of new generations is four, and this allows us, at the same time, to place limits for the electrical charges of quarks and leptons within an SM-like framework. Our result is compatible with the constraints involving new generations and their contributions to the oblique parameters S and T.
Structural, optoelectronic and elastic properties of quaternary perovskites CaPd3B4O12 (B = Ti, V)
Authors: Mehmood Shahid , Ali Zahid , Hashmi Zainab , Khan Sahar
Published: August 2019

Perovskites CaPd3B4O[Formula: see text] (B = Ti, V) are studied theoretically using generalized gradient approximation (GGA), GGA-modified Becke–Johnson (GGA-mBJ), GGA with spin-orbit coupling (GGA + SOC) and hybrid functional (HF) in the domain of density functional theory (DFT). The estimated structural parameters are reliable with the experimentally reported data. Cohesive energy and enthalpy show that these compounds are stable thermodynamically. Bonding nature makes known that the chemical bond between Ca/Ti–O is ionic, Pd/V–O is covalent and Ti/V–Ti/V is metallic. The mechanical properties show that these compounds are stable, elastically anisotropic and ductile in nature. CaPd3Ti4O[Formula: see text] is a 2.94 eV direct-wide bandgap semiconductor through GGA-mBJ and consistent with experiments. The optical properties show that CaPd3Ti4O[Formula: see text] is a good dielectric material. The dense electronic states and the wide-gap semiconductor nature of CaPd3Ti4O[Formula: see text] suggest that it can be used as a good thermoelectric material.
Periodic type and periodic cross-kink wave solutions to the (2 + 1)-dimensional breaking soliton equation arising in fluid dynamics
Authors: Ilhan Onur Alp , Manafian Jalil
Published: August 2019

In this paper, we have acquired the periodic type and cross-kink wave solutions. In this paper, we use the Hirota bilinear method. With the help of the symbolic calculation and applying the used method, we solve the (2[Formula: see text]+[Formula: see text]1)-dimensional Breaking Soliton (BS) equation. We obtain some periodic wave and cross-kink wave that have greatly enriched the existing literature on the BS equation. All solutions have been verified back into its corresponding equation with the aid of the Maple package program via the three-dimensional images and density images with the help of Maple, the physical characteristics of these waves are described very well. These will be widely used to describe many interesting physical phenomena in the fields of gas, plasma, optics, acoustics, heat transfer, fluid dynamics, classical mechanics and so on.
Lévy Noise-Induced Effects in Underdamped Asymmetric Bistable System
Authors: Guo Yongfeng , Wei Fang , Wang Linjie
Published: August 2019

This paper aims to explore the Lévy noise-induced effects in underdamped asymmetric bistable system. Lévy noise is generated by Janicki–Weron algorithm which is different from the usual Gaussian noise. The numerical solutions of system equation are obtained by the fourth-order stochastic Runge–Kutta algorithm. Then the quasi-steady-state probability density (QSPD) is obtained by solving the equation of system, and the stochastic resonance (SR) is determined by the classical measure of signal-to-noise ratio (SNR). The influence of various parameters of the Lévy noise and the system parameters on QSPD and SNR is discussed. Noise-induced transitions occur by varying the parameters of the Lévy noise and the driven system. Moreover, within certain limits, the larger value of the stability index [Formula: see text] of Lévy noise, signal amplitude [Formula: see text], and the absolute values of asymmetric parameter [Formula: see text] can give rise to the SR phenomenon. On the contrary, the larger values of skewness parameters [Formula: see text] of Lévy noise and damping parameter [Formula: see text] further weaken the occurrence of the SR phenomenon in the given system.
Eversible and reversible semigroups and semirings
Authors: Nasehpour Peyman
Published: August 2019

The main purpose of this paper is to investigate the zero-divisors of semigroups with zero and semirings. In particular, we discuss eversible and reversible semigroups and semirings. We also introduce a new ring-like algebraic structure called prenearsemiring and generalize Cohn’s theorem for reversible rings in this context. Finally, we discuss when expectation semirings are reversible or eversible.
The Physiology of Heat Tolerance in Small Endotherms
Authors: McKechnie Andrew E. , Wolf Blair O.
Published: August 2019

