bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dietary nitrate supplementation does not influence thermoregulatory or cardiovascular strain in older individuals during severe ambient heat stress
Authors: Cramer Matthew N. , Hieda Michinari , Huang Mu , Moralez Gilbert , Crandall Craig G. 
Published: August 2020

New Findings

What is the central question of this study?
Does dietary nitrate supplementation with beetroot juice attenuate thermoregulatory and cardiovascular strain in older adults during severe heat stress?

What is the main finding and its importance?
A 7‐day nitrate supplementation regimen lowered resting mean arterial pressure in thermoneutral conditions. During heat stress, core and mean skin temperatures, vasodilatory responses, sweat loss, heart rate and left ventricular function were unchanged, and mean arterial pressure was only transiently reduced, post‐supplementation. These data suggest nitrate supplementation with beetroot juice does not mitigate thermoregulatory or cardiovascular strain in heat‐stressed older individuals.

AbstractThis study tested the hypothesis that dietary nitrate supplementation with concentrated beetroot juice attenuates thermoregulatory and cardiovascular strain in older individuals during environmental heat stress. Nine healthy older individuals (six females, three males; aged 67 ± 5 years) were exposed to 42.5 ± 0.1°C and 34.0 ± 0.5% relative humidity conditions for 120 min before (CON) and after 7 days of dietary nitrate supplementation with concentrated beetroot juice (BRJ; 280 ml, ∼16.8 mmol of nitrate daily). Core and skin temperatures, body mass changes (indicative of whole‐body sweat loss), skin blood flow and cutaneous vascular conductance, forearm blood flow and vascular conductance, heart rate, arterial blood pressures and indices of cardiac function were measured. The 7‐day beetroot juice regimen increased plasma nitrate/nitrite levels from 27.4 ± 15.2 to 477.0 ± 102.5 μmol l−1 (P < 0.01) and lowered resting mean arterial pressure from 90 ± 7 to 83 ± 10 mmHg at baseline under thermoneutral conditions (P = 0.02). However, during subsequent heat stress, no differences in core and skin temperatures, skin blood flow and vascular conductance, forearm blood flow and vascular conductance, whole‐body sweat loss, heart rate, and echocardiographic indices of systolic function and diastolic filling were evident following nitrate supplementation (all P > 0.05). Mean arterial pressure was lower in BRJ vs. CON during heat stress (treatment‐by‐time interaction: P = 0.02). Overall, these findings suggest that dietary nitrate supplementation with concentrated beetroot juice does not attenuate thermoregulatory or cardiovascular strain in older individuals exposed to severe ambient heat stress.
Fine Motor Skills and Unsystematic Spatial Binding in the Common Region Test: Under-Inclusivity in Autism Spectrum Disorder and Over-Inclusivity in Attention-Deficit Hyperactivity Disorder
Authors: Lange-Küttner Christiane , Kochhar Ridhi 
Published: August 2020

Introduction:The Common Region Test (CRT) is useful for predicting children’s visual memory as individual object-place binding predicted better object memory while objects-region coding predicted better place memory.Aim:To test children with autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD) with regards to spatial binding in the CRT.Methods:19 children with ASD and 20 children with ADHD were gender-matched with 39 typically developing children by chronological age and with another 39 children by verbal mental age as control groups (N = 117) and tested with the CRT and Bender Gestalt test. Results:Children with ASD and ADHD showed more unsystematic coding than typically developing children. This was due to lower fine motor skills, and in children with ADHD also because of reduced verbal naming. Almost all children with ASD presented the less mature under-inclusive Type I unsystematic coding which included object-place binding, while children with ADHD showed the over-inclusive Type II unsystematic coding that was overriding the Gestalt-like properties of proximity and similarity.Conclusions:It was demonstrated that the CRT is a useful screening instrument for ASD and ADHD that shows that their spatial categorization varies in their unsystematic visuo-spatial classification due to fine motor skill deficiencies.
Cystic fibrosis newborn screening: the importance of bloodspot sample quality
Authors: Doull Iolo , Course Christopher William , Hanks Ruth E , Southern Kevin W , Forton Julian T , Thia Lena P , Moat Stuart J 
Published: August 2020

