bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mapping genetic vulnerabilities reveals BTK as a novel therapeutic target in oesophageal cancer
Authors: Chong Irene Yushing , Aronson Lauren , Bryant Hanna , Gulati Aditi , Campbell James , Elliott Richard , Pettitt Stephen , Wilkerson Paul , Lambros Maryou B , Reis-Filho Jorge S , Ramessur Anisha , Davidson Michael , Chau Ian , Cunningham David , Ashworth Alan , Lord Christopher J 
Published: August 2017

Objective
Oesophageal cancer is the seventh most common cause of cancer-related death worldwide. Disease relapse is frequent and treatment options are limited.

Design
To identify new biomarker-defined therapeutic approaches for patients with oesophageal cancer, we integrated the genomic profiles of 17 oesophageal tumour-derived cell lines with drug sensitivity data from small molecule inhibitor profiling, identifying drug sensitivity effects associated with cancer driver gene alterations. We also interrogated recently described RNA interference screen data for these tumour cell lines to identify candidate genetic dependencies or vulnerabilities that could be exploited as therapeutic targets.

Results

By integrating the genomic features of oesophageal tumour cell lines with siRNA and drug screening data, we identified a series of candidate targets in oesophageal cancer, including a sensitivity to inhibition of the kinase BTK in
MYC
amplified oesophageal tumour cell lines. We found that this genetic dependency could be elicited with the clinical BTK/ERBB2 kinase inhibitor, ibrutinib. In both
MYC
and
ERBB2
amplified tumour cells, ibrutinib downregulated ERK-mediated signal transduction, cMYC Ser-62 phosphorylation and levels of MYC protein, and elicited G
1
cell cycle arrest and apoptosis, suggesting that this drug could be used to treat biomarker-selected groups of patients with oesophageal cancer.

Conclusions

BTK represents a novel candidate therapeutic target in oesophageal cancer that can be targeted with ibrutinib. On the basis of this work, a proof-of-concept phase II clinical trial evaluating the efficacy of ibrutinib in patients with
MYC
and/or
ERBB2
amplified advanced oesophageal cancer is currently underway (
NCT02884453
).

Trial registration number
NCT02884453; Pre-results
Autosomal recessive chondrodysplasia with severe short stature caused by a biallelic COL10A1 variant
Authors: Ain Noor ul , Makitie Outi , Naz Sadaf 
Published: August 2017

BackgroundHeterozygous mutations in COL10A1 underlie metaphyseal chondrodysplasia, Schmid type (MCDS), an autosomal dominant skeletal dysplasia.ObjectiveTo identify the causative variant in a large consanguineous Pakistani family with severe skeletal dysplasia and marked lower limb deformity.MethodsWhole exome sequencing was completed followed by Sanger sequencing to verify segregation of the identified variants. In silico variant pathogenicity predictions and amino acid conservation analyses were performed.ResultsA homozygous c.133 C>T (p.Pro45Ser) variant was identified in COL10A1 in all six severely affected individuals (adult heights 119–130 cm, mean ~−6.33 SD). The individuals heterozygous for the variant had mild phenotype of short stature (adult heights 140–162 cm, mean ~−2.15 SD) but no apparent skeletal deformities. The variant was predicted to be pathogenic by in silico prediction tools and was absent from public databases and hundred control chromosomes. Pro45 is conserved in orthologues and is located in the non-collagenous 2 domain of COL10A1, variants of which have never been associated with skeletal dysplasia.ConclusionsThis first report of individuals with a homozygous variant in COL10A1 defines a new type of autosomal recessive skeletal dysplasia. The observations in COL10A1 variant carriers suggest a phenotypic overlap between the mildest forms of MCDS and idiopathic short stature.
Puerarin Improves Vascular Insulin Resistance and Cardiovascular Remodeling in Salt-Sensitive Hypertension
Authors: Tan Chunxiang , Wang Aimei , Liu Chan , Li Yao , Shi Yuepin , Zhou Ming-Sheng 
Published: August 2017