Understanding the heat tolerances of small mammals and birds has taken on new urgency with the advent of climate change. Here, we review heat tolerance limits, pathways of evaporative heat dissipation that permit the defense of body temperature during heat exposure, and mechanisms operating at tissue, cellular, and molecular levels.
The Pancreatic Cancer-Initiating Cell Marker CD44v6 Affects Transcription, Translation, and Signaling: Consequences for Exosome Composition and Delivery
Authors: Sun Hanxue , Rana Sanyukta , Wang Zhe , Zhao Kun , Schnölzer Martina , Provaznik Jan , Hackert Thilo , Lv Qingjie , Zöller Margot
Published: August 2019

Pancreatic cancer-initiating cells (PaCIC) express CD44v6 and Tspan8. A knockdown (kd) of these markers hinders the metastatic capacity, which can be rescued, if the cells are exposed to CIC-exosomes (TEX). Additional evidence that CD44v6 regulates Tspan8 expression prompted us to explore the impact of these PaCIC markers on nonmetastatic PaCa and PaCIC-TEX. We performed proteome, miRNA, and mRNA deep sequencing analyses on wild-type, CD44v6kd, and Tspan8kd human PaCIC and TEX. Database comparative analyses were controlled by qRT-PCR, Western blot, flow cytometry, and confocal microscopy. Transcriptome analysis of CD44 versus CD44v6 coimmunoprecipitating proteins in cells and TEX revealed that Tspan8, several signal-transducing molecules including RTK, EMT-related transcription factors, and proteins engaged in mRNA processing selectively associate with CD44v6 and that the membrane-attached CD44 intracytoplasmic tail supports Tspan8 and NOTCH transcription. Deep sequencing uncovered a CD44v6 contribution to miRNA processing. Due to the association of CD44v6 with Tspan8 in internalization prone tetraspanin-enriched membrane domains (TEM) and the engagement of Tspan8 in exosome biogenesis, most CD44v6-dependent changes were transferred into TEX such that the input of CD44v6 to TEX activities becomes largely waved in both a CD44v6kd and a Tspan8kd. Few differences between CD44v6kd- and Tspan8kd-TEX rely on CD44v6 being also recovered in non-TEM derived TEX, highlighting distinct TEX delivery from individual cells that jointly account for TEX-promoted target modulation. This leads us to propose a model in which CD44v6 strongly supports tumor progression by cooperating with signaling molecules, altering transcription of key molecules, and through its association with the mRNA processing machinery. The association of CD44v6 with Tspan8, which plays a crucial role in vesicle biogenesis, promotes metastases by transferring CD44v6 activities into TEM and TEM-independently derived TEX. Further investigations of the lead position of CD44v6 in shifting metastasis-promoting activities into CIC-TEX may offer a means of targeting TEX-CD44v6 in therapeutic applications.
Prevalence and Factors Associated with Acute Kidney Injury among Malaria Patients in Dar es Salaam: A Cross-Sectional Study
Authors: Muhamedhussein M. S. , Ghosh S. , Khanbhai K. , Maganga E. , Nagri Z. , Manji M.
Published: August 2019

