bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identifying crystal accumulation and melt extraction during formation of high-silica granite
Authors: Lu Tian-Yu , He Zhen-Yu , Klemd Reiner 
Published: November 2021

Abstract
High-silica (&gt;70 wt% SiO2) magmas are usually believed to form via shallow crustal–level fractional crystallization of intermediate magmas. However, the broad applicability of this model is controversial, because the required crystal-melt separation processes have rarely been documented globally up to now. The ca. 50 Ma Nyemo composite pluton of the Gangdese batholith belt in southern Tibet, which comprises intrusive rocks with intermediate- to high-silica compositions (65–78 wt%), offers a unique opportunity for substantiating the coexistence of extracted melts and complementary silicic cumulates in one of Earth's most complete transcrustal silicic magmatic systems. The Nyemo pluton intrusive rocks exhibit similar zircon Hf isotopic compositional ranges (mean εHf(t) = +5.7 to +8.3), suggesting a common, non-radiogenic magma source with crustal assimilation in the deep crust. Yet, these rocks have distinct geochemical characteristics. High-silica miarolitic and rapakivi granites are strongly depleted in Ba, Sr, and Eu, and their zircon trace elements show extremely low Eu/Eu* and Dy/Yb. In contrast, monzogranite is relatively enriched in Ba and Sr with minor Eu anomalies, and the zircon trace elements are characterized by relatively high Eu/Eu* and Dy/Yb. Therefore, we propose that the high-silica granites represent highly fractionated melt extracted from a mush reservoir at unusually low storage pressure (∼99–119 MPa), and that the monzogranite constitutes the complementary residual silicic cumulates.
Testing local and extraregional sediment sources for the Late Cretaceous northern Nanaimo basin, British Columbia, using 40Ar/39Ar detrital K-feldspar thermochronology
Authors: Isava V. , Grove M. , Mahoney J.B. , Haggart J.W. 
Published: November 2021

Abstract
Detrital K-feldspar 40Ar/39Ar thermochronology was conducted on clastic sedimentary rock samples collected from northern exposures of the Upper Cretaceous Nanaimo Group on Vancouver Island and adjacent Gulf Islands of British Columbia to constrain the denudation history of the local Coast Mountains batholith source region and determine the origin of extraregional sediment supplied to the basin. Strata of the northern Nanaimo Group deposited between 86 and 83 Ma (Comox and Extension formations) exhibit a 130–85 Ma age distribution of detrital K-feldspar 40Ar/39Ar ages that lack age maxima. These are interpreted to have been sourced from the southwestern Coast Mountains batholith. Younger strata deposited between 83 and 72 Ma (Cedar District and De Courcy formations) yield a broader age range (150–85 Ma) with an age maximum near the depositional age. These results indicate focused denudation of deeper-seated rocks east of the Harrison Lake fault. The youngest units deposited after 72 Ma (Geoffrey, Spray, and Gabriola formations) primarily yield younger than 75 Ma detrital K-feldspar ages with pronounced age maxima near the depositional age. This sediment was sourced extraregionally relative to the Coast Mountains batholith.
We sought to constrain the origin of the extraregional sediment by measuring the thermal histories of 74 samples of basement rocks from throughout the Pacific Northwest, and by compiling a database of over 2400 biotite 40Ar/39Ar and K/Ar cooling ages from predominantly Cretaceous batholiths along the western North American margin. This analysis focused upon two previously proposed source regions: the Idaho batholith and the Mojave-Salina margin of southern California. The Nanaimo detrital K-feldspar 40Ar/39Ar age distributions favor the peraluminous Late Cretaceous Idaho batholith and its Proterozoic Belt-Purcell Supergroup sedimentary wall rock as the more likely source of the extraregional sediment and disfavor the Baja–British Columbia hypothesis for 2000–4000-km-scale translation of rocks along the margin during the Late Cretaceous.
17 Predictive soluble biomarkers of immune response to checkpoint blockade in non-small cell lung cancer (NSCLC) patients
Authors: Raza Afsheen , Mohsen Reyad , Kanbour Aladdin , Zar Gul Abdul Rehman , Philip Anite , Vijayakumar Suma , Hydrose Shereena , Merhi Maysaloun , Inchakalody Varghese , Uddin Shahab , Homsi Mohammed Ussama Al , Dermime Said 
Published: November 2021