Puerarin is an isoflavonoid isolated from the Chinese herb, Kudzu roots (also known as Gegen), which has been widely used for the treatment of hypertensive diseases and diabetic mellitus in traditional Chinese medicine. Dahl salt-sensitive (DS) rat is a genetic model of salt-sensitive hypertension with cardiovascular injury and vascular insulin resistance. Here, we investigated whether puerarin improved vascular insulin resistance and attenuated cardiac and aortic remodeling in salt-sensitive hypertension. DS rats were given a normal (NS) or high salt diet (HS) for five weeks. An additional group of DS rats was pretreated with puerarin and NS for 10 days, then switched to HS plus puerarin for five weeks. HS for five weeks increased systolic blood pressure (SBP), cardiac hypertrophy and fibrosis, and aortic hypertrophy with increased the expression of phosphor-ERK1/2 in the aorta and heart; puerarin attenuated cardiac and aortic hypertrophy, cardiac fibrosis and phosphor-ERK1/2 with a mild reduction in SBP. Hypertensive rats also manifested impairment of acetylcholine- and insulin-mediated vasorelaxation and insulin-mediated Akt and eNOS phosphorylation associated with the activation of NF[Formula: see text]B/TNF[Formula: see text]/JNK pathway. Puerarin improved acetylcholine- and insulin-mediated vasorelaxation and insulin-stimulated Akt/NO signaling with the inhibition of the NF[Formula: see text]B inflammatory pathway. Our results demonstrated that in salt-sensitive hypertension, puerarin improved vascular insulin action with cardiovascular beneficial effects. Our results found that the underlying mechanisms may involve its inhibition of NF[Formula: see text]B/JNK and ERK1/2 pathway. These results suggest that puerarin could be used as a new antihypertensive agent to expand our armamentarium for the prevention and treatment of end-organ damage in individuals with hypertension and metabolic diseases.
A role for the cystic fibrosis transmembrane conductance regulator in the nitric oxide-dependent release of Cl− from acidic organelles in amacrine cells
Authors: Krishnan Vijai , Maddox J. Wesley , Rodriguez Tyler , Gleason Evanna 
Published: August 2017

γ-Amino butyric acid (GABA) and glycine typically mediate synaptic inhibition because their ligand-gated ion channels support the influx of Cl−. However, the electrochemical gradient for Cl− across the postsynaptic plasma membrane determines the voltage response of the postsynaptic cell. Typically, low cytosolic Cl− levels support inhibition, whereas higher levels of cytosolic Cl− can suppress inhibition or promote depolarization. We previously reported that nitric oxide (NO) releases Cl− from acidic organelles and transiently elevates cytosolic Cl−, making the response to GABA and glycine excitatory. In this study, we test the hypothesis that the cystic fibrosis transmembrane conductance regulator (CFTR) is involved in the NO-dependent efflux of organellar Cl−. We first establish the mRNA and protein expression of CFTR in our model system, cultured chick retinal amacrine cells. Using whole cell voltage-clamp recordings of currents through GABA-gated Cl− channels, we examine the effects of pharmacological inhibition of CFTR on the NO-dependent release of internal Cl−. To interfere with the expression of CFTR, we used clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 genome editing. We find that both pharmacological inhibition and CRISPR/Cas9-mediated knockdown of CFTR block the ability of NO to release Cl− from internal stores. These results demonstrate that CFTR is required for the NO-dependent efflux of Cl− from acidic organelles. NEW & NOTEWORTHY Although CFTR function has been studied extensively in the context of epithelia, relatively little is known about its function in neurons. We show that CFTR is involved in an NO-dependent release of Cl− from acidic organelles. This internal function of CFTR is particularly relevant to neuronal physiology because postsynaptic cytosolic Cl− levels determine the outcome of GABA- and glycinergic synaptic signaling. Thus the CFTR may play a role in regulating synaptic transmission.
Monocarboxylate Transporter MCT1 Promotes Tumor Metastasis Independently of Its Activity as a Lactate Transporter
Authors: Payen Valéry L. , Hsu Myriam Y. , Rädecke Kristin S. , Wyart Elisabeth , Vazeille Thibaut , Bouzin Caroline , Porporato Paolo E. , Sonveaux Pierre 
Published: August 2017

