bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential effects of PD-1 and CTLA-4 blockade on the melanoma-reactive CD8 T cell response
Authors: Gangaev Anastasia , Rozeman Elisa A. , Rohaan Maartje W. , Philips Daisy , Patiwael Sanne , van den Berg Joost H. , Ribas Antoni , Schadendorf Dirk , Schilling Bastian , Schumacher Ton N. , Blank Christian U. , Haanen John B.A.G. , Kvistborg Pia 
Published: December 2020

AbstractImmune checkpoint inhibitors targeting programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have revolutionized the treatment of melanoma patients. Based on early studies addressing the mechanism of action, it was assumed that PD-1 blockade mostly influences T cell responses at the tumor site. However, recent work has demonstrated that PD-1 blockade can influence the T cell compartment in peripheral. blood. If activation of circulating tumor-reactive T cells would form an important mechanism of action of PD-1 blockade, it may be predicted that such blockade would alter either the frequency and/or the breadth of the tumor-reactive CD8 T cell response. To address this question, we analyzed CD8 T cell responses towards 71 melanoma associated epitopes in peripheral blood of 24 melanoma patients. We show that both the frequency and the breadth of the melanoma-reactive CD8 T cell response in peripheral blood was unaltered upon PD-1 blockade. In contrast, a broadening of the melanoma-reactive CD8 T cell response was observed upon CTLA-4 blockade, in concordance with our prior data. On the basis of these results, we conclude that PD-1 and CTLA-4 blockade impact the tumor-reactive CD8 T cell response in a distinct manner. In addition, the data provide an argument in favor of the hypothesis that anti-PD-1 therapy may primarily act at the tumor site.One sentence summaryWe demonstrate that, contrary to CTLA-4 blockade, PD-1 blockade in melanoma patients does not lead to an increase in the breadth or magnitude of the melanoma-reactive CD8 T cell response in peripheral blood, thereby arguing for a dominant effect of PD-1 blockade at the tumor site.
Quantitative Genetic Scoring, or how to put a number on an arbitrary genetic region
Authors: Schoenmacker GH , Vlaming P , Pallesen J , Pikulina MY , Ghamarian AH , Demontis D , Børglum A , Galesloot TE , Poelmans G , Franke B , Claassen T , Heskes T , Buitelaar JK , Vásquez A Arias 
Published: December 2020

AbstractMotivationWith the increasing availability of genome-wide genetic data, methods to combine genetic variables with other sources of data in statistical models are required. This paper introduces quantitative genetic scoring (QGS), a dimensionality reduction method to create quantitative genetic variables representing arbitrary genetic regions.MethodsQGS is defined as the sum of absolute differences in the genetic sequence between a subject and a reference population. QGS properties such as distribution and sensitivity to region size were examined, and QGS was tested in six different existing genomic data sets of various sizes and various phenotypes.ResultsQGS can reduce genetic information by >98% yet explain phenotypic variance at low, medium, and high level of granularity. Associations based on QGS are independent of both size and linkage disequilibrium structure of the underlying region. In combination with stability selection, QGS finds significant results where a traditional genome-wide association approaches struggle. In conclusion, QGS preserves phenotypically significant genetic variance while reducing dimensionality, allowing researchers to include quantitative genetic information in any type of statistical analysis.Availabilityhttps://github.com/machine2learn/QGSContactgido.schoenmacker@radboudumc.nlSupplemental informationSupplemental data are available online.
Predicting compound activity from phenotypic profiles and chemical structures
Authors: Moshkov Nikita , Becker Tim , Yang Kevin , Horvath Peter , Dancik Vlado , Wagner Bridget K. , Clemons Paul A. , Singh Shantanu , Carpenter Anne E. , Caicedo Juan C. 
Published: December 2020

