bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation of the variable In(Lu) phenotype caused by KLF1 variants
Authors: Fraser Nicole S. , Knauth Christine M. , Schoeman Elizna M. , Moussa Assia , Perkins Andrew C. , Walsh Terry , Millard Glenda M. , Dean Melinda M. , Hyland Catherine A. , Flower Robert L. 
Published: September 2018

INTRODUCTION
KLF1 is an essential transcriptional activator that drives erythropoiesis. KLF1 variants can result in the Inhibitor of Lutheran, or In(Lu), phenotype where red blood cells (RBCs) have reduced BCAM (LU) and CD44 (IN). Other RBC surface molecules also have changed expression; however, there is controversy in the literature regarding which are truly impacted. We aimed to investigate KLF1 variants in the Australian population.STUDY DESIGN AND METHODSIn(Lu) samples were sourced through screening and through the RBC reference laboratory. Blood donor samples (8036) were screened to identify weakened/absent Lub antigen. Samples were genotyped by massively parallel sequencing, while surface carbohydrates and blood group molecules were assessed by flow cytometry. Hemoglobin (Hb) types were analyzed by high‐performance liquid chromatography.RESULTSFour of 8036 donors were identified to be In(Lu), and two previously identified In(Lu) samples were provided from the RBC reference laboratory. Five different KLF1 variants were identified; two were novel: c.954G>C/p.Trp318Cys and c.421C>T/p.Arg141*. BCAM and CD44 were reduced in all samples, consistent with previous reports. As a group, In(Lu) RBCs had reduced CD35 (KN), ICAM4 (LW), and CD147 (OK), and demonstrated increased binding of lectins ECA and SNAI. One In(Lu) sample had elevated HbF and another elevated HbA2.CONCLUSIONDifferent KLF1 variants may potentially produce variable phenotypes. A framework for investigating KLF1 variants and their phenotypic impact has been provided. In the future, given available international databases, further testing algorithms (as advocated here) will allow for correlation of phenotype with genotype and therefore accurately document this variability between KLF1 variants.
Does using applied muscle tension at strategic time points during donation reduce phlebotomist‐ and donor‐reported vasovagal reaction rates? A three‐armed randomized controlled trial
Authors: Thijsen Amanda , Gemelli Carley N. , Davison Tanya E. , O'Donovan Justine , Bell Barbara , Masser Barbara 
Published: September 2018

BACKGROUNDVasovagal reactions (VVRs) have a negative impact on donor safety and return. Applied muscle tension (AMT) increases blood pressure temporarily and has been suggested as a way to reduce donors' risk of VVRs. This study evaluated whether using AMT at three different time points during the donation procedure reduces the VVR symptoms reported by donors and the VVR reactions recorded by phlebotomists.STUDY DESIGN AND METHODSA three‐arm, multicenter, open‐label randomized controlled trial was used to compare VVR symptoms and reaction rates between those practicing AMT during the entire donation (n = 244) to practicing AMT at VVR high‐risk time points (n = 250) to a standard blood donation control group (n = 240). All participants were asked to drink 500 mL of water in the waiting area, and an even distribution of new and repeat donors was sought across conditions.RESULTSAcross all conditions, donors reported few VVR symptoms and the rate of reporting did not differ significantly across conditions. However, donors who practiced AMT at strategic time points had a significantly lower number of phlebotomist‐registered VVRs in comparison to the other two study groups, with these rates not varying by sex or donor status. Greater compliance by donors with AMT instructions was observed in those asked to practice AMT at strategic time points compared to those asked to practice AMT during the entire donation.CONCLUSIONPracticing AMT at VVR high‐risk time points reduces the number of phlebotomist‐registered VVRs.
Optical probing of acetylcholine receptors on neurons in the medial habenula with a novel caged nicotine drug analogue
Authors: Passlick Stefan , Thapaliya Ek Raj , Chen Zuxin , Richers Matthew T. , Ellis‐Davies Graham C. R. 
Published: September 2018

