bluuebunny/crossref_metadata_2025_split huggingface dataset:
Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans
Authors: Vicencio J. M. , Evans R. , Green R. , An Z. , Deng J. , Treacy C. , Mustapha R. , Monypenny J. , Costoya C. , Lawler K. , Ng K. , De-Souza K. , Coban O. , Gomez V. , Clancy J. , Chen S. H. , Chalk A. , Wong F. , Gordon P. , Savage C. , Gomes C. , Pan T. , Alfano G. , Dolcetti L. , Chan J. N. E. , Flores-Borja F. , Barber P. R. , Weitsman G. , Sosnowska D. , Capone E. , Iacobelli S. , Hochhauser D. , Hartley J. A. , Parsons M. , Arnold J. N. , Ameer-Beg S. , Quezada S. A. , Yarden Y. , Sala G. , Ng T. 
Published: March 2022

AbstractOver the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.
Cell death-induced immunogenicity enhances chemoimmunotherapeutic response by converting immune-excluded into T-cell inflamed bladder tumors
Authors: Nikolos Fotis , Hayashi Kazukuni , Hoi Xen Ping , Alonzo Mark Ellie , Mo Qianxing , Kasabyan Armine , Furuya Hideki , Trepel Jane , Di Vizio Dolores , Guarnerio Jlenia , Theodorescu Dan , Rosser Charles , Apolo Andrea , Galsky Matthew , Chan Keith Syson 
Published: March 2022

AbstractChemoimmunotherapy has recently failed to demonstrate significant clinical benefit in advanced bladder cancer patients; and the mechanism(s) underlying such suboptimal response remain elusive. To date, most studies have focused on tumor-intrinsic properties that render them “immune-excluded”. Here, we explore an alternative, drug-induced mechanism that impedes therapeutic response via disrupting the onset of immunogenic cell death. Using two immune-excluded syngeneic mouse models of muscle-invasive bladder cancer (MIBC), we show that platinum-based chemotherapy diminishes CD8+ T cell tumor infiltration and constraines their antitumoral activity, despite expression of activation markers IFNγ and granzyme B. Mechanistically, chemotherapy induces the release of prostaglandin E2 (PGE2) from dying cancer cells, which is an inhibitory damage-associated molecular pattern (iDAMP) that hinderes dendritic cell maturation. Upon pharmaceutical blockade of PGE2 release, CD8+ T cells become tumoricidal and display an intraepithelial-infiltrating (or inflamed) pattern. This “iDAMP blockade” approach synergizes with chemotherapy and sensitizes bladder tumors towards anti-PD1 immune checkpoint inhibitor therapy. These findings provide a compelling rationale to evaluate this drug combination in future clinical trials.
Wafer-scale epitaxial modulation of quantum dot density
Authors: Bart N. , Dangel C. , Zajac P. , Spitzer N. , Ritzmann J. , Schmidt M. , Babin H. G. , Schott R. , Valentin S. R. , Scholz S. , Wang Y. , Uppu R. , Najer D. , Löbl M. C. , Tomm N. , Javadi A. , Antoniadis N. O. , Midolo L. , Müller K. , Warburton R. J. , Lodahl P. , Wieck A. D. , Finley J. J. , Ludwig A. 
Published: March 2022

AbstractPrecise control of the properties of semiconductor quantum dots (QDs) is vital for creating novel devices for quantum photonics and advanced opto-electronics. Suitable low QD-densities for single QD devices and experiments are challenging to control during epitaxy and are typically found only in limited regions of the wafer. Here, we demonstrate how conventional molecular beam epitaxy (MBE) can be used to modulate the density of optically active QDs in one- and two- dimensional patterns, while still retaining excellent quality. We find that material thickness gradients during layer-by-layer growth result in surface roughness modulations across the whole wafer. Growth on such templates strongly influences the QD nucleation probability. We obtain density modulations between 1 and 10 QDs/µm2 and periods ranging from several millimeters down to at least a few hundred microns. This method is universal and expected to be applicable to a wide variety of different semiconductor material systems. We apply the method to enable growth of ultra-low noise QDs across an entire 3-inch semiconductor wafer.
Single-cell transcriptomic analysis suggests two molecularly distinct subtypes of intrahepatic cholangiocarcinoma
Authors: Song Guohe , Shi Yang , Meng Lu , Ma Jiaqiang , Huang Siyuan , Zhang Juan , Wu Yingcheng , Li Jiaxin , Lin Youpei , Yang Shuaixi , Rao Dongning , Cheng Yifei , Lin Jian , Ji Shuyi , Liu Yuming , Jiang Shan , Wang Xiaoliang , Zhang Shu , Ke Aiwu , Wang Xiaoying , Cao Ya , Ji Yuan , Zhou Jian , Fan Jia , Zhang Xiaoming , Xi Ruibin , Gao Qiang 
Published: March 2022