AbstractRecent advances in deep learning enable using chemical structures and phenotypic profiles to accurately predict assay results for compounds virtually, reducing the time and cost of screens in the drug-discovery process. We evaluate the relative strength of three high-throughput data sources—chemical structures, images (Cell Painting), and gene-expression profiles (L1000)—to predict compound activity using a sparse historical collection of 16,170 compounds tested in 270 assays for a total of 585,439 readouts. All three data modalities can predict compound activity with high accuracy in 6-10% of assays tested; replacing million-compound physical screens with computationally prioritized smaller screens throughout the pharmaceutical industry could yield major savings. Furthermore, the three profiling modalities are complementary, and in combination they can predict 21% of assays with high accuracy, and 64% if lower accuracy is acceptable. Our study shows that, for many assays, predicting compound activity from phenotypic profiles and chemical structures might accelerate the early stages of the drug-discovery process.
Molecular topography of an entire nervous system
Authors: Taylor Seth R , Santpere Gabriel , Weinreb Alexis , Barrett Alec , Reilly Molly B. , Xu Chuan , Varol Erdem , Oikonomou Panos , Glenwinkel Lori , McWhirter Rebecca , Poff Abigail , Basavaraju Manasa , Rafi Ibnul , Yemini Eviatar , Cook Steven J , Abrams Alexander , Vidal Berta , Cros Cyril , Tavazoie Saeed , Sestan Nenad , Hammarlund Marc , Hobert Oliver , Miller David M. 
Published: December 2020

SummaryNervous systems are constructed from a deep repertoire of neuron types but the underlying gene expression programs that specify individual neuron identities are poorly understood. To address this deficit, we have produced an expression profile of all 302 neurons of theC. elegansnervous system that matches the single cell resolution of its anatomy and wiring diagram. Our results suggest that individual neuron classes can be solely identified by combinatorial expression of specific gene families. For example, each neuron class expresses unique codes of ∼23 neuropeptide-encoding genes and ∼36 neuropeptide receptors thus pointing to an expansive “wireless” signaling network. To demonstrate the utility of this uniquely comprehensive gene expression catalog, we used computational approaches to (1) identify cis-regulatory elements for neuron-specific gene expression across the nervous system and (2) reveal adhesion proteins with potential roles in synaptic specificity and process placement. These data are available at cengen.org and can be interrogated at the web application CengenApp. We expect that this neuron-specific directory of gene expression will spur investigations of underlying mechanisms that define anatomy, connectivity and function throughout theC. elegansnervous system.
Sestrins regulate age-induced deterioration of muscle stem cell homeostasis
Authors: Yang Benjamin A. , Castor-Macias Jesus , Fraczek Paula , Brown Lemuel A. , Kim Myungjin , Brooks Susan V. , Lee Jun Hee , Aguilar Carlos A. 
Published: December 2020

AbstractThe health and homeostasis of skeletal muscle is preserved by a population of tissue resident stem cells called satellite cells. Young healthy satellite cells maintain a state of quiescence, but aging or metabolic insults results in reduced capacity to prevent premature activation and stem cell exhaustion. As such, understanding genes and pathways that protect satellite cell maintenance of quiescence are needed. Sestrins are a class of stress-inducible proteins that act as antioxidants and inhibit the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling complex. Despite these pivotal roles, the role of Sestrins has not been explored in adult stem cells. Herein, we show that Sestrin1,2 loss results in hyperactivation of the mTORC1 complex, increased propensity to enter the cell cycle and shifts in metabolic flux. Aging of Sestrin1,2 knockout mice demonstrated a loss of MuSCs and reduced ability to regenerate. These findings demonstrate Sestrins function to help maintain MuSC metabolism that supports quiescence and against aging.HighlightsSestrin deficiency alters mTORC1 signaling in muscle stem cells (MuSCs).In young mice, Sestrins are dispensable for regenerative responses of MuSCs.Sestrin deficiency accelerates age-dependent loss and dysfunction of MuSCs.
Statistically correcting dynamical electron scattering improves the refinement of protein nanocrystals, including charge refinement of coordinated metals
Authors: Blum Thorsten B. , Housset Dominique , Clabbers Max T. B. , van Genderen Eric , Bacia-Verloop Maria , Zander Ulrich , McCarthy Andrew A. , Schoehn Guy , Ling Wai Li , Abrahams Jan Pieter 
Published: December 2020