Key points
A new caged nicotinic acetylcholine receptor (nAChR) agonist was developed, ABT594, which is photolysed by one‐ and two‐photon excitation.
The caged compound is photolysed with a quantum yield of 0.20.
One‐photon uncaging of ABT594 elicited large currents and Ca2+ transients at the soma and dendrites of medial habenula (MHb) neurons of mouse brain slices.
Unexpectedly, uncaging of ABT594 also revealed highly Ca2+‐permeable nAChRs on axons of MHb neurons.
AbstractPhotochemical release of neurotransmitters has been instrumental in the study of their underlying receptors, with acetylcholine being the exception due to its inaccessibility to photochemical protection. We caged a nicotinic acetylcholine receptor (nAChR) agonist, ABT594, via its secondary amine functionality. Effective photolysis could be carried out using either one‐ or two‐photon excitation. Brief flashes (0.5–3.0 ms) of 410 nm light evoked large currents and Ca2+ transients on cell bodies and dendrites of medial habenula (MHb) neurons. Unexpectedly, photorelease of ABT594 also revealed nAChR‐mediated Ca2+ signals along the axons of MHb neurons.
Sex and Maturation Differences in Performance of Functional Jumping and Landing Deficits in Youth Athletes
Authors: Fort-Vanmeerhaeghe Azahara , Benet Ariadna , Mirada Sergi , Montalvo Alicia M. , Myer Gregory D. 
Published: September 2018

Context: Understanding how neuromuscular and biomechanical deficits that are associated with knee injuries change as youth mature may improve injury prevention strategies in this population. Objective: To investigate sex and maturation differences in jump-landing technique performance in youths using a practical clinical tool. Design: Cross-sectional study. Setting: High Performance Center Laboratory. Participants: A total of 165 youth athletes were included in this study. Main Outcome Measures: The main outcome measures were each of the 10 items of the modified tuck jump assessment and the total score. These measures include (1) knee valgus at landing, (2) thighs do not reach parallel, (3) thighs not equal side to side, (4) foot placement not shoulder width apart, (5) foot placement not parallel, (6) foot contact timing not equal, (7) excessive landing contact noise, (8) pause between jumps, (9) technique declines prior to 10 seconds, and (10) does not land in same footprint. Results: Only knee valgus at landing had a significant sex × maturation interaction. The main effect of maturation was significant for items 2, 3, 6, 7, 9, and total score. Plyometric technique performance improved with increasing maturation. The main effect of sex was significant for items 1 and 9, with males performing better than females. Conclusions: Female athletes demonstrate increased knee valgus at landing and fatigue relative to males during jump-landing performance. Overall, there was a trend of improved jump-landing performance with maturation.
The Effect of a 20-Week Corrective Exercise Program on Functional Movement Patterns in Youth Elite Male Soccer Players
Authors: Campa Francesco , Spiga Federico , Toselli Stefania 
Published: September 2018

Context: Poor functional movement patterns negatively affect the ability to perform fundamental movements with precision and efficiency, increasing injury risk in athletes. Objectives: To examine the effect of a 20-week corrective exercise program during the competitive season on functional movement patterns in youth elite male soccer players. Design: Cohort study. Setting: Team facilities. Participants: Sixty-five youth elite male soccer players (age: 15.89 [0.53] y; weight: 67.42 [6.78] kg; and stature: 175.20 [6.34] cm). Of the 4 teams, 2 were randomly selected to take part in the corrective program. Thus, the players were placed into 2 groups: corrective exercise program and control group. Intervention: Corrective exercise program. Main Outcome Measures: Functional Movement Screen (FMS) was used to assess the presence of dysfunctional, asymmetrical, and painful movements in the players before and after the intervention period. In addition to considering the FMS total score (FMStotal), we separated the screen into 3 parts: FMSmove, FMSflex, and FMSstab. A repeated-measures analysis of variance was conducted to determine the effectiveness of the training program on FMS scores. The chi-square test was performed to determine whether there were significant changes in the frequencies of asymmetric and dysfunctional movements after 20 weeks. Results: No athlete experienced severe injuries during the intervention period. There was a significant group by time interaction (P < .01) for FMStotal, FMSmove, and FMSstab, in which only the corrective exercise program increased their scores after the intervention period (P < .05). A chi-square analysis showed a significant (P < .05) decrease in asymmetric and dysfunctional movements at the follow-up in corrective exercise program, whereas these changes were not observed in the control group. Conclusions: Youth elite soccer players demonstrate a high prevalence of asymmetric movements during FMS testing, but their functional movement patterns can be improved during the competitive season following a specific corrective exercise program.
Longitudinal analysis of cardiovascular disease risk profile in neighbourhood poverty subgroups: 5-year results from an afterschool fitness programme in the USA
Authors: D’Agostino Emily M , Patel Hersila H , Hansen Eric , Mathew M Sunil , Nardi Maria , Messiah Sarah E 
Published: September 2018