Introduction. Falciparum malaria still remains as a major cause of morbidity and mortality worldwide. Acute kidney injury is a known complication of malaria, and it is reported to occur in up to 40% of adult patients with severe falciparum malaria in endemic regions like sub-Saharan Africa.Objectives. To determine the prevalence and factors associated with acute kidney injury among falciparum malaria patients in a tertiary level private hospital in Dar es Salaam.Methodology. In a cross-sectional study design, 104 adults with falciparum malaria were enrolled consecutively over 6 months from April to September 2015. The diagnosis of acute kidney injury (AKI) in these patients was established using the KDIGO classification criteria. The prevalence of AKI was obtained at 48 hours from admission and at day 7. Different sociodemographic and clinical parameters which were associated with acute kidney injury at 48 hours and at day 7 were identified by hypothesis testing using chi squared tests followed by multivariate logistic regression analysis. Factors with a p value less than 0.05 were considered significant.Results. The participants were predominantly males 65.4% (68/104) and a third (36.5% (38/104)) were between 46 and 65 years. The prevalence of AKI among malaria patients at 48 hours was 26% (27/104). The prevalence of AKI among malaria patients at day 7 was 18.3% (19/104). On multivariate logistic regression, we found that factors that were significantly associated with AKI at 48 hours were male sex (OR 127, CI 3.4–4700, P = 0.008) and hemoglobin <7.5g/dl (OR 36.5, CI 1.7–797.7, P = 0.022), and factor associated with AKI at day 7 was baseline platelet count <25×103per mm3(OR 77.8 CI 1.045–5798.6, P = 0.048). Only two patients needed hemodialysis (1.9%) and there were no deaths.Conclusion. Acute kidney injury is a common complication in patient with falciparum malaria. When managed well it has an excellent prognosis and necessitates dialysis in only a minority of patients. Male sex and hemoglobin is associated with AKI at 48 hours and baseline platelet count is associated with AKI at 7 days.
YES1 Is a Targetable Oncogene in Cancers Harboring YES1 Gene Amplification
Authors: Hamanaka Natsuki , Nakanishi Yoshito , Mizuno Takakazu , Horiguchi-Takei Kana , Akiyama Nukinori , Tanimura Hiromi , Hasegawa Masami , Satoh Yasuko , Tachibana Yukako , Fujii Toshihiko , Sakata Kiyoaki , Ogasawara Kiyomoto , Ebiike Hirosato , Koyano Hiroshi , Sato Haruhiko , Ishii Nobuya , Mio Toshiyuki
Published: August 2019

Targeting genetic alterations of oncogenes by molecular-targeted agents (MTA) is an effective approach for treating cancer. However, there are still no clinical MTA options for many cancers, including esophageal cancer. We used a short hairpin RNA library to screen for a new oncogene in the esophageal cancer cell line KYSE70 and identified YES proto-oncogene 1 (YES1) as having a significant impact on tumor growth. An analysis of clinical samples showed that YES1 gene amplification existed not only in esophageal cancer but also in lung, head and neck, bladder, and other cancers, indicating that YES1 would be an attractive target for a cancer drug. Because there is no effective YES1 inhibitor so far, we generated a YES1 kinase inhibitor, CH6953755. YES1 kinase inhibition by CH6953755 led to antitumor activity against YES1-amplified cancers in vitro and in vivo. Yes-associated protein 1 (YAP1) played a role downstream of YES1 and contributed to the growth of YES1-amplified cancers. YES1 regulated YAP1 transcription activity by controlling its nuclear translocation and serine phosphorylation. These findings indicate that the regulation of YAP1 by YES1 plays an important role in YES1-amplified cancers and that CH6953755 has therapeutic potential in such cancers.

Significance:

These findings identify the SRC family kinase YES1 as a targetable oncogene in esophageal cancer and describe a new inhibitor for YES1 that has potential for clinical utility.

See related commentary by Rai, p. 5702
Abstract 1: A small molecule inhibits Nrf2 expression and activity in cancer cells
Authors: Zhang Di , Livingston Corbin , Dexheimer Thomas , Ellsworth Edmund , Odom Aaron , Liby Karen
Published: August 2019