BackgroundThere is limited data on the predictive biomarkers of response to immune checkpoint blockade (ICB) treatment of non-small cell lung cancer (NSCLC) patients. The main aim of this prospective study was to understand the utility of pre-treatment soluble immune checkpoint markers as surrogate markers for tissue PD-L1 and as predictors of response in locally advanced/metastatic NSCLC patients treated with ICBs.MethodsThe study was conducted at the National Center for Cancer Care and Research (NCCCR), HMC, Qatar. A total of 30 patients on Pembrolizumab/Nivolumab were enrolled and blood samples were collected before treatment. 17 Healthy controls were also included in the study. Multiplex Magnetic Bead Panel kits for soluble immune checkpoint markers was utilized to measure the concentrations of 24 soluble markers including BTLA, GITR, HVEM, IDO, LAG-3, PD-1, PDL-1, PDL-2, TIM-3, CD28, CD80, 4-1BB, CD27, CTLA-4, ICOS Ligand, CD276, VISTA, B7-H6; CD47 (IAP), BLAST-1, Galectin-9, TIMD-4; OX40 and S100A8/A9. Mann-Whitney test was used to evaluate a) the difference in median values between healthy controls and pre-treatment samples b) compare soluble markers with tissue PD-L1 status and c) response to treatment 4 months after treatment via PET CT imaging data.ResultsThe results showed significant changes in the pre-treatment plasma concentrations of soluble markers in the NSCLC patients compared to healthy controls. Significant upregulation was observed in the immune suppression markers: S100A8/A9 (<0.0001****), PDL-2 (<0.006**), LAG-3 (<0.006**), PD-1 (<0.008*), TIM-3 (<0.002*), CD80 (<0.001*) and Galactin 9 (<0.023*). Significant upregulation was observed for the immune stimulatory markers: TIMD4 (<0.0001****), CD137/4-1BB (<0.007*), CD134/OX40 (<0.006**) in NSCLC patients compared to healthy controls. When soluble markers were compared with tissue PD-L1, significant upregulation of CD276/B7-H3 (<0.039*) and VISTA (<0.034*) was observed in patients expressing >50% of PD-L1 in their tissues.We then corelated the pre-treatment soluble markers expression with the clinical response of the patients to Pembrolizumab/Nivolumab using imaging (PET CT) data obtained 4 months after treatment. Interestingly, significant upregulation of GITR (<0.0005***), PD-L1 (<0.002**) and HVEM (<0.006**) was observed in responding patients.ConclusionsThe study demonstrates that 10 markers show differences in NSCLC patients as compared to healthy controls; 2 markers as surrogates for tissue PDL-1 and 3 markers as predictive biomarkers of response to ICB treatment.AcknowledgementsWe would like to thank all enrolled subjects for their participation in the study.Ethics ApprovalThe study was approved by Hamad Medical Corporation, Medical Research Center Ethics Board; approval number MRC-01-20-507
216 Multiplex base editing of NK cell to enhance cancer immunotherapy
Authors: Wang Minjing , Kluesner Mitchell , Vázquez Patricia Claudio , Webber Beau , Moriarity Branden 
Published: November 2021

BackgroundNatural killer (NK) cells have many unique features that have gained attention in cancer immunotherapy. NK cells can kill in antigen independent and dependent fashion, can be used as an allogeneic product, and perform antibody-dependent cell-mediated cytotoxicity (ADCC). However, NK cell function is regulated by many activating and inhibitory receptors, which cancer cells take advantage of to avoid being killed by NK cells. NK cells are also known for their technical and biological challenges which result in low editing efficiencies, compared to T cells and other immune cells.MethodsBase editing (BE) is a CRISPR-Cas9 based genome editing technology that allows precise single base transitions. Previously, we reported a high efficiency method for multiplex engineering of T cells using BE and thus reasoned that applying similar concepts in NK cells may offer an opportunity to alter many genes simultaneously at higher efficiency through multiplex base editing. We thus selected a panel of genes bearing critical roles in NK cell function for immunotherapy, including inhibitory intracellular regulator AHR and CISH, inhibitory checkpoint receptor KLRG1, TIGIT, KLRC1, and PDCD1, and Fc receptor CD16A. CD16A is responsible for NK cell ADCC and is regulated via cleavage upon NK activation. Non-cleavable CD16A improves ADCC killing and can be achieved through single-base substitution with BE.ResultsUsing the adenosine BE (ABE8e), we achieved multiplex editing (6 genes) rates up to 99% and 95% editing/knockout at DNA and protein levels, respectively. Notably, we assessed for reduction in editing efficiency when additional genes were targeted and found no significant reduction in editing efficiencies when targeting up to 6 genes simultaneously. Moreover, functional evaluation of non-cleavable CD16A NK cells revealed up to 35% increase of cytotoxicity against Raji cells.ConclusionsWe were able to achieve high multiplex editing efficiency in primary human NK cells using ABE8eand there was no significant decrease of editing efficiency as the number of gene of interest increases, up to 6 genes in total. Functional assay confirmed increased NK cell cytotoxicity against tumor cells. Our end goal is to achieve high efficiency multiplex editing in CAR-expressing NK cells to further improve NK cell activity and toxicity for cancer immunotherapy.ReferenceWebber B, Lonetree C, Kluesner M, et al. Highly efficient multiplex human T cell engineering without double-strand breaks usingCas9 base editors. Nat Commun 2019;10:5222.
284 Integrated molecular characterization of primary resistance mechanisms to immune checkpoint blockade in advanced non-small cell lung carcinoma (a-NSCLC)
Authors: Besse Benjamin , Colette DIB , Marquez Eladio , Lee Joon Sang , Yan Shu , Chiron Marielle , Combeau Cecile , Biancotto Angelique , Blanc-Durand Félix , Aldea Mihaela , Planchard David , Scoazec Jean-Yves , Lacroix Ludovic , Rouleau Etienne , Chaput-Gras Nathalie , Rafie Saloomeh , Marabelle Aurélien , Angevin Eric , Pollard Jack 
Published: November 2021