BackgroundThe WHO calls for affordable population-based prevention strategies for reducing the global burden of cardiovascular disease (CVD) on morbidity and mortality; however, effective, sustainable and accessible community-based approaches for CVD prevention in at-risk youth have yet to be identified. We examined the effects of implementing a daily park-based afterschool fitness programme on youth CVD risk profiles over 5 years and across area poverty subgroups.MethodsThe study included 2264 youth (mean age 9.4 years, 54% male, 50% Hispanic, 47% non-Hispanic black, 70% high/very high area poverty) in Miami, Florida, USA. We used three-level repeated measures mixed models to determine the longitudinal effects of programme participation on modifiable CVD outcomes (2010–2016).ResultsDuration of programme participation was significantly associated with CVD risk profile improvements, including body mass index (BMI) z-score, diastolic/systolic blood pressure, skinfold thicknesses, waist–hip ratio, sit-ups, push-ups, Progressive Aerobic Cardiovascular Endurance Run (PACER) score, 400 m run time, probability of developing systolic/diastolic hypertension and overweight/obesity in high/very high poverty neighbourhoods (P<0.001). Diastolic blood pressure decreased 3.4 percentile points (95% CI −5.85 to −0.85), 8.1 percentile points (95% CI –11.98 to −4.26), 6.1 percentile points (95% CI −11.49 to −0.66), 7.6 percentile points (95% CI −15.33 to –0.15) and 11.4 percentile points (95% CI −25.32 to 2.61) for 1–5 years, respectively, in high/very high poverty areas. In contrast, significant improvements were found only for PACER score and waist–hip ratio in low/mid poverty areas.ConclusionThis analysis presents compelling evidence demonstrating that park-based afterschool programmes can successfully maintain or improve at-risk youth CVD profiles over multiple years.
Occupational exposure to pesticides is associated with differential DNA methylation
Authors: van der Plaat Diana A , de Jong Kim , de Vries Maaike , van Diemen Cleo C , Nedeljković Ivana , Amin Najaf , Kromhout Hans ,   Biobank-based Integrative Omics Study Consortium, Vermeulen Roel , Postma Dirkje S , van Duijn Cornelia M , Boezen H Marike , Vonk Judith M 
Published: September 2018

ObjectivesOccupational pesticide exposure is associated with a wide range of diseases, including lung diseases, but it is largely unknown how pesticides influence airway disease pathogenesis. A potential mechanism might be through epigenetic mechanisms, like DNA methylation. Therefore, we assessed associations between occupational exposure to pesticides and genome-wide DNA methylation sites.Methods1561 subjects of LifeLines were included with either no (n=1392), low (n=108) or high (n=61) exposure to any type of pesticides (estimated based on current or last held job). Blood DNA methylation levels were measured using Illumina 450K arrays. Associations between pesticide exposure and 420 938 methylation sites (CpGs) were assessed using robust linear regression adjusted for appropriate confounders. In addition, we performed genome-wide stratified and interaction analyses by gender, smoking and airway obstruction status, and assessed associations between gene expression and methylation for genome-wide significant CpGs (n=2802).ResultsIn total for all analyses, high pesticide exposure was genome-wide significantly (false discovery rate P<0.05) associated with differential DNA methylation of 31 CpGs annotated to 29 genes. Twenty of these CpGs were found in subjects with airway obstruction. Several of the identified genes, for example, RYR1, ALLC, PTPRN2, LRRC3B, PAX2 and VTRNA2-1, are genes previously linked to either pesticide exposure or lung-related diseases. Seven out of 31 CpGs were associated with gene expression levels.ConclusionsWe show for the first time that occupational exposure to pesticides is genome-wide associated with differential DNA methylation. Further research should reveal whether this differential methylation plays a role in the airway disease pathogenesis induced by pesticides.
To Cycle or Fight—CDK4/6 Inhibitors at the Crossroads of Anticancer Immunity
Authors: Ameratunga Malaka , Kipps Emma , Okines Alicia F.C. , Lopez Juanita S. 
Published: September 2018