Activation of the Nrf2-Keap1-ARE pathway is a master defense mechanism protecting against oxidative and electrophilic stress. Nrf2 was traditionally considered cancer-preventing, as Nrf2 deficiency enhances susceptibility to carcinogens in a variety of mouse models. However, increasing evidence suggests a tumor-promoting role for Nrf2 in established tumors: gain of function mutations in NFE2L2, which activates the Nrf2 pathway, or loss of function mutations in its negative regulator, Keap1, have been found most frequently in lung cancer. Constitutive activation of the Nrf2 pathway is associated with chemoresistance and poor survival. Nrf2 inhibitors, therefore, become potential novel drugs for cancer treatment and needed tool compounds to study the Nrf2 pathway in cancer. To identify Nrf2 inhibitors, we conducted a high throughput screen with a diverse set of small molecules (~6500 compounds). 890 compounds were identified as hits, and a funnel strategy was applied to filter through the hits and select lead compounds. Although other known Nrf2 inhibitors were identified, a potentially novel compound, MSU225, was chosen as a lead for further evaluation. MSU225 downregulated tBHQ (tert-butyl hydroquinone)-induced Nrf2 transcriptional activity in a luciferase assay without inducing cell death. When A549 human lung cancer cells, in which Keap1 is mutated inducing constitutive activation of Nrf2, were treated with 5 µM MSU225, the mRNA expression of HMOX1, NQO1, GST1A1, GCLC, GCLM, and UGT1A6, all downstream targets of Nrf2, were decreased. Moreover, MSU225 significantly (p<0.05) decreased the protein level of Nrf2 in A549 cells. The effect of MSU225 on Nrf2 protein levels was blocked by the proteasome inhibitor MG132, suggesting MSU225 enhances Nrf2 degradation through the proteasome system. In addition, MSU225 inhibited the growth of human lung cancer cells (A549, H460, A427) in soft agar. Cells addicted to Nrf2 were more susceptible to MSU225 for suppression of cell proliferation than cells not addicted to Nrf2. MSU225 also sensitized A549 cells to carboplatin treatment. Our results suggest that MSU225 is a novel Nrf2 inhibitor, and additional in vivo studies will be done to determine if it can be used to treat experimental lung cancer.

Citation Format: Di Zhang, Corbin Livingston, Thomas Dexheimer, Edmund Ellsworth, Aaron Odom, Karen Liby. A small molecule inhibits Nrf2 expression and activity in cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1.
Abstract 1009: On the role of DEAR1 as a novel ubiquitin ligase for ER alpha and predictor of tamoxifen response in ER positive breast cancer
Authors: Balasenthil Seetharaman , Chen Nanyue , Killary Ann
Published: August 2019

Estrogen receptor positive (ER+) breast cancer accounts for over 70% of breast cancers. Targeted adjuvant therapies aimed at estrogen receptor have changed the natural history of the disease. However, over time many tumors develop resistance mechanisms which result in overall poor outcome. Thus, biomarkers that could predict response to antiestrogens are critically needed and would have major clinical impact. Thus, it is imperative that additional novel mechanisms be discovered not only to understand the basic underlying biology of ER alpha (ERα) signaling in order to identify genetic alterations that deregulate ERα and its role in breast cancer. DEAR1 is a tumor suppressor gene which is mutated, undergoes loss of heterozygosity in breast cancer. Previously we observed a subset of DEAR1 mutations in early onset breast cancers from premenopausal women, therefore we hypothesized that DEAR1 may function in the regulation of ERα signaling and conversely that mutations in DEAR1 (observed in human breast cancers) will abrogate that effect and could play a role in resistance to antiestrogen therapies. To test this hypothesis we studied the effect of DEAR1 expression on ERα. DEAR1 overexpression downregulated ERα expression and stability suggestive that DEAR1 may regulate ER signaling. DEAR1 interacted with ERα by immunoprecipitation and GST pulldown assays. Next we studied whether E3 ligase DEAR1 facilitates the degradation of ERα by promoting the ubiquitination of ERα. Our results indicate that DEAR1 promoted the polyubiquitination of ERα. To assess the effect of DEAR1 on estrogen mediated response, we examined the effect of DEAR1 on ERα-mediated transactivation using ERE-luciferase reporters. Results indicate that DEAR1 significantly inhibits estrogen-mediated transcriptional activity of ERα. We also studied the effect of DEAR1 in antiestrogen resistance using tamoxifen resistant cells. Preliminary results suggest that the presence of DEAR1 promoted the action of antiestrogen in tamoxifen resistant cell line. We have identified a new novel E3 ligase with regulatory effect of ERα signaling and potential implications in antiestrogen resistance.