BackgroundReinvigoration of anti-tumor immunity via immune checkpoint blockade (ICB) has transformed outcomes in a-NSCLC. However, a majority of patients are innately resistant to ICB, and a better understanding of the resistance mechanisms may guide the development of new treatment strategies and therapies for patients.MethodsBiopsies performed immediately before treatment with single agent ICB in patients with a-NSCLC (MATCH-R trial [NCT02517892]) were analyzed. The stromal microenvironment and immune context were characterized via an integrated analysis of whole transcriptome (RNA-seq), whole exome sequencing (WES), and immunohistochemistry (IHC) of CD3, CD8, FOXP3 and PDL1. Specifically, the immune context and the relative abundance of 10 immune and stromal cell types were assessed with integrated IHC and Cell Populations-counter (MCP-counter) [1] analysis of the RNA-seq. Somatic mutations and Tumor Mutation Burden (TMB) were evaluated. The transcriptional state of the tumor and its microenvironment were assessed by GSVA analysis [2] of the MSigDB collection [3]. Patient‘s outcome was associated to molecular data. Primary resistance to ICB was defined as PD (progressive disease) in the first radiological examination, or a median PFS inferior to 3 months.ResultsFifty-two patients with NSCLC were enrolled (43 adeno, 6 squamous, and 3 other carcinoma): Median age was 61 (34–93), 18 were female, 46 were smokers, 22 were responders, and 30 were non-responders. Median tumor cellularity was 60% (30%–90%).Patients may be divided into two groups (HIGH and LOW) at baseline based on their degree of immune infiltration as assessed by RNAseq or IHC. A hallmark of the HIGH infiltration group is an increase in Interferon Gamma (IFN-γ) pathway signature [4]. In contrast, patients in the LOW infiltration group (relative to the HIGH infiltration group) exhibit a decrease in IFN-γ pathway signaling and concomitantly an increase in hypoxia and gluconeogenic pathway signatures. Response rates to ICB were not associated to immune infiltration groups at baseline, but an analysis within each infiltration group revealed that high TMB is only associated to response in the HIGH infiltration group. Furthermore, only in the LOW infiltration group was increased the transforming growth factor (TGF-β) pathway signature associated to ICB response.ConclusionsThis study suggests that the tumor and its microenvironment influence baseline immune infiltration. Tumors with LOW baseline infiltration show altered metabolism such as gluconeogenic activation and hypoxia activation. In contrast, factors such as TMB are not associated with baseline infiltration
295 Tumor cell- intrinsic expression of FGFR3 drives anti-PDL-1 immunotherapy resistance in a murine bladder cancer model
Authors: Fleming-Trujillo Erica , Bloodworth Jeffrey , Fernald Anthony , Ramsland Aubrianna , Gajewski Thomas , Sweis Randy 
Published: November 2021