Abstract
Dysregulation of cell division resulting in aberrant cell proliferation is a key hallmark of cancer, making it a rational and important target for innovative anticancer drug development. Three selective cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors are FDA and European Medicines Agency (EMA) approved for hormone receptor–positive/HER2-negative advanced breast cancer. A major emerging appreciation is that these inhibitors not only are cytostatic, but also play critical roles in the interaction between tumor cells and the host immune response. However, to trigger an effective immune response, lymphocytes must also proliferate. This review aims to assimilate our emerging understanding on the role of CDK4/6 inhibitors in cell-cycle control, as well as their biological effect on T cells and other key immune cells, and the confluence of preclinical evidence of augmentation of anticancer immunity by these drugs. We aim to provide a framework for understanding the role of the cell cycle in anticancer immunity, discussing ongoing clinical trials evaluating this concept and challenges for developing rational combinations with immunotherapy.
Impact of BRAF Mutation Class on Disease Characteristics and Clinical Outcomes in BRAF-mutant Lung Cancer
Authors: Dagogo-Jack Ibiayi , Martinez Pablo , Yeap Beow Y. , Ambrogio Chiara , Ferris Lorin A. , Lydon Christine , Nguyen Tom , Jessop Nicholas A. , Iafrate A. John , Johnson Bruce E. , Lennerz Jochen K. , Shaw Alice T. , Awad Mark M. 
Published: September 2018

Abstract

Purpose:
BRAF mutations are divided into functional classes distinguished by signaling mechanism and kinase activity: V600-mutant kinase-activating monomers (class I), kinase-activating dimers (class II), and kinase-inactivating heterodimers (class III). The relationship between functional class and disease characteristics in BRAF-mutant non–small cell lung cancer (NSCLC) has not been fully explored.

Experimental Design:
We performed a retrospective analysis of BRAF-mutant NSCLCs treated at 2 institutions from 2005 to 2017 to determine clinicopathologic characteristics, progression-free survival (PFS) on chemotherapy, and overall survival (OS).

Results:
We identified 236 patients with BRAF-mutant NSCLC (n = 107 class I, n = 75 class II, and n = 54 class III). Patients with class II or III mutations were more likely to have brain metastases (P ≤ 0.01) and RAS coalterations (P ≤ 0.001) than class I. Compared with class I, PFS on chemotherapy was shorter for class II (P = 0.069) and class III (P = 0.034). OS was shorter for class II and III (class I, 40.1 months; class II, 13.9 months; and class III, 15.6 months; I vs. II, P &lt; 0.001; I vs. III, P = 0.023); however, this difference was driven by fewer extrathoracic metastases and higher use of targeted therapies in class I patients. When patients treated with targeted therapy and those with thoracic-only metastases were excluded, there was no difference in OS across the 3 classes.

Conclusions:
BRAF-mutant NSCLC is a heterogeneous disease that encompasses 3 distinct functional classes. Classes II and III have more aggressive clinical features leading to less favorable outcomes. The distinct biological characteristics of class II and III tumors suggest that class-specific therapies may be necessary to effectively target these molecular subsets.
Establishment and Genetic Landscape of Precancer Cell Model Systems from the Head and Neck Mucosal Lining
Authors: de Boer D. Vicky , Brink Arjen , Buijze Marijke , Stigter-van Walsum Marijke , Hunter Keith D. , Ylstra Bauke , Bloemena Elisabeth , Leemans C. René , Brakenhoff Ruud H. 
Published: September 2018

AbstractHead and neck squamous cell carcinomas (HNSCC) develop in fields of genetically altered cells. These fields are often dysplastic and a subset can be recognized as (erythro)leukoplakia, but most are macroscopically invisible. There is a lack of adequate treatment options to eradicate these fields, whereas they underlie the development of primary tumors as well as part of the local relapses. Unfortunately, there are almost no representative cellular models available to identify suitable treatment options. To this end, clinical biopsy specimens (n = 98) were cultured from normal appearing mucosa of the surgical margins of patients with primary HNSCCs (n = 32) to generate precancer cell culture models. This collection was extended with six previously established precancer cell cultures. Genetic analysis was performed on cultures with an extended life span (≥20 population doublings), the previously established cultures, and some randomly selected cultures. In total, cancer-associated changes were detected in 18 out of 34 (53%) cultures analyzed, which appeared to be independent of life span. A variety of genetic changes were identified, including somatic mutations as well as chromosomal copy-number aberrations (CNA). Loss of CDKN2A/p16Ink4A and mutations in TP53/p53 were most prominent. Remarkably, in some of these precancer cell cultures only chromosomal CNAs were detected, and none of the frequently occurring driver mutations.Implications:The precancer cell cultures, characterized herein, form a representative collection of field models that can be exploited to identify and validate new therapeutic strategies to prevent primary HNSCCs and local relapses.
High-Salt Diet Causes Expansion of the Lymphatic Network and Increased Lymph Flow in Skin and Muscle of Rats
Authors: Karlsen Tine V. , Nikpey Elham , Han Jianhua , Reikvam Tore , Rakova Natalia , Castorena-Gonzalez Jorge A. , Davis Michael J. , Titze Jens M. , Tenstad Olav , Wiig Helge 
Published: September 2018