AbstractIntrahepatic cholangiocarcinoma (iCCA) is a highly heterogeneous cancer with limited understanding of its classification and tumor microenvironment. Here, by performing single-cell RNA sequencing on 144,878 cells from 14 pairs of iCCA tumors and non-tumor liver tissues, we find that S100P and SPP1 are two markers for iCCA perihilar large duct type (iCCAphl) and peripheral small duct type (iCCApps). S100P + SPP1− iCCAphlhas significantly reduced levels of infiltrating CD4+T cells, CD56+NK cells, and increased CCL18+macrophages and PD1+CD8+T cells compared to S100P-SPP1 + iCCApps. The transcription factor CREB3L1 is identified to regulate the S100P expression and promote tumor cell invasion. S100P-SPP1 + iCCAppshas significantly more SPP1+macrophage infiltration, less aggressiveness and better survival than S100P + SPP1− iCCAphl. Moreover, S100P-SPP1 + iCCAppsharbors tumor cells at different status of differentiation, such as ALB + hepatocyte differentiation and ID3+ stemness. Our study extends the understanding of the diversity of tumor cells in iCCA.
Flexible auditory training, psychophysics, and enrichment of common marmosets with an automated, touchscreen-based system
Authors: Calapai A. , Cabrera-Moreno J. , Moser T. , Jeschke M. 
Published: March 2022

AbstractDevising new and more efficient protocols to analyze the phenotypes of non-human primates, as well as their complex nervous systems, is rapidly becoming of paramount importance. This is because with genome-editing techniques, recently adopted to non-human primates, new animal models for fundamental and translational research have been established. One aspect in particular, namely cognitive hearing, has been difficult to assess compared to visual cognition. To address this, we devised autonomous, standardized, and unsupervised training and testing of auditory capabilities of common marmosets with a cage-based standalone, wireless system. All marmosets tested voluntarily operated the device on a daily basis and went from naïve to experienced at their own pace and with ease. Through a series of experiments, here we show, that animals autonomously learn to associate sounds with images; to flexibly discriminate sounds, and to detect sounds of varying loudness. The developed platform and training principles combine in-cage training of common marmosets for cognitive and psychoacoustic assessment with an enriched environment that does not rely on dietary restriction or social separation, in compliance with the 3Rs principle.
Modeling of waning immunity after SARS-CoV-2 vaccination and influencing factors
Authors: Pérez-Alós Laura , Armenteros Jose Juan Almagro , Madsen Johannes Roth , Hansen Cecilie Bo , Jarlhelt Ida , Hamm Sebastian Rask , Heftdal Line Dam , Pries-Heje Mia Marie , Møller Dina Leth , Fogh Kamille , Hasselbalch Rasmus Bo , Rosbjerg Anne , Brunak Søren , Sørensen Erik , Larsen Margit Anita Hørup , Ostrowski Sisse Rye , Frikke-Schmidt Ruth , Bayarri-Olmos Rafael , Hilsted Linda Maria , Iversen Kasper Karmark , Bundgaard Henning , Nielsen Susanne Dam , Garred Peter 
Published: March 2022