BackgroundImmune checkpoint blockade therapy has recently shown efficacy in treating advanced urothelial bladder cancer and anti-PD-1/PD-L1 therapy is currently the standard of care. However, most patients do not respond to these drugs and resistance mechanisms remain elusive. The non-T cell-inflamed tumor microenvironment phenotype correlates with poor prognosis and immunotherapy resistance. We previously found that activating mutations in Fibroblast Growth Factor Receptor 3 (FGFR3) were exclusive to non-T cell-inflamed bladder cancers. We investigated the impact of tumor cell-intrinsic FGFR3 activation on T cell infiltration and tumor responsiveness to anti-PD-1/PD-L1 in a murine model.MethodsWe developed a syngeneic transplantable murine bladder cancer model using the MB49 cell line engineered to express FGFR3 with either the activating G370C mutation (FGFR3-G370C), a kinase-dead mutation K508M (FGFR3-K508M), a truncating mutation resulting in a secreted receptor (FGFR3-sec), or control. Mice were injected subcutaneously into flank and size was measured every 3 days along with PD-L1 therapy (BioXcell clone 10F.9G2). Tumors, draining lymph nodes, and spleens were harvested at endpoint for flow cytometry.ResultsTumors from mice inoculated with MB49-FGFR3-G370C cells showed diminished CD8+ T cell accumulation within the tumor and were resistant to anti-PD-L1 checkpoint blockade compared to MB49 controls. To determine if FGFR3-mediated immune resistance was dependent on FGFR3 kinase activity, MB49-FGFR3-K508M tumors were evaluated and unexpectedly found to be resistant to anti-PD-L1 treatment. Tumors with a secreted FGFR3 receptor (FGFR3-sec) retained responsiveness to anti-PD-L1 therapy.ConclusionsIn a murine bladder cancer model, FGFR3 activation led to relative T cell exclusion and resistance to immune checkpoint blockade. The mechanism of resistance was not dependent on receptor kinase activity. Further studies are ongoing to determine the biochemical mechanisms of FGFR3-mediated immunotherapy resistance in bladder cancer.
307 Interaction of anti-PD-1/PD-1 immunocomplexes with human FcRs: binding properties and functional implication
Authors: Daveri Elena , Luison Elena , Vallacchi Viviana , Vergani Barbara , Huber Veronica , Cova Agata , Leone Biagio Eugenio , Garassino Marina , Figini Mariangela , Rivoltini Licia 
Published: November 2021

BackgroundRescue of exhausted T cell immunity through the inhibition of PD-1/PD-L1 interaction is a pillar of immunotherapeutic anti-PD-1 monoclonal antibodies (mAbs), as Nivolumab and Pembrolizumab. Despite the IgG4 subclass, anti-PD-1 mAbs can bind different FcγRs and trigger immunosuppressive activity in FcR-expressing myeloid cells. This effect is evident when anti-PD-1 mAbs engage soluble PD-1 (sPD-1) forming a stable sPD-1-antiPD-1mAb immune complex (PD-1 IC). In the present study we dissect the process by investigating which of the FcγRs displays the highest affinity for monomeric or complexed Nivolumab. In addition, methods for detecting and quantifying PD-1 ICs in plasma of patients treated with PD-1 blockers mAbs are under development for clinical application.MethodsBy surface plasmon resonance (SRP) (BiacoreTM T200, Cytiva), the interaction of FcγRI/CD64, FcγRIIa/CD32a, FcγRIIb/CD32b, FcγRIIIa/CD16a and FcγRIIIb/CD16b with anti-PD1 Nivolumab and the corresponding PD-1-IC has been evaluated, and their cellular localization has been assessed by confocal microscopy. Further, sPD-1 and PD-1 IC has been determined by customized ELISAs and western blot approaches in plasma of anti-PD-1 mAb-treated patients.ResultsThe binding of anti-PD1 and PD-1-IC occurred with all the FcγRs tested, albeit sensorgrams revealed diverse degrees of affinity. No major difference in the overall affinity of the monomeric anti-PD-1 versus PD-1 IC is observed for FcγRI/CD64, FcγRIIa/CD32a, FcγRIIb/CD32b. Instead, the dissociation phase was clearly slowest for PD-1 IC with respect to the monomeric mAb in FcγRIIIa/CD16a and FcγRIIIb/CD16b binding studies. Nevertheless, only PD-1 IC undergoes internalization when interacting with human FcγR+ myeloid cells in vitro, through pathways that does not appear to lead to lysosomal co-localization. Customized ELISA for PD-1 IC quantification has been developed to detect the complex after enrichment of plasma IgG4 by specific matrix. Data concerning the evaluation of PD-1 IC concentration in plasma of cancer patients treated with Nivolumab, will be presented.ConclusionsDespite the IgG4 subclass is expected to display the lowest binding affinity to Fcγs, we report here that anti-PD-1 therapeutic antibodies bind significantly to CD16, CD32 and CD64, particularly if stabilized in the IC form by engaging soluble PD-1. This evidence, if occurring in vivo, could introduce novel functional properties to these therapeutic agents, with potential detrimental effects on their clinical efficacy. Our findings imply that tools to antagonize PD-1-related exhaustion by Fc-null mAbs or non-mAb-based strategies could be preferred to engage full-fledged antitumor immune responses without unwanted effects related to FcR triggering.
377 Characterization of peripheral biomarkers of GS-1423, a first in class bifunctional anti-CD73-TGFβ receptor II- trap molecule, in a phase 1 dose escalation study in patients with advanced solid tumors
Authors: Zavodovskaya Marianna , Tolcher Anthony , Gordon Michael , Strauss James , Mahoney Kathleen , Yi Ping Cheng , Sorensen Rick , Yang Xiaoyun , Lin Kai-Wen , Li Biao , Seto Anna , Peach Matthew , Goddard Audrey , Chen Tianling , Jürgensmeier Juliane 
Published: November 2021