Abstract
Extracellular acidosis resulting from intense metabolic activities in tumors promotes cancer cell migration, invasion, and metastasis. Although host cells die at low extracellular pH, cancer cells resist, as they are well equipped with transporters and enzymes to regulate intracellular pH homeostasis. A low extracellular pH further activates proteolytic enzymes that remodel the extracellular matrix to facilitate cell migration and invasion. Monocarboxylate transporter MCT1 is a passive transporter of lactic acid that has attracted interest as a target for small-molecule drugs to prevent metastasis. In this study, we present evidence of a function for MCT1 in metastasis beyond its role as a transporter of lactic acid. MCT1 activates transcription factor NF-κB to promote cancer cell migration independently of MCT1 transporter activity. Although pharmacologic MCT1 inhibition did not modulate MCT1-dependent cancer cell migration, silencing or genetic deletion of MCT1 in vivo inhibited migration, invasion, and spontaneous metastasis. Our findings raise the possibility that pharmacologic inhibitors of MCT1-mediated lactic acid transport may not effectively prevent metastatic dissemination of cancer cells. Cancer Res; 77(20); 5591–601. ©2017 AACR.
Targeting TAO Kinases Using a New Inhibitor Compound Delays Mitosis and Induces Mitotic Cell Death in Centrosome Amplified Breast Cancer Cells
Authors: Koo Chuay-Yeng , Giacomini Caterina , Reyes-Corral Marta , Olmos Yolanda , Tavares Ignatius A. , Marson Charles M. , Linardopoulos Spiros , Tutt Andrew N. , Morris Jonathan D.H. 
Published: August 2017

Abstract
Thousand-and-one amino acid kinases (TAOK) 1 and 2 are activated catalytically during mitosis and can contribute to mitotic cell rounding and spindle positioning. Here, we characterize a compound that inhibits TAOK1 and TAOK2 activity with IC50 values of 11 to 15 nmol/L, is ATP-competitive, and targets these kinases selectively. TAOK inhibition or depletion in centrosome-amplified SKBR3 or BT549 breast cancer cell models increases the mitotic population, the percentages of mitotic cells displaying amplified centrosomes and multipolar spindles, induces cell death, and inhibits cell growth. In contrast, nontumorigenic and dividing bipolar MCF-10A breast cells appear less dependent on TAOK activity and can complete mitosis and proliferate in the presence of the TAOK inhibitor. We demonstrate that TAOK1 and TAOK2 localize to the cytoplasm and centrosomes respectively during mitosis. Live cell imaging shows that the TAOK inhibitor prolongs the duration of mitosis in SKBR3 cells, increases mitotic cell death, and reduces the percentages of cells exiting mitosis, whereas MCF-10A cells continue to divide and proliferate. Over 80% of breast cancer tissues display supernumerary centrosomes, and tumor cells frequently cluster extra centrosomes to avoid multipolar mitoses and associated cell death. Consequently, drugs that stimulate centrosome declustering and induce multipolarity are likely to target dividing centrosome-amplified cancer cells preferentially, while sparing normal bipolar cells. Our results demonstrate that TAOK inhibition can enhance centrosome declustering and mitotic catastrophe in cancer cells, and these proteins may therefore offer novel therapeutic targets suitable for drug inhibition and the potential treatment of breast cancers, where supernumerary centrosomes occur. Mol Cancer Ther; 16(11); 2410–21. ©2017 AACR.
Impact of Extreme Land Surface Heterogeneity on Micrometeorology over Spring Snow Cover
Authors: Mott R. , Schlögl S. , Dirks L. , Lehning M. 
Published: August 2017

Abstract
The melting mountain snow cover in spring typically changes from a continuous snow cover to a mosaic of patches of snow and bare ground, inducing an extreme heterogeneity of the land surface. A comprehensive measurement campaign, the Dischma experiment, was conducted during three entire ablation seasons. The aim of this study was to experimentally investigate the small-scale boundary layer dynamics over a melting snow cover with a gradually decreasing snow cover fraction and the associated heat exchange at the snow surface. This study presents a unique dataset combining eddy covariance measurements at different atmospheric levels with maps of snow surface temperatures and snow cover fractions. The experiments evidence diurnal mountain wind systems driving the diurnal cycle of turbulent sensible heat fluxes over snow and the formation of katabatic flows over long-lasting snow patches strongly affecting the temporal evolution of snow surface temperature patterns. The snow cover distribution is also shown to be of vital importance for the frequency of stable internal boundary layer development over snow. For situations with a clear evidence of stable internal boundary layer development over snow, the data reveal a very shallow atmospheric layer adjacent to the snow cover decoupled from the warm-air advection above. These measurements confirm previous wind tunnel experiments that also evidenced a decoupling of the air adjacent to the snow cover from the warmer air above, especially within topographical depressions and when ambient wind velocities are low. For these situations, in particular, all tested energy balance models strongly overestimated the turbulent sensible heat flux directed toward the snow cover.
A W-Band Radar–Radiometer System for Accurate and Continuous Monitoring of Clouds and Precipitation
Authors: Küchler Nils , Kneifel Stefan , Löhnert Ulrich , Kollias Pavlos , Czekala Harald , Rose Thomas 
Published: August 2017