ObjectiveWales has an immunoreactive trypsin (IRT)-DNA cystic fibrosis (CF) newborn screening (NBS) programme. Most CF NBS false negative cases are due to an IRT concentration below the screening threshold. The accuracy of IRT results is dependent on the quality of the dried bloodspot (DBS) sample. The aim of this study was to determine the cause of false negative cases in CF NBS and their relationship to DBS quality.DesignLongitudinal birth cohort.SettingWales 1996–2016.PatientsChildren with CF.InterventionsIdentification of all CF patients with triangulation of multiple data sources to detect false negative cases.Main outcome measuresFalse negative cases.ResultsOver 20 years, 673 952 infants were screened and 239 were diagnosed with CF (incidence 1:2819). The sensitivity of the programme was 0.958, and positive predictive value was 0.476. Eighteen potential false negatives were identified, of whom eight were excluded: four screened outside Wales, two had complex comorbidities, no identified cystic fibrosis transmembrane conductance regulator (CFTR) variants on extended analysis and thus not considered to have CF and two were diagnosed after their 16th birthday. Of the 10 false negatives, 9 had a low DBS IRT and at least one common CFTR variant and thus should have received a sweat test under the programme. DBS cards were available for inspection for five of the nine false negative cases—all were classified as small/insufficient or poor quality.ConclusionsThe majority of false negatives had a low bloodspot IRT, and this was associated with poor quality DBS. The optimal means to improve the sensitivity of our CF NBS programme would be to improve DBS sample quality.
Survival of the fittest: phacoemulsification outcomes in four corneal transplants by Dr Ramon Castroviejo
Authors: Franco Jovany Jeomar , Reyes Luis Jose Luis , Rahim Salma , Greenstein Stephen , Pineda Roberto 
Published: August 2020

AimTo evaluate and report the outcomes following phacoemulsification on four eyes, 45 years or more after corneal transplantation.MethodsA retrospective case series of four eyes in three patients (P1, P2, P3), undergoing phacoemulsification at least 45 years after corneal transplantation by Dr Ramon Castroviejo. Corneal graft survival outcome measures included central corneal thickness (CCT), best-corrected visual acuity (BCVA), corneal clarity and endothelial cell count (ECC).ResultsPhacoemulsification was successfully completed in all four cases with no instances of graft failure during the postoperative follow-up period, which ranged from 17 months to 76 months. At the conclusion of the follow-up period, all four grafts remained clear, and BCVA remained better than or similar to preoperative values. Long-term follow-up revealed no meaningful changes in CCT after phacoemulsification. All but one case experienced a decrease in ECC, with ECC values in the four cases ranging from 538 cells/mm2 to 1436 cells/mm2 at the conclusion of postoperative follow-up.ConclusionLimited data have been published on the long-term survival of corneal grafts after intraocular surgery, especially for extremely ‘mature’ corneal transplants. This case series demonstrates that with appropriate preoperative, intraoperative and postoperative measures, successful phacoemulsification can be performed in these cases with excellent long-term results.
Exposure to Chinese famine in early life and the risk of sensory impairment in adulthood
Authors: Rong Hongguo , Lai Xiaozhen , Mahmoudi Elham , Fang Hai 
Published: August 2020

BackgroundStudies have shown that malnutrition in early life has a negative effect on midlife cognitive functions. Little is known, however, about the relationship between early-life malnutrition and visual, hearing or dual sensory impairments in adulthood. This study aims to investigate the association between exposure to the 1959–1961 Chinese famine in early life and sensory impairments in adulthood.MethodsA total of 6347 adults born between 1952 and 1964 surveyed in the 2015 China Health and Retirement Longitudinal Study were included in this study. The presence of sensory impairments was identified by self-reported assessment of visual and hearing functions. The associations between multi-stage early-life famine exposure and sensory functions were estimated using the multiple generalised linear model.ResultsCompared with the unexposed group, respondents exposed to famine in the fetal period and late childhood had a significantly higher risk of hearing impairment (OR 1.54, 95% CI 1.06 to 2.24; OR 1.75, 95% CI 1.23 to 2.50) and dual sensory impairments (OR 1.45, 95% CI 1.00 to 2.11; OR 1.55, 95% CI 1.09 to 2.21), respectively. Furthermore, in severely famine-affected areas, the early, mid and late childhood-exposed groups were more likely to have hearing and dual sensory impairments than the unexposed group. Those associations were not observed in less famine-affected areas. However, no significant association was found between famine exposure and visual impairment in early-life famine-exposed group.ConclusionExposure to Chinese famine in the fetal period and late childhood was linked to hearing and dual sensory impairments in adulthood.
Antigen processing and presentation in cancer immunotherapy
Authors: Lee Maxwell Y , Jeon Jun W , Sievers Cem , Allen Clint T 
Published: August 2020

