bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Neoadjuvant Paclitaxel/Trastuzumab/Pertuzumab on Breast Tumor Downsizing for Patients with HER2+ Breast Cancer: Single-Arm Prospective Clinical Trial
Authors: Weiss Anna , Li Tianyu , Desai Neelam V , Tung Nadine M , Poorvu Philip D , Partridge Ann H , Nakhlis Faina , Dominici Laura , Sinclair Natalie , Spring Laura M , Faggen Meredith , Constantine Michael , Krop Ian E , DeMeo Michelle , Wrabel Eileen , Alberti Jillian , Chikarmane Sona , Tayob Nabihah , King Tari A , Tolaney Sara M , Winer Eric P , Mittendorf Elizabeth A , Waks Adrienne G 
Published: May 2023

BACKGROUND:
The impact of abbreviated neoadjuvant regimens for HER2+ breast cancer on rates of breast conservation therapy (BCT) is unclear. We aimed to determine BCT rates in a single-arm prospective trial of neoadjuvant paclitaxel/trastuzumab/pertuzumab (THP) in patients with stage II or III HER2+ breast cancer.

STUDY DESIGN:
BCT eligibility was prospectively recorded before and after THP. Pre- and posttreatment mammogram and breast ultrasound were required; breast MRI was encouraged. Patients with a large tumor to breast size ratio were eligible for downsizing. Multifocal/multicentric tumors, extensive calcifications, and contraindications to radiation were considered BCT contraindications.

RESULTS:
Overall, 92 patients who received neoadjuvant THP on trial were included. At presentation, 39 (42.4%) were considered eligible for BCT and 53 (57.6%) were not. BCT-eligible patients were older (median 54 vs 47 years, respectively; p = 0.006) and had smaller tumors by palpation (median 2.5 vs 3 cm, respectively; p = 0.004). Of 53 BCT-ineligible patients, 28 were candidates for tumor downsizing, whereas 25 had contraindications to BCT. Overall, 51 (55.4%) patients underwent BCT. Of the 28 patients who were candidates for downsizing, 22 (78.6%) became BCT-eligible after THP and 18 of 22 (81.8%) underwent BCT. In total, 44 of 92 (47.8%) patients experienced breast pathologic complete response (ypT0), including 11 of 25 (44.0%) patients with BCT contraindications at presentation.

CONCLUSIONS:
De-escalated neoadjuvant systemic therapy led to high BCT rates in this cohort. The impact of de-escalated systemic therapy on local therapy and outcomes in early stage HER2+ breast cancer warrants further investigation.
Stimulator of interferon genes is required for Toll-Like Receptor-8 induced interferon response
Authors: García-Martínez K. , Chen J. , Jones J. , Woo A. , Aucapina A. , Brito I. , Leifer CA 
Published: May 2023

AbstractThe innate immune system is equipped with multiple receptors to detect microbial nucleic acids and induce type I interferon (IFN) to restrict viral replication. When dysregulated these receptor pathways induce inflammation in response to host nucleic acids and promote development and persistence of autoimmune diseases like Systemic Lupus Erythematosus (SLE). IFN production is regulated by the Interferon Regulatory Factor (IRF) transcription factor family of proteins that function downstream of several innate immune receptors such as Toll-like receptors (TLRs) and Stimulator of Interferon Genes (STING). Although both TLRs and STING activate the same downstream molecules, the pathway by which TLRs and STING activate IFN response are thought to be independent. Here we show that STING plays a previously undescribed role in human TLR8 signaling. Stimulation with the TLR8 ligands induced IFN secretion in primary human monocytes, and inhibition of STING reduced IFN secretion from primary monocytes from 8 healthy donors. We demonstrate that TLR8-induced IRF activity was reduced by STING inhibitors. Moreover, TLR8-induced IRF activity was blocked by inhibition or loss of IKKε, but not TBK1. Bulk RNA transcriptomic analysis supported a model where TLR8 induces transcriptional responses associated with SLE that can be downregulated by inhibition of STING. These data demonstrate that STING is required for full TLR8-to-IRF signaling and provide evidence for a new framework of crosstalk between cytosolic and endosomal innate immune receptors, which could be leveraged to treat IFN driven autoimmune diseases.BackgroundHigh levels of type I interferon (IFN) is characteristic of multiple autoimmune diseases, and while TLR8 is associated with autoimmune disease and IFN production, the mechanisms of TLR8-induced IFN production are not fully understood.ResultsSTING is phosphorylated following TLR8 signaling, which is selectively required for the IRF arm of TLR8 signaling and for TLR8-induced IFN production in primary human monocytes.ConclusionSTING plays a previously unappreciated role in TLR8-induced IFN productionSignificanceNucleic acid-sensing TLRs contribute to development and progression of autoimmune disease including interferonopathies, and we show a novel role for STING in TLR-induced IFN production that could be a therapeutic target.
Synergistic activity of IL-2 mutein with tolerogenic ImmTOR nanoparticles leads to massive expansion of antigen-specific Tregs and protection against autoimmune disease
Authors: Kishimoto Takashi Kei , Fournier Max , Michaud Alicia , Rizzo Gina , Roy Christopher , Capela Teresa , Nukolova Natasha , Li Ning , Doyle Liam , Fu Fen-ni , VanDyke Derek , Traber Peter G. , Spangler Jamie B. , Leung Sheldon S. , Ilyinskii Petr O. 
Published: May 2023

