bluuebunny/crossref_metadata_2025_split huggingface dataset:
3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib
Authors: Meraz Ismail M. , Majidi Mourad , Fang Bingliang , Meng Feng , Gao Lihui , Shao RuPing , Song Renduo , Li Feng , Ha Min Jin , Wang Qi , Wang Jing , Shpall Elizabeth , Jung Sung Yun , Haderk Franziska , Gui Philippe , Riess Jonathan Wesley , Olivas Victor , Bivona Trever G , Roth Jack A. 
Published: December 2021

AbstractOsimertinib sensitive and resistant NSCLC NCI-H1975 clones were used to model osimertinib acquired resistance in humanized mice and delineate potential resistance mechanisms. No new EGFR mutations or loss of the EGFR T790M mutation were found in resistant clones. Resistant tumors in humanized mice were initially partially responsive to osimertinib, then aggressive tumor regrowth occurred accompanied by an immunosuppressive tumor microenvironment. 3-phosphoinositide-dependent kinase 1 (PDK1) was identified as a potential driver of osimertinib acquired resistance, and its selective inhibition by BX795 and CRISPR gene knock out, sensitized resistant clones and a patient derived xenograft (PDX) with acquired resistance to osimertinib. PDK1 knock-out dysregulated PI3K/Akt/mTOR signaling, promoted cell cycle arrest at the G1 phase, and inhibited nuclear translocation of yes-associated protein (YAP). Higher expression of PDK1 was found in patients with progressive disease following osimertinib treatment. PDK1 is a central upstream regulator of two critical drug resistance pathways: PI3K/AKT/mTOR and YAP.
Proteome Microarray Screening Identifies Human Polyphosphate-Binding Proteins in the Phosphatidylinositol Signaling Pathway
Authors: Krenzlin Viola , Roewe Julian , Strueve Marcel , Martínez-Negro María , Reinhardt Christoph , Morsbach Svenja , Bosmann Markus 
Published: December 2021

AbstractPolyphosphates are linear chains of orthophosphate residues that are present in all living cells. Polyphosphates are released from platelet d-granules and are also produced in bacteria. Polyphosphates are procoagulant in mammalian species and in bacteria are required for energy and phosphate storage, stress resistance, chelation of metal ions and escaping host immunity. Despite these pleiotropic effects, sparse information is available on molecular binding partners of polyphosphates. Here, we used a slide-based human proteome microarray screen for the search of polyphosphate-binding proteins. This approach suggested several novel proteins with relation to the phosphatidylinositol signaling pathway. The highest signals were obtained for Disabled-1 (DAB1) and phosphatidylinositol-5-phosphate 4-kinase 2B (PIP4K2B). Isothermal titration calorimetry was used for confirmation of DAB1 interactions with long-chain polyphosphates. These results offer new rationale to further investigate the interference of polyphosphates with intracellular signaling pathways.
Combined Pan-, Population-, and Phylo-Genomic Analysis of Aspergillus fumigatus Reveals Population Structure and Lineage-Specific Diversity
Authors: Lofgren Lotus A. , Ross Brandon S. , Cramer Robert A. , Stajich Jason E. 
Published: December 2021

ABSTRACTAspergillus fumigatus is a deadly agent of human fungal disease, where virulence heterogeneity is thought to be at least partially structured by genetic variation between strains. While population genomic analyses based on reference genome alignments offer valuable insights into how gene variants are distributed across populations, these approaches fail to capture intraspecific variation in genes absent from the reference genome. Pan-genomic analyses based on de novo assemblies offer a promising alternative to reference-based genomics, with the potential to address the full genetic repertoire of a species. Here, we use a combination of population genomics, phylogenomics, and pan-genomics to assess population structure and recombination frequency, phylogenetically structured gene presence-absence variation, evidence for metabolic specificity, and the distribution of putative antifungal resistance genes in A. fumigatus. We provide evidence for three primary populations of A. fumigatus, structured by both gene variation (SNPs and indels) and distinct gene presence-absence variation with unique suites of accessory genes present exclusively in each clade. Accessory genes displayed functional enrichment for nitrogen and carbohydrate metabolism, suggesting that populations may be stratified by environmental niche specialization. Similarly, the distribution of antifungal resistance genes and resistance alleles were often structured by phylogeny. A. fumigatus demonstrated exceptionally high levels of recombination and one of the largest fungal pan-genomes reported to date including many genes unrepresented in the Af293 reference genome. These results highlight the inadequacy of relying on a single-reference genome-based approach for evaluating intraspecific variation, and the power of combined genomic approaches to elucidate population structure, genetic diversity, and putative ecological drivers of clinically relevant fungi.
Improved neutralisation of the SARS-CoV-2 Omicron variant after Pfizer-BioNTech (BNT162b2) COVID-19 vaccine boosting with a third dose
Authors: Basile Kerri , Rockett Rebecca J , McPhie Kenneth , Fennell Michael , Johnson-Mackinnon Jessica , Agius Jessica E , Fong Winkie , Rahman Hossinur , Ko Danny , Donavan Linda , Hueston Linda , Lam Connie , Arnott Alicia , Chen Sharon C-A , Maddocks Susan , O’Sullivan Matthew V , Dwyer Dominic E , Sintchenko Vitali , Kok Jen 
Published: December 2021