Electron diffraction allows protein structure determination when only nanosized crystals are available. Nevertheless, multiple elastic (or dynamical) scattering, which is prominent in electron diffraction, is a concern. Current methods for modeling dynamical scattering by multi-slice or Bloch wave approaches are not suitable for protein crystals because they are not designed to cope with large molecules. Here, dynamical scattering of nanocrystals of insulin, thermolysin and thaumatin was limited by collecting data from thin crystals. To accurately measure the weak diffraction signal from the few unit cells in the thin crystals, a low-noise hybrid pixel Timepix electron-counting detector was used. The remaining dynamical component was further reduced in refinement using a likelihood-based correction, which was introduced previously for analyzing electron diffraction data of small-molecule nanocrystals and was adapted here for protein crystals. The procedure is shown to notably improve the structural refinement, in one case allowing the location of solvent molecules. It also allowed refinement of the charge states of bound metal atoms, an important element in protein function, through B-factor analysis of the metal atoms and their ligands. These results clearly increase the value of macromolecular electron crystallography as a complementary structural biology technique.
Effect of percutaneous aortic valve position on stress map in ascending aorta: A fluid‐structure interaction analysis
Authors: Ibanez Ivan , de Azevedo Gomes Bruno A. , Nieckele Angela O. 
Published: December 2020

AbstractTranscatheter aortic valve implantation (TAVI) is an increasingly widespread procedure. Although this intervention is indicated for high and low surgical risk patients, some issues still remain, such as prosthesis positioning optimization in the aortic annulus. Coaxial positioning of the percutaneous prosthesis influences directly on the aortic wall stress map. The determination of the mechanical stress that acts on the vascular endothelium resulting from blood flow can be considered an important task, since TAVI positioning can lead to unfavorable hemodynamic patterns, resulting in changes in parietal stress, such as those found in post‐stenotic dilatation region. This research aims to investigate the influence of the prosthetic valve inclination angle in the mechanical stresses acting in the ascending aortic wall. Aortic compliance and blood flow during cardiac cycle were numerically obtained using fluid structure interaction. The aortic model was developed through segmentation of a computed tomography image of a specific patient submitted to TAVI. When compared to standard position (coaxiality match between the prosthesis and the aortic annulus), the inclination of 4° directed to the left main coronary artery decreased the aortic wall area with high values of wall shear stress and pressure. Coaxial positioning optimization of percutaneous aortic prosthesis may decrease the high mechanical stress area. These changes may be important to reduce the aortic remodeling process, vascular calcification or even the prosthesis half‐life. Computational fluid dynamics makes room for personalized medicine, with manufactured prosthesis tailored to each patient.
Complement activation by dialysis membranes and its association with secondary membrane formation and surface charge
Authors: Melchior Pascal , Erlenkötter Ansgar , Zawada Adam M. , Delinski Dirk , Schall Christian , Stauss‐Grabo Manuela , Kennedy James P. 
Published: December 2020

AbstractActivation of the complement system may occur during blood‐membrane interactions in hemodialysis and contribute to chronic inflammation of patients with end‐stage renal disease. Hydrophilic modification with polyvinylpyrrolidone (PVP) has been suggested to increase the biocompatibility profile of dialysis membranes. In the present study we compared the complement activation of synthetic and cellulose‐based membranes, including the polysulfone membrane with α‐tocopherol‐stabilized PVP‐enriched inner surface of the novel FX CorAL dialyzer, and linked the results to their physical characteristics. Eight synthetic and cellulose‐based dialyzers (FX CorAL, FX CorDiax [Fresenius Medical Care]; Polyflux, THERANOVA [Baxter]; ELISIO, SUREFLUX [Nipro]; xevonta [B. Braun]; FDX [Nikkisio Medical]) were investigated in the present study. Complement activation (C3a, C5a, and sC5b‐9) was evaluated in a 3 hours ex vivo recirculation model with human blood. Albumin sieving coefficients were determined over a 4 hours ex vivo recirculation model with human plasma as a surrogate of secondary membrane formation. Zeta potential was measured as an indicator for the surface charge of the membranes. The FX CorAL dialyzer induced the lowest activation of the three complement factors (C3a: −39.4%; C5a: −57.5%; and sC5b‐9: −58.9% compared to the reference). Highest complement activation was found for the cellulose‐based SUREFLUX (C3a: +154.0%) and the FDX (C5a: +335.0% and sC5b‐9: +287.9%) dialyzers. Moreover, the FX CorAL dialyzer had the nearest‐to‐neutral zeta potential (−2.38 mV) and the lowest albumin sieving coefficient decrease over time. Albumin sieving coefficient decrease was associated with complement activation by the investigated dialyzers. Our present results indicate that the surface modification implemented in the FX CorAL dialyzer reduces the secondary membrane formation and improves the biocompatibility profile. Further clinical studies are needed to investigate whether these observations will result in a lower inflammatory burden of hemodialysis patients.
Systemic counterregulatory response of angiopoietin‐2 after aflibercept therapy for nAMD: a potential escape mechanism
Authors: Angermann Reinhard , Rauchegger Teresa , Nowosielski Yvonne , Seifarth Christof , Egger Stefan , Kralinger Martina T. , Kieselbach Gerhard F. , Zehetner Claus 
Published: December 2020