BackgroundKnowledge about and identification of T cell tumor antigens may inform the development of T cell receptor-engineered adoptive cell transfer or personalized cancer vaccine immunotherapy. Here, we review antigen processing and presentation and discuss limitations in tumor antigen prediction approaches.MethodsOriginal articles covering antigen processing and presentation, epitope discovery, and in silico T cell epitope prediction were reviewed.ResultsNatural processing and presentation of antigens is a complex process that involves proteasomal proteolysis of parental proteins, transportation of digested peptides into the endoplasmic reticulum, loading of peptides onto major histocompatibility complex (MHC) class I molecules, and shuttling of peptide:MHC complexes to the cell surface. A number of T cell tumor antigens have been experimentally validated in patients with cancer. Assessment of predicted MHC class I binding and total score for these validated T cell antigens demonstrated a wide range of values, with nearly one-third of validated antigens carrying an IC50of greater than 500 nM.ConclusionsAntigen processing and presentation is a complex, multistep process. In silico epitope prediction techniques can be a useful tool, but comprehensive experimental testing and validation on a patient-by-patient basis may be required to reliably identify T cell tumor antigens.
Dark matter in inert doublet model with one scalar singlet and $$U(1)_X$$ gauge symmetry
Authors: Arroyo-Ureña M. A. , Gaitan R. , Martinez R. , Montes de Oca Yemha J. H. 
Published: August 2020

AbstractWe study dark matter (DM) abundance in the framework of the extension of the Standard Model (SM) with an additional $$U(1)_X$$U(1)X gauge symmetry. One complex singlet is included to break the $$U(1)_X$$U(1)X gauge symmetry, meanwhile one of the doublets is considered inert to introduce a DM candidate. The stability of the DM candidate is analyzed with a continuous $$U(1)_X$$U(1)X gauge symmetry as well as discrete $$Z_2$$Z2 symmetry. We find allowed regions for the free model parameters which are in agreement with the most up-to-date experimental results reported by CMS and ATLAS Collaborations, the upper limit on WIMP-nucleon cross section imposed by XENON1T Collaboration and the upper limit on the production cross-section of a $$Z^{\prime }$$Z′ gauge boson times the branching ratio of the $$Z^{\prime }$$Z′ boson decaying into $$\ell ^-\ell ^+$$ℓ-ℓ+. We also obtain allowed regions for the DM candidate mass from the relic density reported by the PLANCK Collaboration including light, intermediate and heavy masses; depending mainly on two parameters of the scalar potential, $$\lambda _{2x}$$λ2x and $$\lambda _{345}=\lambda _3+\lambda _4+2\lambda _5$$λ345=λ3+λ4+2λ5. We find that trough $$pp\rightarrow \chi \chi \gamma $$pp→χχγ production, it may only be possible for a future hadron–hadron circular collider (FCC-hh) to be able to detect a DM candidate within the range of masses 10–60 GeV.
Viability tests of f(R)-gravity models with Supernovae Type 1A data
Authors: Hough R. T. , Abebe A. , Ferreira S. E. S. 
Published: August 2020

AbstractIn this work, we will be testing four different general f(R)-gravity models, two of which are the more realistic models (namely the Starobinsky and the Hu–Sawicki models), to determine if they are viable alternative models to pursue a more vigorous constraining test upon them. For the testing of these models, we use 359 low- and intermediate-redshift Supernovae Type 1A data obtained from the SDSS-II/SNLS2 Joint Light-curve Analysis (JLA). We develop a Markov Chain Monte Carlo (MCMC) simulation to find a best-fitting function within reasonable ranges for each f(R)-gravity model, as well as for the Lambda Cold Dark Matter ($$\varLambda $$ΛCDM) model. For simplicity, we assume a flat universe with a negligible radiation density distribution. Therefore, the only difference between the accepted $$\varLambda $$ΛCDM model and the f(R)-gravity models will be the dark energy term and the arbitrary free parameters. By doing a statistical analysis and using the $$\varLambda $$ΛCDM model as our “true model”, we can obtain an indication whether or not a certain f(R)-gravity model shows promise and requires a more in-depth view in future studies. In our results, we found that the Starobinsky model obtained a larger likelihood function value than the $$\varLambda $$ΛCDM model, while still obtaining the cosmological parameters to be $$\varOmega _{m} = 0.268^{+0.027}_{-0.024}$$Ωm=0.268-0.024+0.027 for the matter density distribution and $${\bar{h}} = 0.690^{+0.005}_{-0.005}$$h¯=0.690-0.005+0.005 for the Hubble uncertainty parameter. We also found a reduced Starobinsky model that are able to explain the data, as well as being statistically significant.
Pleiotropic Mechanisms Drive Endocrine Resistance in the Three-Dimensional Bone Microenvironment
Authors: Dhimolea Eugen , de Matos Simoes Ricardo , Kansara Dhvanir , Weng Xiang , Sharma Shruti , Awate Pallavi , Liu Zhiyi , Gao Dong , Mitsiades Nicholas , Schwab Joseph H. , Chen Yu , Jeselsohn Rinath , Culhane Aedín C. , Brown Myles , Georgakoudi Irene , Mitsiades Constantine S. 
Published: August 2020