AbstractIn late November 2021, the World Health Organization declared the SARS-CoV-2 lineage B.1.1.529 the fifth variant of concern, Omicron. This variant has acquired 15 mutations in the receptor binding domain of the spike protein, raising concerns that Omicron could evade naturally acquired and vaccine-derived immunity. We utilized an authentic virus, multicycle neutralisation assay to demonstrate that sera collected one, three and six months post-two doses of Pfizer-BioNTech BNT162b2 has a limited ability to neutralise SARS-CoV-2. However, four weeks after a third dose, neutralising antibody titres are boosted. Despite this increase, neutralising antibody titres are reduced four-fold for Omicron compared to lineage A.2.2 SARS-CoV-2.
Impaired dynamics of prefrontal beta-band networks during cognitive action control in Parkinson’s disease
Authors: Duprez Joan , Tabbal Judie , Hassan Mahmoud , Modolo Julien , Kabbara Aya , Mheich Ahmad , Drapier Sophie , Vérin Marc , Sauleau Paul , Wendling Fabrice , Benquet Pascal , Houvenaghel Jean-François 
Published: December 2021

AbstractAmong the cognitive symptoms that are associated with Parkinson’s disease (PD), alterations in cognitive action control (CAC) are commonly reported in patients. CAC enables the suppression of an automatic action, in favor of a goal-directed one. The implementation of CAC is time-resolved and arguably associated with dynamic changes in functional brain networks. However, the electrophysiological functional networks involved, their dynamic changes, and how these changes are affected by PD, still remain unknown. In this study, to address this gap of knowledge, 21 PD patients and 10 healthy controls (HC) underwent a Simon task while high-density electroencephalography (HD-EEG) was recorded. Source-level dynamic connectivity matrices were estimated using the phase-locking value in the beta (12-25 Hz) and gamma (30-45 Hz) frequency bands. Temporal independent component analyses were used as a dimension reduction tool to isolate the group-specific brain network states that were dominant during the task. Typical microstate metrics were quantified to investigate the presence of these states at the subject-level. Our results first confirmed that PD patients experienced difficulties in inhibiting automatic responses during the task. At the group-level, HC displayed a significant functional network state that involved typical CAC-related prefrontal and cingulate nodes (e.g., inferior frontal cortex). Both group- and subject-level analyses showed that this network was less present in PD to the benefit of other networks involving lateralized temporal and insular components. The presence of this prefrontal network was associated with decreased reaction time. In the gamma band, two networks (fronto-cingulate and fronto-temporal) followed one another in HC, while 3 partially overlapping networks that included fronto-temporal, fronto-occipital and cross-hemispheric temporal connections were found in PD. At the subject-level, differences between PD and HC were less marked. Altogether, this study showed that the functional brain networks observed during CAC and their temporal changes were different in PD patients as compared to HC, and that these differences partially relate to behavioral changes. This study also highlights that task-based dynamic functional connectivity is a promising approach in understanding the cognitive dysfunctions observed in PD and beyond.HighlightsCognitive action control is associated with dynamic functional networksPrefrontal and cingulate beta connectivity are prominent in healthy controlsPD patients have different dynamic networks in which prefrontal nodes are absentThe occurrence of prefrontal beta networks was associated with a decreased reaction timeFunctional networks in the gamma band were temporally organized in HC, but overlapping in PD patients
Adaptive discrimination of antigen risk by predictive coding in immune system
Authors: Yoshido Kana , Naoki Honda 
Published: December 2021