Citation Format: Seetharaman Balasenthil, Nanyue Chen, Ann Killary. On the role of DEAR1 as a novel ubiquitin ligase for ER alpha and predictor of tamoxifen response in ER positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1009.
Abstract 101: Pentraxin-3 exacerbates glioblastoma invasion and angiogenesis through IL8-VEGF signaling in tumor microenvironment: PTX3 is a potential target for GBM suppression
Authors: Wesley Umadevi V. , Clark Paul , Sutton Ian , Kuo John , Dempsey Robert
Published: August 2019

Background: Glioblastoma (GBM) is highly invasive and resistant to multimodal treatment due to distorted vasculature and aggravated inflammation in a tumor microenvironment rich in dysregulated cytokines and growth factors. This phenomenon is partly attributed to GBM stem cells (GSC) that release angiogenic and inflammatory cytokines. The glycoprotein pentraxin-3 (PTX3), a modulator of inflammation, is correlated with disease severity in some cancers. However, its role in GBM and the molecular mechanisms of PTX3-mediated oncogenesis remain unclear. In this study, we examined the role of PTX3 in GBM growth and invasion, using in vitro and in vivo models.

Methods: Patient derived GSC lines were isolated and validated. Tumor tissue micro arrays (TMA) were used to determine the association of PTX3 expression with patient GBM specimens representing various degree of disease. Intracranial tumor xenograft/orthotopic mouse models, cell culture models, proteomic profiling, immunohistochemistry, molecular and biochemical approaches were used.

Results: Proteomic profiling identified increased PTX3 expression in GSCs as compared to GBM lines, and correlated with the degree of GSC invasiveness in an orthotopic tumor xenograft model. Increased PTX3 correlated with cell cycle progression and survival under hypoxic micro-environment. Conditioned media obtained from PTX3-over-expressing U87 cell line enhanced pro-angiogenic tube formation from endothelial cells. TMA screening showed that PTX3 expression is substantially increased in more than 70% of GBM specimans. Furthermore, PTX3 over-expression significantly increased survival of U87 cells under hypoxic conditions and resulted in increased tumor growth and invasion in an intracranial tumor xenograft mouse model. Upregulation of PTX3 in these tumors was associated with increased levels of inflammatory and angiogenic markers including interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF), but decreased levels of thrombospondin1, a major anti-angiogenic factor. Downstream activation of PI3K/Akt - NFkB signaling pathways was also observed.

Conclusion: PTX3 is dysregulated in GBM, and may augment inflammation and angiogenesis in tumor microenvironment. Thus, PTX3 may serve as an inflammatory marker for GBM microenvironment and also may represent a potential therapeutic target for GBM suppresion.

Citation Format: Umadevi V. Wesley, Paul Clark, Ian Sutton, John Kuo, Robert Dempsey. Pentraxin-3 exacerbates glioblastoma invasion and angiogenesis through IL8-VEGF signaling in tumor microenvironment: PTX3 is a potential target for GBM suppression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 101.
Abstract 1020: p300 and CBP targeting in castration therapy resistant prostate cancer
Authors: Furlan Tobias , Sampson Natalie , Santer Frédéric R. , Culig Zoran
Published: August 2019