Abstract

Although hormonal therapy (HT) inhibits the growth of hormone receptor–positive (HR+) breast and prostate cancers, HT resistance frequently develops within the complex metastatic microenvironment of the host organ (often the bone), a setting poorly recapitulated in 2D culture systems. To address this limitation, we cultured HR+ breast cancer and prostate cancer spheroids and patient-derived organoids in 3D extracellular matrices (ECM) alone or together with bone marrow stromal cells (BMSC). In 3D monocultures, antiestrogens and antiandrogens induced anoikis by abrogating anchorage-independent growth of HR+ cancer cells but exhibited only modest effects against tumor cells residing in the ECM niche. In contrast, BMSC induced hormone-independent growth of breast cancer and prostate cancer spheroids and restored lumen filling in the presence of HR-targeting agents. Molecular and functional characterization of BMSC-induced hormone independence and HT resistance in anchorage-independent cells revealed distinct context-dependent mechanisms. Cocultures of ZR75-1 and LNCaP with BMSCs exhibited paracrine IL6-induced HT resistance via attenuation of HR protein expression, which was reversed by inhibition of IL6 or JAK signaling. Paracrine IL6/JAK/STAT3-mediated HT resistance was confirmed in patient-derived organoids cocultured with BMSCs. Distinctly, MCF7 and T47D spheroids retained ER protein expression in cocultures but acquired redundant compensatory signals enabling anchorage independence via ERK and PI3K bypass cascades activated in a non–IL6-dependent manner. Collectively, these data characterize the pleiotropic hormone-independent mechanisms underlying acquisition and restoration of anchorage-independent growth in HR+ tumors. Combined analysis of tumor and microenvironmental biomarkers in metastatic biopsies of HT-resistant patients can help refine treatment approaches.

Significance:
This study uncovers a previously underappreciated dependency of tumor cells on HR signaling for anchorage-independent growth and highlights how the metastatic microenvironment restores this malignant property of cancer cells during hormone therapy.
Circulating Tumor DNA Genomics Reveal Potential Mechanisms of Resistance to BRAF-Targeted Therapies in Patients withBRAF-Mutant Metastatic Non–Small Cell Lung Cancer
Authors: Ortiz-Cuaran Sandra , Mezquita Laura , Swalduz Aurélie , Aldea Mihalea , Mazieres Julien , Leonce Camille , Jovelet Cecile , Pradines Anne , Avrillon Virginie , Chumbi Flores Washington R. , Lacroix Ludovic , Loriot Yohann , Westeel Virginie , Ngo-Camus Maud , Tissot Claire , Raynaud Christine , Gervais Radj , Brain Etienne , Monnet Isabelle , Giroux Leprieur Etienne , Caramella Caroline , Mahier-Aït Oukhatar Celine , Hoog-Labouret Natalie , de Kievit Frank , Howarth Karen , Morris Clive , Green Emma , Friboulet Luc , Chabaud Sylvie , Guichou Jean-François , Perol Maurice , Besse Benjamin , Blay Jean-Yves , Saintigny Pierre , Planchard David 
Published: August 2020