AbstractPurposeTo analyse the effect of intravitreal aflibercept injections on systemic angiopoietin‐2 (Ang2) and vascular endothelial growth factor (VEGF)‐A levels in patients with neovascular age‐related macular degeneration (nAMD).MethodsIn a prospective, randomized study, aflibercept (2.0 mg/50 µl) or ranibizumab (0.5 mg/50 µl) was administered intravitreally to 38 treatment‐naive patients. Blood samples were taken before, 7 days after, and 28 days after the first intravitreal therapy. Cytokine levels were measured by enzyme‐linked immunosorbent assay. Twenty‐two age‐ and sex‐matched individuals served as controls.ResultsAt baseline, there were no significant differences of systemic Ang2 and VEGF‐A levels among the treatment and control groups. After intravitreal aflibercept administration, median (interquartile range: IQR) systemic Ang2 was significantly upregulated from 1819 pg/ml (1262–3099) to 2123 pg/ml (1441–3769; p = 0.011) 7 days after the drug injection and remained non‐significantly elevated at 1944 pg/ml (1431–2546 pg/ml; p = 0.653) 28 days after the drug injection. Median (IQR) systemic VEGF‐A levels were significantly reduced from 43 pg/ml (30–57) to 8 pg/ml (8–8; p < 0.0001) 7 days and 16 pg/ml (8–26; p = 0.001) 28 days after the injection in the aflibercept group. There were no significant effects on systemic VEGF‐A and Ang2 levels in the ranibizumab group at any time point following the first injection.ConclusionIn this study, we report significant systemic upregulation of Ang2 after intravitreal aflibercept administration. This counterregulatory response may represent a potential escape mechanism from antiangiogenic therapy.
Retroperitoneal fibrosis and β‐blocking agents: Is there an association?
Authors: Kharagjitsing Hardjit , van Eekeren Rike , van Puijenbroek Eugène P. , van Gelder Teun , van Bommel Eric F. H. 
Published: December 2020

AimsRetroperitoneal fibrosis (RPF) is a rare chronic fibro‐inflammatory disorder that may be secondary to certain drugs, including β‐blocking agents (BBAs). However, their causative role is unclear. We aimed to investigate this association.MethodsDisproportionality analysis was carried out on cases from 1985 to 4 October 2020 in VigiBase, the World Health Organization pharmacovigilance database. The Bayesian‐based IC025 metric and reporting odds ratio were used in order to assess the adverse event signal. We also analysed all published case reports from the literature regarding BBA‐associated RPF to assess the value of suggested supportive clinical evidence.ResultsIn total, 1599 individual case safety reports of RPF were reported to VigiBase, of which 132 (32%) concerned 16 different single BBA. For 12 of these agents (75%), reporting of RPF was disproportionate, indicating a potential safety signal. Line listing analysis of individual case safety reports showed no consistent time interval from start of BBA to RPF diagnosis (range 0.7–264 mo). Dechallenge was negative or unknown in the majority of cases (74%). In 18 published cases from the literature, time from start of BBA to RPF diagnosis varied widely (range 3–156 mo). BBA were discontinued 6 months before (n = 1) or at the time of RPF diagnosis (n = 17). Most patients (84%) also received RPF specific treatment. Follow‐up duration was short (median 5 mo [range 1–24 mo]) and in most cases (83%) relevant follow‐up data were lacking.ConclusionAlthough disproportionality analysis indicated a potential safety signal for RPF associated with BBAs, clinical evidence did not support a cause‐and‐effect relationship.
A Comparison between Mygind and Kaiteki positions in administration of drops to the olfactory cleft
Authors: Milk Dafna G. , Khong Grace C. , Çam Osman H. , Alfaro‐Iraheta Fernando , Tierney Claire , Kassem Firas , Leong Samuel C. 
Published: December 2020

