bluuebunny/crossref_metadata_2025_split huggingface dataset:
Spatial heterogeneity of T cell repertoire across NSCLC tumors, tumor edges, adjacent and distant lung tissues
Authors: Hu Qikang , Gao Yang , Frank Meredith , Ji Liyan , Peng Muyun , Chen Chen , Wang Bin , Hu Yan , Wu Zeyu , Li Jina , Shu Lu , He Qiongzhi , Zhang Yingqian , Xia Xuefeng , Zhang Jianjun , Yi Xin , Reuben Alexandre , Yu Fenglei 
Published: October 2022

AbstractBackgroundA better understanding of the T cells in lung cancer and their distribution across tumor-adjacent lungs and the peripheral blood is needed to improve efficacy and minimize toxicity from immunotherapy to lung cancer patients.MethodsHere, we performed CDR3β TCR sequencing of 143 samples from 21 patients with early-stage NSCLC including peripheral blood mononuclear cells, tumor, tumor edges (<1cm from tumor), as well as adjacent lungs 1cm, 2cm, 5cm, and 10cm away from the tumor to gain insight into the spatial heterogeneity of T cells across the lungs in patients with NSCLC. PD-L1, CD4 and CD8 expression was assessed by immunohistochemical staining and genomic features were derived by targeted sequencing of 1,021 cancer related genes.ResultsOur study reveals a decreasing gradient in TIL homology with the tumor-edge, adjacent lungs, and peripheral blood but no discernible distance-associated patterns of T cell trafficking within the adjacent lung itself. Furthermore, we show a decrease in pathogen-specific TCRs in regions with high T cell clonality and PD-L1 expression.ConclusionsThe exclusion in T cells at play across the lungs of patients with NSCLC may be potentially the mechanism for lung cancer occurrence.
Exploring the causal role of the human gut microbiome in colorectal cancer: Application of Mendelian randomization
Authors: Hatcher Charlie , Richenberg George , Waterson Samuel , Nguyen Long H. , Joshi Amit D. , Carreras-Torres Robert , Moreno Victor , Chan Andrew T. , Gunter Marc , Lin Yi , Qu Conghui , Song Mingyang , Casey Graham , Figueiredo Jane C , Gruber Stephen B , Hampe Jochen , Hampel Heather , Jenkins Mark A , Keku Temitope O , Peters Ulrike , Tangen Catherine M , Wu Anna H , Hughes David A , Rühlemann Malte C , Raes Jeroen , Timpson Nicholas J. , Wade Kaitlin H. 
Published: October 2022

AbstractAimThe role of the human gut microbiome in colorectal cancer (CRC) is unclear as most studies on the topic are unable to discern correlation from causation. We apply two-sample Mendelian randomization (MR) to estimate the causal relationship between the gut microbiome and CRC.Materials and methodsWe used summary-level data from independent genome-wide association studies to estimate the causal effect of 14 microbial traits (n=3,890 individuals) on overall CRC (55,168 cases, 65,160 controls) and site-specific CRC risk, conducting several sensitivity analyses to understand the nature of results.ResultsInitial MR analysis suggested that a higher abundance ofBifidobacteriumand presence of an unclassified group of bacteria within theBacteroidalesorder in the gut increased overall and site-specific CRC risk. However, sensitivity analyses suggested that instruments used to estimate relationships were likely complex and involved in many potential horizontal pleiotropic pathways, demonstrating that caution is needed when interpreting MR analyses with gut microbiome exposures. In assessing reverse causality, we did not find strong evidence that CRC causally affected these microbial traits.ConclusionsWhilst our study initially identified potential causal roles for two microbial traits in CRC, importantly, further exploration of these relationships highlighted that these were unlikely to reflect causality.
Assessment of Added Activity of An Antitumor Agent
Authors: Chen Cong , Sun Linda Zhiping , Ren Yixin , Rubin Eric H. , Weinstock David M. , Schmidt Emmett V. 
Published: October 2022

AbstractAn unprecedented number of novel oncology drugs are under preclinical and clinical development, and nearly all are developed in combinations. With an over-reliance on biological hypotheses, there is less effort to establish single agent activity before initiating late clinical development. This may be contributing to a decreased success rate going from phase 1 to approval in the immunotherapy era. Growing evidence in clinical trial data shows that the treatment benefit from most approved combination therapies can be explained by the independent drug action model. Using this working model, we develop a simple index to measure the added antitumor activity of a new drug based on mean response duration, an endpoint that naturally combines both response status and duration information for all patients, which is shown to be highly predictive of clinical benefit of FDA-approved anti-PD-(L)1 immunotherapies. This index sheds light on challenges and opportunities in contemporary oncology drug development and provides a practical tool to assist with decision-making.
Neuronal Morphology Enhances Robustness to Perturbations of Channel Densities
Authors: Zang Yunliang , Marder Eve 
Published: October 2022