AbstractLow dose IL-2 therapy and IL-2 molecules engineered to be selective for the high affinity IL-2 receptor have been shown to expand Tregs in vivo, and, in the case of low dose IL-2 therapy, has demonstrated promising therapeutic benefit in autoimmune diseases. One of the potential limitations of IL-2 therapy is the nonselective expansion of pre-existing Treg populations rather than induction of antigen-specific Tregs, as well as potential activation of effector cells. We have recently developed biodegradable nanoparticles encapsulating rapamycin, called ImmTOR, to induce selective immune tolerance to co-administered antigens, such as immunogenic biologic drugs. Unlike Treg-selective IL-2 therapy, ImmTOR alone does not increase total Treg numbers. However, here we demonstrate that the combination of ImmTOR and an engineered Treg-selective IL-2 variant (termed IL-2 mutein) increases the number and durability of total Tregs, as well as inducing a profound synergistic increase in antigen-specific Treg when combined with a target antigen. We demonstrate that the combination of ImmTOR and an IL-2 mutein leads to durable inhibition of antibody responses to co-administered AAV gene therapy capsid, even at sub-optimal doses of ImmTOR, and provides protection in autoimmune models of type 1 diabetes and primary biliary cholangitis. ImmTOR also showed the potential to increase the therapeutic window of engineered IL-2 molecules by mitigating effector T cell expansion typically observed at higher doses of IL-2 and preventing exacerbation of disease in a model of graft-versus-host-disease. At the same time, engineered IL-2 molecules showed potential for dose-sparing of ImmTOR. Overall, these results establish that the combination of ImmTOR and an IL-2 mutein show synergistic benefit on both safety and efficacy to provide durable antigen-specific immune tolerance to mitigate drug immunogenicity and to treat autoimmune diseases.
Global stability and parameter analysis reinforce therapeutic targets of PD-L1-PD-1 and MDSCs for glioblastoma
Authors: Anderson Hannah G. , Takacs Gregory P. , Harris Duane C. , Kuang Yang , Harrison Jeffrey K. , Stepien Tracy L. 
Published: May 2023