AbstractA new 94-GHz frequency-modulated continuous wave (FMCW) Doppler radar–radiometer system [Jülich Observatory for Cloud Evolution (JOYCE) Radar–94 GHz (JOYRAD-94)] is presented that is suitable for long-term continuous observations of cloud and precipitation processes. New features of the system include an optimally beam-matched radar–radiometer; a vertical resolution of up to 5 m with sensitivities down to −62 dBZ at 100-m distance; adjustable measurement configurations within the vertical column to account for different observational requirements; an automatic regulation of the transmitter power to avoid receiver saturation; and a high-powered blowing system that prevents hydrometeors from adhering to the radome. JOYRAD-94 has been calibrated with an uncertainty of 0.5 dB that was assessed by observing a metal sphere in the radar’s far field and by comparing radar reflectivities to a collocated 35-GHz radar. The calibrations of the radar receiver and the radiometric receiver are performed via a two-point calibration with liquid nitrogen. The passive channel at 89 GHz is particularly useful for deriving an estimate of the liquid water path (LWP). The developed retrieval shows that the LWP can be retrieved with an RMS uncertainty (not including potential calibration offsets) of about ±15 g m−2 when constraining the integrated water vapor from an external source with an uncertainty of ±2 kg m−2. Finally, a dealiasing method [dual-radar dealiasing method (DRDM)] for FMCW Doppler spectra is introduced that combines measurements of two collocated radars with different measurement setups. The DRDM ensures high range resolution with a wide unambiguous Doppler velocity range.
Estimation of Eddy Viscosity Profile in the Bottom Ekman Boundary Layer
Authors: Cao An-Zhou , Chen Hui , Fan Wei , He Hai-Lun , Song Jin-Bao , Zhang Ji-Cai 
Published: August 2017

AbstractPrevious studies have shown that strong tidal currents can cause intense turbulent mixing near the seafloor in continental shelf areas. To quantify the turbulent mixing, the eddy viscosity coefficient is generally used. In this study, an estimation scheme is proposed to evaluate the eddy viscosity profile (EVP) in the bottom Ekman boundary layer based on the adjoint method. The estimation scheme is composed of the bottom Ekman boundary layer model and its adjoint model, and a minimization algorithm. The feasibility and effectiveness of the proposed scheme are validated by a series of twin experiments, where the proposed scheme is compared with three other schemes in previous studies. When large measurement errors exist, the proposed scheme performs better than the three other schemes. When large Ekman balance errors exist, the proposed scheme is better than two of the other schemes. The selection of components of the steady current and tidal constituents also influences the performance of the proposed scheme. Successful estimation of the EVP requires the usage of intense components of the steady current and tidal constituents. With the usage of the intense components, increasing the number of tidal constituents cannot lead to a more accurate estimation of the EVP.
Impact of Timely Treatment Intensification on Glycemic Goal Achievement in Patients With Type 2 Diabetes Failing Metformin Monotherapy
Authors: Mahabaleshwarkar Rohan , Templin Megan , Gohs Frank , Mulder Holly , DeSantis Andrea , Ejzykowicz Flavia , Rajpathak Swapnil , Wilkins Nick 
Published: August 2017

Purpose The purpose of the study was to examine the association between timely treatment intensification (TTI) and glycemic goal achievement in patients with type 2 diabetes (T2D) failing metformin monotherapy (MM). Methods This study was set at a large integrated health care system in the United States. The study cohort included T2D patients aged 18 to 85 years who were on MM between January 2009 and September 2013 and had an uncontrolled glycated hemoglobin (A1C) reading (≥8%) after at least 3 months of MM (corresponding date was index date). Secondary analyses were performed using A1C <7% as T2D control. TTI was defined as receipt of an add-on therapy within 180 days after the index date. Impact of TTI on glycemic goal achievement was determined using multivariate Cox proportional hazards regression. Patients were censored at their last A1C reading or health care visit during 2 years after the index date. Results The study cohort consisted of 996 patients, ~58% male and ~59% Caucasian, with a mean age of ~54 (±12) years. TTI was observed in 50.2% of the patients. The rate of glycemic goal achievement was higher in patients with TTI compared with patients without TTI (hazards ratio = 1.632, 95% confidence interval = 1.328-2.006). The results for the secondary analyses were largely consistent with the primary findings. Conclusions TTI positively affected glycemic goal achievement among T2D patients failing MM and could be a useful strategy to increase the currently low proportion of patients with their T2D controlled in the United States.
Use of Ultrasound for Sizing Tracheoesophageal Puncture Prostheses
Authors: Smith Aaron , Thimmappa Vikrum , Jones Julia , Shires Courtney , Sebelik Merry 
Published: August 2017