AbstractThe immune system discriminates between harmful and harmless antigens based on past experiences; however, the underlying mechanism is largely unknown. From the viewpoint of machine learning, the learning system predicts the observation and updates the prediction based on prediction error, a process known as ‘predictive coding’. Here, we modeled the population dynamics of T cells by adopting the concept of predictive coding; helper and regulatory T cells predict the antigen amount and excessive immune response, respectively. Their prediction error signals, possibly via cytokines, induce their differentiation to memory T cells. Through numerical simulations, we found that the immune system identifies antigen risks depending on the concentration and input rapidness of the antigen. Further, our model reproduced history-dependent discrimination, as in allergy onset and subsequent therapy. Together, this study provided a novel framework to improve our understanding of how the immune system adaptively learns the risks of diverse antigens.
Personalized models of breast cancer desmoplasia reveal biomechanical determinants of drug penetration
Authors: Offeddu Giovanni S. , Cambria Elena , Shelton Sarah E. , Wan Zhengpeng , Haase Kristina , Possenti Luca , Nguyen Huu Tuan , Gillrie Mark R. , Hickman Dean , Knutson Charles G. , Kamm Roger D. 
Published: December 2021

ABSTRACTBreast cancer desmoplasia heterogeneity contributes to high disease mortality due to discrepancies in treatment efficacy between patients. Personalizedin vitrobreast cancer models can be used for high throughput testing and ranking of therapeutic strategies to normalize the aberrant microenvironment in a patient-specific manner. Here, tumoroids assembled from patient-derived cells cultured in microphysiological systems including perfusable microvasculature reproduce key aspects of stromal and vascular dysfunction. Increased hyaluronic acid and collagen deposition, loss of vascular glycocalyx and reduced perfusion, and elevated interstitial fluid pressure in the models result in impaired drug distribution to tumor cells. We demonstrate the application of these personalized models as tools to rank molecular therapies for the normalization of the tumoroid microenvironment and to discover new therapeutic targets such as IL8 and CD44, which may ultimately improve drug efficacy in breast cancer patients.
Dehalobium species implicated in 2,3,7,8-tetrachloro-p-dioxin dechlorination in the contaminated sediments of Sydney Harbour Estuary
Authors: Lee Matthew , Liang Gan , Holland Sophie I. , O’Farrell Casey , Osbourne Keith , Manefield Michael J. 
Published: December 2021

AbstractPolychlorinated dibenzo-p-dioxins and furans (PCDD/F) are some of the most environmentally recalcitrant and toxic compounds. They are naturally occurring and by-products of anthropogenic activity. Sydney Harbour Estuary (Sydney, Australia), is heavily contaminated with PCDD/F. Analysis of sediment cores revealed that the contamination source in Homebush Bay continues to have one of the highest levels of PCDD/F contamination in the world (5207 pg WHO-TEQ g-1) with >50% of the toxicity attributed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD) the most toxic and concerning of the PCDD/F congeners. Comparison of congener profiles at the contamination source with surrounding bays and historical data provided evidence for the attenuation of 2,3,7,8-TCDD and other congeners at the source. This finding was supported by the detection of di-, mono- and unchlorinated dibenzo-p-dioxin. Microbial community analysis of sediments by 16S amplicon sequencing revealed an abundance of lineages from the class Dehalococcoidia (up to 15% of the community), including the genus Dehalobium (up to 0.5%). Anaerobic seawater enrichment cultures using perchloroethene as a more amenable growth substrate enriched only the Dehalobium population by more than six-fold. The enrichment culture then proved capable of reductively dechlorinating 2,3,7,8-TCDD to 2,3,7-TCDD and octachlorodibenzo-p-dibenzodioxin to hepta and hexa congeners. This work is the first to show microbial reductive dehalogenation of 2,3,7,8-TCDD with a bacterium from outside the Dehalococcoides genus, and one of only a few that demonstrates PCDD/F degradation in a marine environment.
In vitro validation of neoantigen prediction algorithm for developing personalized cancer vaccine therapy
Authors: Choe Yun-jeong , Kim Eunyoung , Oh Jooyeon , Jang Miran , Fu Weixan , Lee Hanna , Chung Minho , Pyo Kyung-Ho , Synn Chung-Bong , Kim Sora , Yang Yohan , Kim Ahyeon , Cho Byung Chul , Kim Han Sang , Kim Sangwoo , Carreno Beatriz , Kim Jee Ye , Paik Soonmyung 
Published: December 2021