AbstractSARS-CoV-2 vaccines are crucial in controlling COVID-19, but knowledge of which factors determine waning immunity is limited. We examined antibody levels and T-cell gamma-interferon release after two doses of BNT162b2 vaccine or a combination of ChAdOx1-nCoV19 and BNT162b2 vaccines for up to 230 days after the first dose. Generalized mixed models with and without natural cubic splines were used to determine immunity over time. Antibody responses were influenced by natural infection, sex, and age. IgA only became significant in naturally infected. A one-year IgG projection suggested an initial two-phase response in those given the second dose delayed (ChAdOx1/BNT162b2) followed by a more rapid decrease of antibody levels. T-cell responses correlated significantly with IgG antibody responses. Our results indicate that IgG levels will drop at different rates depending on prior infection, age, sex, T-cell response, and the interval between vaccine injections. Only natural infection mounted a significant and lasting IgA response.
Age-dependent formation of TMEM106B amyloid filaments in human brains
Authors: Schweighauser Manuel , Arseni Diana , Bacioglu Mehtap , Huang Melissa , Lövestam Sofia , Shi Yang , Yang Yang , Zhang Wenjuan , Kotecha Abhay , Garringer Holly J. , Vidal Ruben , Hallinan Grace I. , Newell Kathy L. , Tarutani Airi , Murayama Shigeo , Miyazaki Masayuki , Saito Yuko , Yoshida Mari , Hasegawa Kazuko , Lashley Tammaryn , Revesz Tamas , Kovacs Gabor G. , van Swieten John , Takao Masaki , Hasegawa Masato , Ghetti Bernardino , Spillantini Maria Grazia , Ryskeldi-Falcon Benjamin , Murzin Alexey G. , Goedert Michel , Scheres Sjors H. W. 
Published: March 2022

AbstractMany age-dependent neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, are characterized by abundant inclusions of amyloid filaments. Filamentous inclusions of the proteins tau, amyloid-β, α-synuclein and transactive response DNA-binding protein (TARDBP; also known as TDP-43) are the most common1,2. Here we used structure determination by cryogenic electron microscopy to show that residues 120–254 of the lysosomal type II transmembrane protein 106B (TMEM106B) also form amyloid filaments in human brains. We determined the structures of TMEM106B filaments from a number of brain regions of 22 individuals with abundant amyloid deposits, including those resulting from sporadic and inherited tauopathies, amyloid-β amyloidoses, synucleinopathies and TDP-43 proteinopathies, as well as from the frontal cortex of 3 individuals with normal neurology and no or only a few amyloid deposits. We observed three TMEM106B folds, with no clear relationships between folds and diseases. TMEM106B filaments correlated with the presence of a 29-kDa sarkosyl-insoluble fragment and globular cytoplasmic inclusions, as detected by an antibody specific to the carboxy-terminal region of TMEM106B. The identification of TMEM106B filaments in the brains of older, but not younger, individuals with normal neurology indicates that they form in an age-dependent manner.
In vivo topical gene therapy for recessive dystrophic epidermolysis bullosa: a phase 1 and 2 trial
Authors: Gurevich Irina , Agarwal Pooja , Zhang PeiPei , Dolorito John A. , Oliver Stacie , Liu Henry , Reitze Nicholas , Sarma Nikhil , Bagci Isin Sinem , Sridhar Kunju , Kakarla Visesha , Yenamandra Vamsi K. , O’Malley Mark , Prisco Marco , Tufa Sara F. , Keene Douglas R. , South Andrew P. , Krishnan Suma M. , Marinkovich M. Peter 
Published: March 2022

AbstractRecessive dystrophic epidermolysis bullosa (RDEB) is a lifelong genodermatosis associated with blistering, wounding, and scarring caused by mutations in COL7A1, the gene encoding the anchoring fibril component, collagen VII (C7). Here, we evaluated beremagene geperpavec (B-VEC), an engineered, non-replicating COL7A1 containing herpes simplex virus type 1 (HSV-1) vector, to treat RDEB skin. B-VEC restored C7 expression in RDEB keratinocytes, fibroblasts, RDEB mice and human RDEB xenografts. Subsequently, a randomized, placebo-controlled, phase 1 and 2 clinical trial (NCT03536143) evaluated matched wounds from nine RDEB patients receiving topical B-VEC or placebo repeatedly over 12 weeks. No grade 2 or above B-VEC-related adverse events or vector shedding or tissue-bound skin immunoreactants were noted. HSV-1 and C7 antibodies sometimes presented at baseline or increased after B-VEC treatment without an apparent impact on safety or efficacy. Primary and secondary objectives of C7 expression, anchoring fibril assembly, wound surface area reduction, duration of wound closure, and time to wound closure following B-VEC treatment were met. A patient-reported pain–severity secondary outcome was not assessed given the small proportion of wounds treated. A global assessment secondary endpoint was not pursued due to redundancy with regard to other endpoints. These studies show that B-VEC is an easily administered, safely tolerated, topical molecular corrective therapy promoting wound healing in patients with RDEB.
Causal relationship of excess body weight on cardiovascular events through risk factors
Authors: Limpijankit Thosaphol , Vathesatogkit Prin , Matchariyakul Dujrudee , Wiriyatanakorn Sirichai , Siriyotha Sukanya , Thakkinstian Ammarin , Sritara Piyamitr 
Published: March 2022