AbstractObjectivesTopical nasal steroids are a common treatment intervention for olfactory dysfunction. Penetration of topical treatment to the olfactory cleft (OC), such as nasal drops, is greatly dependent on the position of the head when the treatment is administered. We aimed to examine the penetrance of nasal drops to the OC in two different head positions: the Mygind (lying head back) position and the Kaiteki position.Design and SettingThe specimens were firstly positioned in Mygind, and thereafter in Kaiteki positions. Nasal drops mixed with blue food dye were administered into the nostrils in each of the head position. Endoscopic videos were recorded, and two blinded observers scored the extent of olfactory cleft penetration (OCP) using a 4‐point scale (0 = none, 3 = heavy).ParticipantsTwelve fresh‐frozen cadaver specimens.Main outcome measuresPenetration of the dye into the OC.ResultsThe mean score of nasal drops penetrance to the OC in the Mygind position was 1.34 (standard deviation, SD = 0.92), as compared to 1.76 (SD = 0.65) in the Kaiteki position. The difference in the OCP score between the two groups was not statistically significant (P > .05).ConclusionBoth Mygind and Kaiteki head positions are reasonable options for patients considering topical nasal drops for olfaction impairment. The preference of one position over the other should be determined by patient's preference and comfort.
GSTP1andABCB1Polymorphisms Predicting Toxicities and Clinical Management on Carboplatin and Paclitaxel‐Based Chemotherapy in Ovarian Cancer
Authors: Ferracini Amanda Canato , Lopes-Aguiar Leisa , Lourenço Gustavo Jacob , Yoshida Adriana , Lima Carmen Silva Passos , Sarian Luis Otávio , Derchain Sophie , Kroetz Deanna L. , Mazzola Priscila Gava 
Published: December 2020

Variation in drug disposition genes might contribute to susceptibility to toxicities and interindividual differences in clinical management on chemotherapy for epithelial ovarian cancer (EOC). This study was designed to explore the association ofGSTandABCB1genetic variation with hematologic and neurologic toxicity, changes in chemotherapy, and disease prognosis in Brazilian women with EOC. A total of 112 women with a confirmed histological diagnosis of EOC treated with carboplatin/paclitaxel were enrolled (2014–2019). The samples were analyzed by multiplex polymerase chain reaction (PCR) for the deletion ofGSTM1andGSTT1genes.GSTP1(c.313A>G/rs1695) andABCB1(c.1236C>T/rs1128503; c.3435C>T/rs1045642; c.2677G>T>A/rs2032582) single nucleotide polymorphisms (SNPs) were detected by real‐time PCR. Subjects with theGSTP1c.313A>G had reduced risk of anemia (odds ratio (OR): 0.17, 95% confidence interval (CI): 0.04–0.69,P = 0.01, dominant model) and for thrombocytopenia (OR: 0.27, 95% CI: 0.12–0.64,P < 0.01; OR 0.18, 95% CI 0.03–0.85,P = 0.03, either dominant or recessive model), respectively. TheGSTP1c.313A>G AG genotype was associated with a lower risk of dose delay (OR: 0.35, 95% CI: 0.13–0.90,P = 0.03). TheABCB1c.1236C>T was associated with increased risk of thrombocytopenia (OR: 0.15, 95% CI: 0.03–0.82,P = 0.03), whereasABCB1c.3435C>T had increased risk of grade 2 and 3 neurotoxicity (OR: 3.61, 95% CI: 1.08–121.01,P = 0.03) in recessive model (CC + CT vs. TT). This study suggests thatGSTP1c.313A>G,ABCB1c.1236C>T, and c.3435C>T SNP detection is a potential predictor of hematological toxicity and neurotoxicity and could help predict the clinical management of women with EOC.
The many faces of Sox2 function in neural crest development
Authors: Wakamatsu Yoshio , Uchikawa Masanori 
Published: December 2020

AbstractNeural crest (NC) cells give rise to a wide variety of cell types and tissues, such as neurons and glial cells in the peripheral nervous system. Sox2, which encodes an HMG‐box transcription factor, is known to mediate pluripotency of primordial germ cells and embryonic stem (ES)/induced pluripotent stem (iPS) cells, and to regulate central nervous system development. Previous studies have revealed that Sox2 is also an important regulator of NC development. This review summarizes the well‐established inhibitory roles of Sox2 in NC formation and subsequent neuronal differentiation of NC‐derived cells. This review also covers recent studies suggesting additional roles for Sox2 in early NC development, neurogenesis, and glial differentiation of NC‐derived cells.