BackgroundGS-1423 is a first-in-class bifunctional molecule comprised of an anti-CD73 antibody fused to the extracellular domain of TGFβ receptor II (TGFβRII). GS-1423 is designed to inhibit CD73-mediated adenosine production and neutralize active TGFβ within the tumor microenvironment. Dual antagonism of these 2 broadly immunosuppressive barriers is anticipated to facilitate productive anti-tumor immunity.MethodsThis open label Phase 1a study (NCT03954704) evaluated the safety, tolerability, and pharmacokinetics of GS-1423. Exploratory biomarkers included the evaluation of the inhibition of GS-1423 targets, i.e.CD73 and TGFβ, in the periphery. Biomarker assessments were performed in serial blood samples from patients receiving GS-1423 every two weeks (Q2W). Biomarker assays, unless otherwise stated, were custom built and qualified to measure the following: 1) TGF-beta 1/2/3 (Luminex, Bio-Rad) in platelet poor plasma, 2) CD73 target occupancy (TO) on B and CD8 T cells in whole blood, 3) free soluble CD73 (sCD73) not bound to GS-1423, and 4) sCD73 activity in platelet poor plasma. Biomarker values were plotted longitudinally by patient and by dose.ResultsA dose dependent decrease in TGF-beta 1/2/3 in plasma of patients was observed on treatment. There was no detectable TGFβ at the 20 mg/kg dose level and above at 2 hours post first dose and for the duration of the Q2W dosing interval. A dose dependent increase in CD73 TO on B and CD8 T cells was also observed with treatment, and complete TO was achieved at 20 mg/kg and above at 2 hours post first dose for the duration of the Q2W dosing interval. Free sCD73 decreased at 2 hours post first dose, while remaining above the lower limit of quantitation, and then increased above baseline after 24 hours post-dose at the 3 mg/kg dose level and above. The sCD73 activity in blood correlated with changes in free sCD73 levels.ConclusionsBlood biomarker analyses of GS-1423 in patients with advanced solid tumors demonstrated undetectable soluble TGFβ1/2/3 and complete TO of CD73 on B and T cells at the 20 mg/kg dose level and above. The mechanism underlying the increase in sCD73 following GS-1423 treatment remains to be elucidated.Ethics ApprovalThe study obtained ethics approval from the IRB/IEC and all participants gave informed consent before taking part in the study.
Circumventing tobacco control and safety policies to promote waterpipe use in smoking venues: the perspective of staff in waterpipe smoking venues
Authors: Lee Jung Jae , Yeung Karly Cheuk Yin , Wang Man Ping , Thorne Sally , Tong Henry Sau Chai , Lai Vienna 
Published: November 2021

ObjectiveTo understand Hong Kong waterpipe smoking (WPS) sales and promotion, including strategies to avoid policy enforcement, from the perspective of WPS venue staff.MethodsQualitative interviews and observations were guided by interpretive description. 20 WPS venue staff who were responsible for preparing and serving waterpipes to patrons and had worked at the bar for at least 3 months were recruited. In-depth semistructured interviews with WPS venue staff were conducted, in addition to covert and participant observations in 10 WPS venues in Hong Kong. Interpretive description involving constant comparative analysis of qualitative data was adopted to facilitate an inductive analytic approach to generate findings.ResultsTwo primary themes emerged from analyses of interview and observation data: strategies to avoid law enforcement, and perceived health and safety concerns linked to working and smoking in waterpipe venues. The findings suggest that many Hong Kong venues may be failing to comply with tobacco control policies and developing strategies to circumvent law enforcement. Moreover, waterpipe preparation, allowance of WPS and burning of charcoal in indoor areas were perceived as negatively affecting the health and safety of staff and customers.ConclusionsThe study provides preliminary evidence indicating the ineffectiveness of current tobacco control policy on WPS. Due to its risks to health and safety, and the need to sustain tobacco control efforts for their intended purpose, waterpipe-specific regulations and stricter surveillance on waterpipe sales and promotion are urgently required.