AbstractExcess body weight is associated with cardiovascular events (CVEs) and premature death. This study aimed to find the causal pathways between excess body weight and CVEs through risk factors in a general adult population. A total of 7921 employees of the Electricity Generating Authority of Thailand were enrolled during 1997–2009. Baseline characteristics and blood test results were collected. A body mass index (BMI) ≥ 23 kg/m2, using WHO criteria for Asians was defined as excess body weight. A mediation analysis was applied to assess potential causal pathways. BMI ≥ 23 kg/m2 was considered as an independent variable, whereas diabetes mellitus (DM), hypertension (HT), and chronic kidney disease (CKD) were considered as mediators, and CVEs (i.e., fatal and non-fatal coronary artery disease or stroke) were considered as the outcomes. The prevalence of BMI ≥ 23 kg/m2, DM, HT, and CKD were 62.7%, 7.8%, 28.1% and 11.8% respectively. During an average of 17.2 ± 5.5 years follow-up, subjects with BMI ≥ 23 kg/m2 compared with those with lower BMIs more frequently developed CVEs (9.4 vs 6.2%, P < 0.001). The effects of BMI ≥ 23 kg/m2 on CVEs were mediated indirectly through DM and HT with significant ORs of 1.61 (1.34, 2.09) and 1.57 (1.39, 1.80), respectively. The indirect effect of CKD on CVEs was significantly increased if mediated through DM → HT or HT [ORs of 1.17 (1.09, 1.32) and 1.20 (1.10, 1.32), respectively]. Subjects with excess body weight were prone to develop CVEs which were mediated indirectly through DM and HT. The effect of CKD on CVEs was small but enhanced if it occurred as a complication of DM or HT.
Sex differences in audience effects on anogenital scent marking in the red-fronted lemur
Authors: Peckre Louise R. , Michiels Alexandra , Socias-Martínez Lluís , Kappeler Peter M. , Fichtel Claudia 
Published: March 2022

AbstractHow the presence of conspecifics affects scent mark deposition remains an understudied aspect of olfactory communication, even though scent marking occurs in different social contexts. Sex differences in scent-marking behaviour are common, and sex-specific effects of the audience could therefore be expected. We investigated sex differences in intra-group audience effects on anogenital scent marking in four groups of wild red-fronted lemurs (Eulemur rufifrons) by performing focal scent-marking observations. We observed a total of 327 events divided into 223 anogenital scent-marking events and 104 pass-by events (i.e. passage without scent marking). Using a combination of generalised linear mixed models and exponential random graph models, we found that scent marking in red-fronted lemurs is associated with some behavioural flexibility linked to the composition of the audience at the time of scent deposition. In particular, our study revealed sex differences in the audience effects, with males being overall more sensitive to their audience than females. Moreover, we show that these audience effects were dependent on the relative degree of social integration of the focal individual compared to that of individuals in the audience (difference in Composite Sociality Index) as well as the strength of the dyadic affiliative relationship (rank of Dyadic Composite Sociality Index within the group). The audience effects also varied as a function of the audience radius considered. Hence, we showed that scent marking in red-fronted lemurs is associated with some behavioural flexibility linked to the composition of the audience, ascribing red-fronted lemurs’ social competence in this context.
High magnetoelectric coupling of Metglas and P(VDF-TrFE) laminates
Authors: Staaf Henrik , Sawatdee Anurak , Rusu Cristina , Nilsson David , Schäffner Philipp , Johansson Christer 
Published: March 2022