p300 and CBP interact with transcription factors and other proteins via their histone acetyltransferase domain (HAT) and a bromodomain (Bd). In prostate cancer, p300 and CBP act as oncogenes and are commonly upregulated. p300 and CBP are valid targets for therapy due to their function as androgen receptor (AR) coactivators and involvement in castration resistance. Revealing downstream pathways and their function in cancer cell proliferation and resistance should further identify potential novel therapeutic targets. The effect of the p300/CBP HAT inhibitor C646 and the Bd inhibitor ICBP-112 on viability was tested. To this end several human PCa cell lines with different AR expression levels and resistance status were used. The resistant cells were derived from DUCaP, LAPC4 and LNCaP cells chronically treated with Enzalutamide (DUCaP ENZA, LAPC4 ENZA and LNCaP ABL ENZA). Resistance was verified by viability assay. Regulation of AR downstream targets was studied by qRT-PCR and Western blot. Gene expression in the different DUCaP and LNCaP sublines after inhibitor treatment was analyzed with RNAseq. Both inhibitors exhibited IC50 values on viability at micromolar concentrations with a significantly lesser effect on androgen-insensitive PC3 cells compared to AR sensitive cells. Significantly increased sensitivity to inhibitors was observed in enzalutamide-resistant DUCaP ENZA, LAPC4 ENZA and LNCaP ABL ENZA cell lines relative to parental cells: respectively 1.83- (*), 2- (*) and 2.7-fold (*) for C646 and not significant, 1.8- (p<0.1) and 1.56-fold (*) for ICBP-112. Moreover, ICBP-112 treatment of DUCaP cells significantly reduced expression of the AR target genes FKBP5, PSA and TMPRSS2 0.6- (**), 0.57- (**) and 0.37-fold (***) respectively. Similar results were obtained with DUCaP ENZA cells 0.46- (*), 0.45- (*) and 0.57-fold (ns) for FKBP5, PSA and TMPRSS2, respectively. Whilst less pronounced, this regulation was also observed at the protein level. Similar results were obtained with C646. RNAseq results suggest multiple changes in sublines after chronic enzalutamide treatment in DUCaP and LNCaP cells. Inhibition of p300 and CBP reduced androgen-, myc- and parts of an EMT-signature, which are likely involved in the development of enzalutamide resistance. Taken together, C646 and ICBP-112 are effective inhibitors of AR dependent PCa. Furthermore, differences between cell lines suggest that the AR background and other factors influence the inhibitor effectivity. A significantly increased effect of the HAT and Bd inhibitors in CRPC suggests an important role for p300/CBP in CRPC.

Citation Format: Tobias Furlan, Natalie Sampson, Frédéric R. Santer, Zoran Culig. p300 and CBP targeting in castration therapy resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1020.
Abstract 1022: The role of dopamine signaling in prostate cancer disparities
Authors: Pickett Isaiah R. , Boston Ava M. , Almathkour Marwah M. , Ragin Camille , Bilen Mehmet A. , Osunkoya Adeboye O. , Cinar Bekir
Published: August 2019

Prostate cancer is the second leading cause of cancer-related deaths among men in western countries. Majority of prostate tumors often evolves as metastatic castration-resistant prostate cancer (CRPC) following hormonal therapy. Metastatic prostate cancer is the major cause of mortalities from this disease. African-American (AA) men have the highest incidence and mortality rate compared to any other race such as Caucasian American (CA). Despite recent advances, the cellular and molecular mechanisms that contribute to this disparity are unknown, obstructing the development of an effective therapy for this disease. Genetic and epigenetic studies have indicated that the biology of prostate cancer in AA men is substantially different from CA. Here, we investigate the dopamine (DA) signaling to better understand the mechanism of prostate cancer disparity. Our analysis of the prostate cancer public data sets showed that the dopamine receptor (DR) genes were amplified in up to 18% prostate cancer clinical cases. We have demonstrated that the levels of DR transcripts were significantly higher in the metastatic prostate cancer cell lines with African genetic ancestry than CA counters. We also demonstrate that the efficacy of pimozide, a potent DRD inhibitor and an FDA-approved antipsychotic, on AA cells was significantly higher than CA cells. In addition, we have found that L-dopa, an immediate precursor of DA differentially regulates the growth of AA and CA prostate cancer cells in a dose dependent manner. We also found that carbidopa, a potent inhibitor of the dopa decarboxylase, suppressed prostate cancer cell growth by L-dopa and showed that carbidopa re-sensitized CRPC cell line to enzalutamide, a potent inhibitor of androgen receptor (AR) signaling. These observations suggest that DA/DR signaling plays a critical role in prostate cancer disparity, making the DA/DR-AR axis a viable therapeutic target to reduce disparities in cancer mortality.

Citation Format: Isaiah R. Pickett, Ava M. Boston, Marwah M. Almathkour, Camille Ragin, Mehmet A. Bilen, Adeboye O. Osunkoya, Bekir Cinar. The role of dopamine signaling in prostate cancer disparities [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1022.