AbstractGlioblastoma (GBM) is an aggressive primary brain cancer that currently has minimally effective treatments. Like other cancers, immunosuppression by the PD-L1-PD-1 immune checkpoint complex is a prominent axis by which glioma cells evade the immune system. Myeloid-derived suppressor cells (MDSCs), which are recruited to the glioma microenviroment, also contribute to the immunosuppressed GBM microenvironment by suppressing T cell functions. In this paper, we propose a GBM-specific tumor-immune ordinary differential equations model of glioma cells, T cells, and MDSCs to provide theoretical insights into the interactions between these cells. Equilibrium and stability analysis indicates that there are unique tumorous and tumor-free equilibria which are locally stable under certain conditions. Further, the tumor-free equilibrium is globally stable when T cell activation and the tumor kill rate by T cells overcome tumor growth, T cell inhibition by PD-L1-PD-1 and MDSCs, and the T cell death rate. Bifurcation analysis suggests that a treatment plan that includes surgical resection and therapeutics targeting immune suppression caused by the PD-L1-PD1 complex and MDSCs results in the system tending to the tumor-free equilibrium. Using a set of preclinical experimental data, we implement the Approximate Bayesian Computation (ABC) rejection method to construct probability density distributions that estimate model parameters. These distributions inform an appropriate search curve for global sensitivity analysis using the extended Fourier Amplitude Sensitivity Test (eFAST). Sensitivity results combined with the ABC method suggest that parameter interaction is occurring between the drivers of tumor burden, which are the tumor growth rate and carrying capacity as well as the tumor kill rate by T cells, and the two modeled forms of immunosuppression, PD-L1-PD-1 immune checkpoint and MDSC suppression of T cells. Thus, treatment with an immune checkpoint inhibitor in combination with a therapeutic targeting the inhibitory mechanisms of MDSCs should be explored.
The ENCODE4 long-read RNA-seq collection reveals distinct classes of transcript structure diversity
Authors: Reese Fairlie , Williams Brian , Balderrama-Gutierrez Gabriela , Wyman Dana , Çelik Muhammed Hasan , Rebboah Elisabeth , Rezaie Narges , Trout Diane , Razavi-Mohseni Milad , Jiang Yunzhe , Borsari Beatrice , Morabito Samuel , Liang Heidi Yahan , McGill Cassandra J. , Rahmanian Sorena , Sakr Jasmine , Jiang Shan , Zeng Weihua , Carvalho Klebea , Weimer Annika K. , Dionne Louise A. , McShane Ariel , Bedi Karan , Elhajjajy Shaimae I. , Upchurch Sean , Jou Jennifer , Youngworth Ingrid , Gabdank Idan , Sud Paul , Jolanki Otto , Strattan J. Seth , Kagda Meenakshi S. , Snyder Michael P. , Hitz Ben C. , Moore Jill E. , Weng Zhiping , Bennett David , Reinholdt Laura , Ljungman Mats , Beer Michael A. , Gerstein Mark B. , Pachter Lior , Guigó Roderic , Wold Barbara J. , Mortazavi Ali 
Published: May 2023

The majority of mammalian genes encode multiple transcript isoforms that result from differential promoter use, changes in exonic splicing, and alternative 3’ end choice. Detecting and quantifying transcript isoforms across tissues, cell types, and species has been extremely challenging because transcripts are much longer than the short reads normally used for RNA-seq. By contrast, long-read RNA-seq (LR-RNA-seq) gives the complete structure of most transcripts. We sequenced 264 LR-RNA-seq PacBio libraries totaling over 1 billion circular consensus reads (CCS) for 81 unique human and mouse samples. We detect at least one full-length transcript from 87.7% of annotated human protein coding genes and a total of 200,000 full-length transcripts, 40% of which have novel exon junction chains.To capture and compute on the three sources of transcript structure diversity, we introduce a gene and transcript annotation framework that uses triplets representing the transcript start site, exon junction chain, and transcript end site of each transcript. Using triplets in a simplex representation demonstrates how promoter selection, splice pattern, and 3’ processing are deployed across human tissues, with nearly half of multitranscript protein coding genes showing a clear bias toward one of the three diversity mechanisms. Evaluated across samples, the predominantly expressed transcript changes for 74% of protein coding genes. In evolution, the human and mouse transcriptomes are globally similar in types of transcript structure diversity, yet among individual orthologous gene pairs, more than half (57.8%) show substantial differences in mechanism of diversification in matching tissues. This initial large-scale survey of human and mouse long-read transcriptomes provides a foundation for further analyses of alternative transcript usage, and is complemented by short-read and microRNA data on the same samples and by epigenome data elsewhere in the ENCODE4 collection.
Inoculation withPseudomonas fluorescensUM270 alters the maize root-associated endobiome and interacting networks in a milpa model
Authors: Rojas-Sánchez Blanca , Castelán-Sánchez Hugo , Santoyo Gustavo 
Published: May 2023

AbstractThe traditional milpa system is a polyculture originating in Mesoamerica, whose core is maize (Zea maysL.), associated with squash (Cucurbitaspp.) and beans (Phaseolus vulgarisL.). In recent years, milpa-type crops have decreased owing to climate change, rapid population growth, and the excessive use of agrochemicals; therefore, the application of plant growth-promoting rhizobacteria (PGPR) to counteract these negative effects has been little explored. In this study, a maize crop in a milpa system was fertilized with the PGPRPseudomonas fluorescensUM270, and the endophytic root microbiome (endobiome) of maize was assessed by 16S rRNA and internal transcribed spacer regions (ITS) sequencing. The results showed that UM270 the rhizosphere inoculation ofP. fluorescensUM270 did not increase alpha diversity in either monoculture or the milpa, but it did alter the endophytic microbiome of maize plant roots by stimulating the presence of bacterial operational taxonomic units (OTUs) of the generaBurkholderiaandPseudomonas(in a monoculture), whereas in the milpa system, the PGPR stimulated a greater endophytic diversity and the presence of genera such asBurkholderia, Variovorax, and N-fixing rhizobia genera, includingRhizobium, MesorhizobiumandBradyrhizobium. No clear association was found between fungal diversity and the presence of strain UM270, but beneficial fungi such asRizophagus irregularisandExophiala pisciphilawere detected in the milpa system. In addition, network analysis revealed unique interactions with species likeStenotrophomonassp.,Burkholderia xenovorans, andSphingobium yanoikuyae, which would potentially be playing a beneficial role with the plant. To the best of our knowledge, this is the first study in which the root microbiome of maize growing under a milpa model was assessed by bio-inoculation with PGPRs.
UBL3 interaction with α-synuclein is downregulated by silencing MGST3
Authors: Yan Jing , Zhang Hengsen , Chen Bin , Ping Yashuang , Islam Md. Shoriful , Tomochika Yuna , Aramaki Shuhei , Sato Tomohito , Nagashima Yu , Nakamura Tomohiko , Kahyo Tomoaki , Kaneda Daita , Ogawa Kenji , Yoshida Minoru , Setou Mitsutoshi 
Published: May 2023