ABSTRACTBackgroundThe development of personalized neoantigen-based therapeutic cancer vaccines relies on computational algorithm-based pipelines. One of the critical issues in the pipeline is obtaining higher positive predictive value (PPV) performance, i.e., how many are immunogenic when selecting the top 5 to 20 candidate neoepitopes for the vaccination. We attempted to test the PPV of a neoepitope prediction algorithm Neopepsee.MethodsSix breast cancer patients and patient-derived xenografts from three lung cancer patients and their paired peripheral blood samples were subjected to whole-exome and RNA sequencing. Neoantigen was predicted using two different algorithms (Neopepsee and pVACseq). Response of induced memory T cells to neopeptide candidates was evaluated by IFN-γ Enzyme-linked immune absorbent spot (ELISpot) assays of peripheral blood mononuclear cell (PBMC) from three HLA-matched donors. Positive ELISpot response to a candidate peptide in at least 2 of 3 donor PBMC was regarded as an immunogenic response.ResultsNeopepsee predicted 159 HLA-A matched neoepitope candidates out of 898 somatic mutations in nine patients (six breast and three lung cancer patients), whereas pVACseq predicted 84 HLA-A matched candidates. A total of 26 neopeptide candidates overlapped between the two predicted candidate pools. Among the candidates, 28 (20%, 28/ 137) and 15 (20%, 15/ 75) were positive by ELISpot assay, respectively. Among 26 overlapped candidates, 20 could be tested, and 7 of them (35%) were validated by ELISpot. Neopepsee identified at least one neoepitope in 7 of 9 patients (range 0-6), compared to 6 by pVACseq (range 0-5).ConclusionAs suggested by Tumor Neoantigen Selection Alliance (TESLA), our results demonstrate low PPV of individual prediction models as well as the complementary nature of the Neopepsee and pVACseq and may help design neoepitope targeted cancer vaccines. Our data contribute a significant addition to the database of tested neoepitope candidates that can be utilized to further train and improve the prediction algorithms.
Proteomics analysis in urinary bladder cancer patients identifies urinary SOD2 as a predictive marker of recurrence
Authors: Kumari Nitu , Bishwal Subasa Chandra , Chaudhary Shweta , Malalkar Deepankar , Dubey Uma S. , Vasudeva Pawan , Kumar Anup , Saxena Sunita , Nanda Ranjan Kumar , Agrawal Usha 
Published: December 2021

AbstractEarly non-invasive detection of tumor is an urgent clinical need for managing urothelial bladder cancer. Cystoscopy and cytology are the current standards for diagnosis of recurrence, but are limited by low sensitivity. Quantitative proteomics tool was employed to identify important deregulated molecules in bladder cancer tissues and validated using Western blot and immunohistochemistry analysis. A set of 1137 proteins were identified in four paired bladder cancer patients. Among these, 64 proteins were deregulated in all cases among which 9 were commonly up-regulated. The Ingenuity Pathway Analysis (IPA) generated top 11 Networks in which three commonly upregulated (SERPING1, SOD2 and HSPB6) proteins were involved and selected for further validation. Tissue expression of SOD2, SERPING1 and HSPB6 monitored in an independent sample set (n=18) by immuno-histochemical analysis showed similar profile. Western blot analysis of these proteins in urine of bladder cancer (n=26) and healthy subjects (n=10) showed a specificity and sensitivity of >80% for SOD2 and so was selected for further validation in a separate set (n=150) by ELISA. Significant elevation in urinary SOD2 level was found in urothelial bladder cancer patients compared to healthy controls and in recurrent cases compared to primary (p-value<0.001). Kaplan Meier survival analysis showed urinary SOD2 concentration >2,100 pg/ml was significantly associated with poorer survival.Cumulative survival of patient with low SOD2 concentration was 34.4% compared to 18.9% in patient with high SOD2 at 24 months (p=0.025). The study identifies SOD2 as a non-invasive biomarker which may help to extend the period between cystoscopies during follow-up.SignificanceCystoscopy is an invasive and painful method commonly used for diagnosis of urothelial bladder cancer. Non-invasive methods having high specificity and sensitivity to monitor the patients for recurrence are unavailable. Our study reveals significantly higher SOD2 level in drug naive and reoccurring bladder cancer tissues, and similar profile was observed in the parallel urine samples. Hence, SOD2 seems to be a useful biomarker of recurrent urothelial bladder cancer and predict the survival of patients.
Broad anti-SARS-CoV-2 antibody immunity induced by heterologous ChAdOx1/mRNA-1273 prime-boost vaccination
Authors: Kaku Chengzi I. , Champney Elizabeth R. , Normark Johan , Johnson Carl E. , Ahlm Clas , Sakharkar Mrunal , Ackerman Margaret E. , Forsell Mattias N. E. , Walker Laura M. 
Published: December 2021