Objective—

A commonly accepted pivotal mechanism in fluid volume and blood pressure regulation is the parallel relationship between body Na
+
and extracellular fluid content. Several recent studies have, however, shown that a considerable amount of Na
+
can be retained in skin without commensurate water retention. Here, we asked whether a salt accumulation shown to result in VEGF (vascular endothelial growth factor)-C secretion and lymphangiogenesis had any influence on lymphatic function.

Approach and Results—

By optical imaging of macromolecular tracer washout in skin, we found that salt accumulation resulted in an increase in lymph flow of 26% that was noticeable only after including an overnight recording period. Surprisingly, lymph flow in skeletal muscle recorded with a new positron emission tomography/computed tomography method was also increased after salt exposure. The transcapillary filtration was unaffected by the high-salt diet and deoxycorticosterone-salt treatment, suggesting that the capillary barrier was not influenced by the salt accumulation. A significant reduction in lymph flow after depletion of macrophages/monocytes by clodronate suggests these cells are involved in the observed lymph flow response, together with collecting vessels shown here to enhance their contraction frequency as a response to extracellular Na
+
.

Conclusions—
The observed changes in lymph flow suggest that the lymphatics may influence long-term regulation of tissue fluid balance during salt accumulation by contributing to fluid homeostasis in skin and muscle. Our studies identify lymph clearance as a potential disease-modifying factor that might be targeted in conditions characterized by salt accumulation like chronic kidney disease and salt-sensitive hypertension.
Factor XII Activation Promotes Platelet Consumption in the Presence of Bacterial-Type Long-Chain Polyphosphate In Vitro and In Vivo
Authors: Zilberman-Rudenko Jevgenia , Reitsma Stéphanie E. , Puy Cristina , Rigg Rachel A. , Smith Stephanie A. , Tucker Erik I. , Silasi Robert , Merkulova Alona , McCrae Keith R. , Maas Coen , Urbanus Rolf T. , Gailani David , Morrissey James H. , Gruber András , Lupu Florea , Schmaier Alvin H. , McCarty Owen J.T. 
Published: September 2018

Objective—
Terminal complications of bacterial sepsis include development of disseminated intravascular consumptive coagulopathy. Bacterial constituents, including long-chain polyphosphates (polyP), have been shown to activate the contact pathway of coagulation in plasma. Recent work shows that activation of the contact pathway in flowing whole blood promotes thrombin generation and platelet activation and consumption distal to thrombus formation ex vivo and in vivo. Here, we sought to determine whether presence of long-chain polyP or bacteria in the bloodstream promotes platelet activation and consumption in a coagulation factor (F)XII-dependent manner.

Approach and Results—

Long-chain polyP promoted platelet P-selectin expression, microaggregate formation, and platelet consumption in flowing whole blood in a contact activation pathway-dependent manner. Moreover, long-chain polyP promoted local fibrin formation on collagen under shear flow in a FXI-dependent manner. Distal to the site of thrombus formation, platelet consumption was dramatically enhanced in the presence of long-chain polyP in the blood flow in a FXI- and FXII-dependent manner. In a murine model, long-chain polyP promoted platelet deposition and fibrin generation in lungs in a FXII-dependent manner. In a nonhuman primate model of bacterial sepsis, pre-treatment of animals with an antibody blocking FXI activation by FXIIa reduced lethal dose
100
Staphylococcus aureus
–induced platelet and fibrinogen consumption.

Conclusions—
This study demonstrates that bacterial-type long-chain polyP promotes platelet activation in a FXII-dependent manner in flowing blood, which may contribute to sepsis-associated thrombotic processes, consumptive coagulopathy, and thrombocytopenia.