AbstractUbiquitin-like 3 (UBL3) is a membrane-anchored protein that has been discovered to function as a protein post-translational modifier, helping to sort proteins into small extracellular vesicles (sEVs). Aggregations of alpha-synuclein (α-syn) are associated with the pathology of neurodegenerative diseases such as Parkinson’s disease (PD). The aggregation and toxicity of α-syn can be influenced by its interactions with specific proteins. Recently, the interactions between UBL3 and α-syn was uncovered. It is believed to play a role in eliminating excess α-syn from neurons, or in the spread of α-syn pathology in the brain associated with neurodegenerative diseases. However, the regulator that can mediate the interaction between UBL3 and α-syn remains unclear. In this study, we employed the split gaussian luciferase complementation assay and RNA interference (RNAi) technology to discover that QSOX2, HTATIP2, UBE3C, MGST3, NSF, HECTD1, SAE1 and ATG3 are involved in downregulating the interaction between UBL3 and α-syn. Among these proteins, silencing MGST3 had the most significant impact on the UBL3-α-syn interaction (with a fold change log2 of less than - 1). MGST3 is a part of the antioxidant system, and silencing MGST3 is believed to contribute to oxidative stress. We used hydrogen peroxide (H2O2) to induce oxidative stress and observed its effect on the UBL3-α-syn interaction. Our finding showed that an 800μM concentration of H2O2could also downregulate this interaction. However, the effect of oxidative stress caused by 800μM H2O2on the UBL3-α-syn interaction did not be enhanced by silencing MGST3. In conclusion, the interaction between UBL3 and α-syn is downregulated by silencing MGST3.
A systematic literature review of methodological approaches, challenges, and opportunities in the application of Mendelian randomisation to lifecourse epidemiology
Authors: Power Grace M. , Sanderson Eleanor , Pagoni Panagiota , Fraser Abigail , Morris Tim , Prince Claire , Frayling Timothy M. , Heron Jon , Richardson Tom G. , Richmond Rebecca , Tyrrell Jessica , Smith George Davey , Howe Laura D. , Tilling Kate 
Published: May 2023

AbstractBackgroundDiseases diagnosed in adulthood may have antecedents throughout – including prenatal – life. Gaining a better understanding of how exposures at different stages in the lifecourse influence health outcomes is key to elucidating the potential benefits of specific disease prevention strategies. However, confounding is highly likely in studies with earlier life or time-varying exposures. Mendelian randomisation (MR) is therefore increasingly used to estimate causal effects of exposures across the lifecourse on later life outcomes.MethodsThis systematic literature review aims to identify MR methods used to perform lifecourse investigations and review previous work that has utilised MR to elucidate the effects of factors acting at different stages of the lifecourse. We conducted a systematic search in PubMed, Embase, Medline and MedRXiv databases to comprehensively obtain lifecourse epidemiology studies that have employed MR.ResultsThirteen methodological studies were identified. Four studies focused on the impact of time-varying exposures on the interpretation of “standard” MR techniques, five presented methods for analysing repeat measures of the same exposure, and four described novel methodological approaches to handling parental exposures in relation to offspring outcomes. A further 84 studies presented the results of an applied research question with relevance to lifecourse epidemiology. Over half of these estimated effects in a single generation and were largely confined to the exploration of questions regarding body composition. Of the one generational studies employed in this review, 59% estimated the effect of exposures at birth, birth to/and childhood, birth to/and adolescence or birth to/and adulthood, 30% at childhood, childhood to/and adolescence or childhood to/and adulthood, and 11% at adolescence or adulthood. The remaining looked across two generations. These estimated effects of maternal exposures, with one study additionally examining paternal exposures, in relation to offspring outcomes.ConclusionThere is a growing body of research focused on the development and application of MR methods to address lifecourse research questions. The possibility that genetic effects have different levels of importance in the progression of an exposure at different ages should be more commonly considered for application in an MR context. Limitations exist, however, specifically regarding data constraints.
Empiric treatment with aspirin and ticagrelor is the most cost-effective strategy in patients with minor stroke or transient ischemic attack
Authors: Narasimhalu Kaavya , Chan Jeremy , Ang Yoong Kwei , De Silva Deidre Anne , Tan Kelvin Bryan 
Published: May 2023