AbstractMagnetoelectric (magnetic/piezoelectric) heterostructures bring new functionalities to develop novel transducer devices such as (wireless) sensors or energy harvesters and thus have been attracting research interest in the last years. We have studied the magnetoelectric coupling between Metglas films (2826 MB) and poly(vinylidene fluoride-trifluoroethylene) (P(VDF-TrFE)) in a laminate structure. The metallic Metglas film itself served as bottom electrode and as top electrode we used an electrically conductive polymer, poly(3,4-ethylene-dioxythiophene):poly(styrene sulfonate) (PEDOT:PSS). Besides a direct electrical wiring via a graphite ink, a novel contactless readout method is presented using a capacitive coupling between the PEDOT:PSS layer and an electrode not in contact with the PEDOT:PSS layer. From the experimental result we determined a magnetoelectric coupling of 1445 V/(cm·Oe) at the magnetoelastic resonance of the structure, which is among the highest reported values for laminate structures of a magnetostrictive and a piezoelectric polymer layer. With the noncontact readout method, a magnetoelectric coupling of about 950 V/(cm·Oe) could be achieved, which surpasses previously reported values for the case of direct sample contacting. 2D laser Doppler vibrometer measurements in combination with FE simulations were applied to reveal the complex vibration pattern resulting in the strong resonant response.
Coating Ti6Al4V implants with nanocrystalline diamond functionalized with BMP-7 promotes extracellular matrix mineralization in vitro and faster osseointegration in vivo
Authors: Nemcakova Ivana , Litvinec Andrej , Mandys Vaclav , Potocky Stepan , Plencner Martin , Doubkova Martina , Nanka Ondrej , Olejnickova Veronika , Sankova Barbora , Bartos Martin , Ukraintsev Egor , Babčenko Oleg , Bacakova Lucie , Kromka Alexander , Rezek Bohuslav , Sedmera David 
Published: March 2022

AbstractThe present study investigates the effect of an oxidized nanocrystalline diamond (O-NCD) coating functionalized with bone morphogenetic protein 7 (BMP-7) on human osteoblast maturation and extracellular matrix mineralization in vitro and on new bone formation in vivo. The chemical structure and the morphology of the NCD coating and the adhesion, thickness and morphology of the superimposed BMP-7 layer have also been assessed. The material analysis proved synthesis of a conformal diamond coating with a fine nanostructured morphology on the Ti6Al4V samples. The homogeneous nanostructured layer of BMP-7 on the NCD coating created by a physisorption method was confirmed by AFM. The osteogenic maturation of hFOB 1.19 cells in vitro was only slightly enhanced by the O-NCD coating alone without any increase in the mineralization of the matrix. Functionalization of the coating with BMP-7 resulted in more pronounced cell osteogenic maturation and increased extracellular matrix mineralization. Similar results were obtained in vivo from micro-CT and histological analyses of rabbit distal femurs with screws implanted for 4 or 12 weeks. While the O-NCD-coated implants alone promoted greater thickness of newly-formed bone in direct contact with the implant surface than the bare material, a further increase was induced by BMP-7. It can be therefore concluded that O-NCD coating functionalized with BMP-7 is a promising surface modification of metallic bone implants in order to improve their osseointegration.
Effects of Early Intervention Frequency on Expressive Vocabulary Growth Rates of Very Young Children Who Are Deaf or Hard of Hearing: How Much Is Enough?
Authors: Rudge Amanda M. , Brooks Betsy Moog , Grantham Heather 
Published: March 2022

Purpose:
The aims of this study were to explore expressive vocabulary growth rates of children who are deaf or hard of hearing (DHH) during critical periods of brain development (birth to 3 years) as well as the factors that influence the trajectories of vocabulary growth in these early years of development. Of primary interest was the effect of intervention frequency on expressive vocabulary growth.

Method:
Hierarchical linear modeling was used to investigate trajectories of expressive vocabulary growth using multiple measures of longitudinal vocabulary scores. A total of 417 assessments across 105 participants were analyzed to determine the average rate of lexical growth in a young population of children who are DHH receiving early intervention before age 3 years. Expected growth trajectories were constructed based on varying frequencies of intervention during critical periods of brain development.

Results:
Results indicated average growth rates of 5.21 new words expressed per week. Increased intervention hours prior to age 3 years was significantly associated with higher degrees of expressive vocabulary growth.

Conclusion:
The findings of this study suggest that greater intervention hours received before age 3 years are associated with higher degrees of expressive vocabulary growth for children who are DHH.