AbstractHeterologous prime-boost immunization strategies have the potential to augment COVID-19 vaccine efficacy and address ongoing vaccine supply challenges. Here, we longitudinally profiled SARS-CoV-2 spike (S)-specific serological and memory B cell (MBC) responses in individuals receiving either homologous (ChAdOx1:ChAdOx1) or heterologous (ChAdOx1:mRNA-1273) prime-boost vaccination. Heterologous mRNA booster immunization induced significantly higher serum neutralizing antibody and MBC responses compared to homologous ChAdOx1 boosting. Specificity mapping of circulating S-specific B cells revealed that mRNA-1273 booster immunization dramatically immunofocused ChAdOx1-primed responses onto epitopes expressed on prefusion-stabilized S. Monoclonal antibodies isolated from mRNA-1273-boosted participants displayed higher binding affinities and increased breadth of reactivity against variants of concern (VOCs) relative to those isolated from ChAdOx1-boosted participants. Overall, the results provide fundamental insights into the B cell response induced by ChAdOx1 and a molecular basis for the enhanced immunogenicity observed following heterologous mRNA booster vaccination.
Durability of mRNA-1273 against COVID-19 in the time of Delta: Interim results from an observational cohort study
Authors: Florea Ana , Sy Lina S. , Luo Yi , Qian Lei , Bruxvoort Katia J. , Ackerson Bradley K. , Lee Gina S. , Ku Jennifer H. , Tubert Julia E. , Tian Yun , Talarico Carla A. , Tseng Hung Fu 
Published: December 2021

AbstractBackgroundWe conducted a prospective cohort study at Kaiser Permanente Southern California to study the vaccine effectiveness (VE) of mRNA-1273 over time and during the emergence of the Delta variant.MethodsThe cohort for this planned interim analysis consisted of individuals aged ≥18 years receiving 2 doses of mRNA-1273 through June 2021, matched 1:1 to randomly selected unvaccinated individuals by age, sex, and race/ethnicity, with follow-up through September 2021. Outcomes were SARS-CoV-2 infection, and COVID-19 hospitalization and hospital death. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHR) with 95% confidence intervals (CIs) comparing outcomes in the vaccinated and unvaccinated groups. Adjusted VE (%) was calculated as (1-aHR)x100. HRs and VEs were also estimated for SARS-CoV-2 infection by age, sex, race/ethnicity, and during the Delta period (June-September 2021). VE against SARS-CoV-2 infection and COVID-19 hospitalization was estimated at 0-<2, 2-<4, 4-<6, and 6-<8 months post-vaccination.Results927,004 recipients of 2 doses of mRNA-1273 were matched to 927,004 unvaccinated individuals. VE (95% CI) was 82.8% (82.2-83.3%) against SARS-CoV-2 infection, 96.1% (95.5-96.6%) against COVID-19 hospitalization, and 97.2% (94.8-98.4%) against COVID-19 hospital death. VE against SARS-CoV-2 infection was similar by age, sex, and race/ethnicity, and was 86.5% (84.8-88.0%) during the Delta period. VE against SARS-CoV-2 infection decreased from 88.0% at 0-<2 months to 75.5% at 6-<8 months.ConclusionsThese interim results provide continued evidence for protection of 2 doses of mRNA-1273 against SARS-CoV-2 infection over 8 months post-vaccination and during the Delta period, and against COVID-19 hospitalization and hospital death.SummaryThis prospective cohort study provides evidence for continued protection of 2 doses of mRNA-1273 against SARS-CoV-2 infection over 8 months post-vaccination and during the Delta period. VE against COVID-19 hospitalization remained robust and stable over the same period.