AbstractBackgroundPatients with minor ischemic stroke or transient ischemic attacks (TIAs) are often treated with dual antiplatelet therapy regimens as part of secondary stroke prevention. Clopidogrel, an antiplatelet used in these regimens, is metabolised into its active form by theCYP2C19enzyme. Patients with loss of function (LOF) mutations inCYP2C19are at risk for poorer secondary outcomes when prescribed clopidogrel. We aimed to determine the cost effectiveness of three different treatment antiplatelet regimens in ischemic stroke populations with minor strokes or TIAs and how these treatment regimens are influenced by the LOF prevalence in the population.MethodsMarkov models were developed to look at the cost effectiveness of empiric treatment with aspirin and clopidogrel versus empiric treatment with aspirin and ticagrelor, versus genotype guided therapy for either 21 or 30 days. Effect ratios were obtained from the literature and incidence rates and costs were obtained from the national data published by the Singapore Ministry of Health. The primary endpoints were the incremental cost-effectiveness ratios (ICERs).ResultsEmpiric treatment with aspirin and ticagrelor was the most cost-effective treatment regimen if the prevalence of LOF was below 7.5%. Genotype guided therapy was more cost effective than empiric aspirin and clopidogrel if the LOF was above 65.5%. Empiric ticagrelor and aspirin was cost saving when compared to genotype guided therapy. Results in models of dual antiplatelet therapy for 30 days were similar.ConclusionThis study suggests that in patients with minor stroke and TIA planned for dual antiplatelet regimens, empiric ticagrelor and aspirin is the most cost-effective treatment regimen. If ticagrelor is not available, genotype guided therapy is the most cost-effective treatment regimen if the LOF prevalence in the population is more than 65.5%.Clinical PerspectiveWhat is new?We show that empiricial ticagrelor and aspirin is the most cost-effective treatment strategy in patients with minor stroke and transient ischemic attackWhat are the clinical implications?In patients with minor stroke/ transient ischemic attack, it may not be necessary to screen forCYP2C19status as empirical ticagrelor and aspirin is cost effective.
Mediators between body mass index and atrial fibrillation: a Mendelian Randomization study
Authors: Gao Ziting , Xiao Jun , Huang Wuqing 
Published: May 2023

AbstractBackgroundAlthough obesity is a recognized risk factor of atrial fibrillation (AF), the mechanisms are not fully understood. Thus, we aimed to identify the potential mediators between body mass index (BMI) and AF.MethodsWe conducted a two-sample Mendelian randomization (MR) analysis using publicly available summary-level data from genome-wide association studies. Univariable MR analyses were applied to identify potential mediators, and then the multivariable MR analyses were conducted to explore the mediated roles of circulating cytokines, metabolic markers and comorbidities in the association between BMI and AF.ResultsThis MR study found a significant causal association between BMI and AF (OR=1.41, 95%CI=1.33-1.50; P<0.001), which was attenuated to 1.21 (95%CI=1.03-1.43) after being adjusted for leptin, in which 48.78% excess risk was mediated. After further adjustment for leptin and sleep apnoea or coronary heart disease, the association was attenuated to null (adjusted for leptin and sleep apnoea: OR=1.05, 95%CI=0.85-1.30; adjusted for leptin and coronary heart disease: OR=1.08, 95%CI=0.90-1.30), resulting in 87.80% and 80.49% excess risk being mediated, respectively.ConclusionThese results identified an important mediated role of leptin, particularly for individuals with sleep apnoea or coronary heart disease, providing some clues for the underlying mechanisms behind the impact of obesity on AF risk.FundingNatural Science Foundation of Fujian Province (grant no. 2022J01706) and the Start-up Fund for high-level talents of Fujian Medical University (XRCZX2021026).