AbstractPurpose:The limited knowledge on the molecular profile of patients with BRAF-mutant non–small cell lung cancer (NSCLC) who progress under BRAF-targeted therapies (BRAF-TT) has hampered the development of subsequent therapeutic strategies for these patients. Here, we evaluated the clinical utility of circulating tumor DNA (ctDNA)-targeted sequencing to identify canonical BRAF mutations and genomic alterations potentially related to resistance to BRAF-TT, in a large cohort of patients with BRAF-mutant NSCLC.Experimental Design:This was a prospective study of 78 patients with advanced BRAF-mutant NSCLC, enrolled in 27 centers across France. Blood samples (n = 208) were collected from BRAF-TT–naïve patients (n = 47), patients nonprogressive under treatment (n = 115), or patients at disease progression (PD) to BRAF-TT (24/46 on BRAF monotherapy and 22/46 on BRAF/MEK combination therapy). ctDNA sequencing was performed using InVisionFirst-Lung. In silico structural modeling was used to predict the potential functional effect of the alterations found in ctDNA.Results:BRAFV600E ctDNA was detected in 74% of BRAF-TT–naïve patients, where alterations in genes related with the MAPK and PI3K pathways, signal transducers, and protein kinases were identified in 29% of the samples. ctDNA positivity at the first radiographic evaluation under treatment, as well as BRAF-mutant ctDNA positivity at PD were associated with poor survival. Potential drivers of resistance to either BRAF-TT monotherapy or BRAF/MEK combination were identified in 46% of patients and these included activating mutations in effectors of the MAPK and PI3K pathways, as well as alterations in U2AF1, IDH1, and CTNNB1.Conclusions:ctDNA sequencing is clinically relevant for the detection of BRAF-activating mutations and the identification of alterations potentially related to resistance to BRAF-TT in BRAF-mutant NSCLC.
The Long and Winding Road for Breast Cancer Biomarkers to Reach Clinical Utility
Authors: Hunter Natasha B. , Kilgore Mark R. , Davidson Nancy E. 
Published: August 2020

Abstract
Tumor data from the ABCSG 5 trial of chemotherapy versus endocrine therapy for premenopausal ER+ breast cancer supports molecular subtyping by Ki-67 IHC as a prognostic marker. But while this tissue was handled uniformly, Ki-67 testing overall is unstandardized, complicating clinical utility. Increasing potential biomarkers herald more challenges in biomarker validation.
See related article by Bago-Horvath et al., p. 5682
Heart Rate–Induced Myocardial Ca
2+
Retention and Left Ventricular Volume Loss in Patients With Heart Failure With Preserved Ejection Fraction
Authors: Silverman Daniel N. , Rambod Mehdi , Lustgarten Daniel L. , Lobel Robert , LeWinter Martin M. , Meyer Markus 
Published: August 2020

Background

Increases in heart rate are thought to result in incomplete left ventricular (LV) relaxation and elevated filling pressures in patients with heart failure with preserved ejection fraction (HFpEF). Experimental studies in isolated human myocardium have suggested that incomplete relaxation is a result of cellular Ca
2+
overload caused by increased myocardial Na
+
levels. We tested these heart rate paradigms in patients with HFpEF and referent controls without hypertension.

Methods and Results

In 22 fully sedated and instrumented patients (12 controls and 10 patients with HFpEF) in sinus rhythm with a preserved ejection fraction (≥50%) we assessed left‐sided filling pressures and volumes in sinus rhythm and with atrial pacing (95 beats per minute and 125 beats per minute) before atrial fibrillation ablation. Coronary sinus blood samples and flow measurements were also obtained. Seven women and 15 men were studied (aged 59±10 years, ejection fraction 61%±4%). Patients with HFpEF had a history of hypertension, dyspnea on exertion, concentric LV remodeling and a dilated left atrium, whereas controls did not. Pacing at 125 beats per minute lowered the mean LV end‐diastolic pressure in both groups (controls −4.3±4.1 mm Hg versus patients with HFpEF −8.5±6.0 mm Hg,
P
=0.08). Pacing also reduced LV end‐diastolic volumes. The volume loss was about twice as much in the HFpEF group (controls −15%±14% versus patients with HFpEF −32%±11%,
P
=0.009). Coronary venous [Ca
2+
] increased after pacing at 125 beats per minute in patients with HFpEF but not in controls. [Na
+
] did not change.

Conclusions

Higher resting heart rates are associated with lower filling pressures in patients with and without HFpEF. Incomplete relaxation and LV filling at high heart rates lead to a reduction in LV volumes that is more pronounced in patients with HFpEF and may be associated with myocardial Ca
2+
retention.