Tracheoesophageal puncture (TEP) with voice prosthesis placement is the gold standard voice rehabilitation following total laryngectomy. Ultrasound may be useful to determine tracheoesophageal wall thickness, guiding prosthesis choice. Therefore, 14 patients undergoing total laryngectomy and TEP or prosthesis change with 16‐mHz ultrasound measurement of the posterior tracheal wall were included. Seven patients underwent secondary TEP, 3 primary TEP, and 4 TEP changes. Six patients underwent flap reconstruction, while 8 patients were closed primarily. Average party wall thickness was 9.6 ± 1.7 mm, without a difference (P =. 08) between primary closure (10.3 ± 1.7 mm) and flap reconstruction (8.6 ± 1.4 mm). Change from the hypothesized sizing was noted in 11 patients (79%). Prosthesis size did not correlate with age (–0.19, P =. 51), height (–0.12, P =. 69), weight (0.26, P =. 38), body mass index (0.22, P =. 46), or flap status (–0.48, P =. 079). These data suggest that ultrasound is beneficial in patients with distorted or less predictable anatomy (eg, flap reconstruction) but also important for those patients undergoing primary closure.
Social capital and idiosyncratic return volatility
Authors: Hasan Mostafa Monzur , Habib Ahsan 
Published: August 2017

We examine whether regional social capital has any impact on idiosyncratic return volatility. Using US data, we find that firms headquartered in high social capital counties exhibit significantly lower idiosyncratic return volatility. This effect is more pronounced in the presence of financial reporting quality and corporate social responsibility. When we estimate the direct and indirect effects of social capital, our study reveals that the direct effect of social capital captures around 80% of the total effect. These findings suggest that firm-specific variables do not explain all of a firm’s idiosyncratic return volatility, but regional social capital also plays a role. JEL classification: G10, G12, G30, M14
Prevalence of Iron Deficiency and Iron Deficiency Anemia in the Northern and Southern Provinces of Rwanda
Authors: Donahue Angel Moira , Berti Peter , Siekmans Kendra , Tugirimana Pierrot Lundimu , Boy Erick 
Published: August 2017

Background: Anemia remains a public health problem in Rwanda, affecting 38% of young children and 17% of reproductive-aged women (Demographic and Health Survey [DHS] 2010). The importance of iron deficiency (ID) as a cause of anemia in Rwanda is not known. Objective: We aimed to estimate the prevalence of ID and iron deficiency anemia (IDA) among young children and women in 2 provinces of Rwanda. Methods: We conducted a cluster randomized survey, selecting 408 rural households each in the Northern and Southern Provinces of Rwanda in 2010. Anemia was defined as hemoglobin <110 g/L in children and <120 g/L in nonpregnant women after correction for altitude. We defined ID as (1) serum transferrin receptor (TfR) >8.3 mg/L or (2) serum ferritin (SF) <12 μg/L in children and <15 μg/L in nonpregnant women after correction for inflammation. Results: The prevalence of anemia was 30.9% (95% confidence interval [CI], 26.4-35.8) in children (n = 577) and 11.2% (95% CI, 8.4-14.7) in women (n = 595). The prevalence of ID in children was 3.1% (95% CI, 1.8-5.1) as defined by high TfR and 5.9% (95% CI, 4.0-8.4) as defined by low SF. Similarly, 3.0% (95% CI, 1.8-4.8) of women had high TfR and 4.8% (95% CI, 3.2-7.2) had low SF. The prevalence of IDA (low SF with concurrent anemia) ranged from 1.4% (95% CI, 0.5-3.6) among women in the North to 5.6% (95% CI, 3.1-10.0) among children in the South. Conclusions: ID is likely not an important contributor to anemia in the Northern and Southern Provinces of Rwanda. This finding warrants further investigation into other causes of anemia.