AbstractBiological neurons show significant cell-to-cell variability but have the striking ability to maintain their key firing properties in the face of unpredictable perturbations and stochastic noise. Using a population of multi-compartment models consisting of soma, neurites, and axon for the lateral pyloric (LP) neuron in the crab stomatogastric ganglion, we explored how rebound bursting is preserved when the 14 channel conductances in each model are all randomly varied. The soma-axon coupling is critical for the ability of the axon to spike during bursts and consequently determines the set of successful solutions. When the coupling deviates from a biologically realistic range, the neuronal tolerance of conductance variations is significantly lessened. Thus, the gross morphological features of these neurons enhance their robustness to perturbations of channel densities and expands the space of individual variability that can maintain a desired output pattern.
Ethnicity-Specific Effects on Cardiac Arrest During the COVID-19 Pandemic: A Two-Year Prospective Evaluation in a North American Community
Authors: Chugh Harpriya S , Sargsyan Arayik , Nakamura Kotoka , Uy-Evanado Audrey , Dizon Bernadine , Norby Faye L , Young Christopher , Hadduck Katy , Jui Jonathan , Shepherd Daniel , Salvucci Angelo , Chugh Sumeet S , Reinier Kyndaron 
Published: October 2022

ABSTRACTBackgroundOut-of-hospital sudden cardiac arrest (SCA) is a major public health problem with mortality >90%, and incidence has increased during the COVID-19 pandemic. Information regarding ethnicity-specific effects on SCA incidence and survival is lacking.MethodsIn a prospective, population-based study of Ventura County, CA residents (2020 Pop. 843,843; 44.1% Hispanic), we compared SCA incidence and outcomes during the first two years of the COVID-19 pandemic to the prior four years, overall and by ethnicity (Hispanic vs non-Hispanic).FindingsOf 2,222 OHCA cases identified, 907 occurred during the pandemic (March 2020 - Feb 2022) and 1315 occurred pre-pandemic (March 2016 - Feb 2020). Overall age-standardized annual SCA incidence increased from 38.9/100,000 [95% CI 36.8-41.0] pre-pandemic to 53.8/100,00 [95% CI 50.3 - 57.3, p<0.001] during the pandemic. Among Hispanics, incidence increased by 77%, from 38.2/100,00 [95% CI 33.8-42.5] to 67.7/100,00 [95% CI 59.5- 75.8, p<0.001]. Among non-Hispanics, incidence increased by 26% from 39.4/100,000 [95% CI 36.9-41.9, p<0.001] to 49.8/100,00 [95% CI 45.8-53.8]. SCA incidence rates closely tracked COVID-19 infection rates. During the pandemic, SCA survival was significantly reduced (15.3% to 10.0%, p<0.001) and Hispanics were less likely than non-Hispanics to have bystander CPR (44.6% vs. 54.7%, p=0.005) and shockable rhythm (15.3% vs. 24.1%, p=0.003).InterpretationHispanic residents experienced higher SCA rates during the pandemic with less favorable resuscitation profiles. These findings implicate potential ethnicity-specific barriers to acute care and represent an urgent call to action at the community and health-system levels.FundingNational Heart Lung and Blood Institute Grants R01HL145675 and R01HL147358.
Bacterial anomalies in seabed sediments associated with deep water hydrocarbon seepage
Authors: Li Carmen , Adebayo Oyeboade , Ferguson Deidra K. , Wang Scott , Rattray Jayne E. , Fowler Martin , Webb Jamie , Campbell Calvin , Morrison Natasha , MacDonald Adam , Hubert Casey R.J. 
Published: October 2022

ABSTRACTDeep sea hydrocarbon seep detection relies predominantly on geochemical analyses of seabed marine sediment cores to identify the presence of gas or oil. The presence of seeping hydrocarbons in these locations alters resident microbial community structure, leading to culture-based biodegradation assays as a complement to geochemical tools for seep detection. Biodiversity surveys of microbial communities can offer a similar proxy for seeping hydrocarbons, but this strategy has not been extensively investigated in deep water settings. In this study, 16S rRNA gene sequencing of bacterial communities was performed on sediment cores obtained in >2500 m water depth at 43 different locations in the NW Atlantic Ocean. Core samples from as deep as 10 metres below seafloor (mbsf) were assessed for gas composition, gas isotopes and liquid hydrocarbons. Over 650 bacterial 16S rRNA gene amplicon libraries were constructed from different sediment depths at these locations. Select sites showed strong evidence for the presence of thermogenic or biogenic hydrocarbons such that bacterial population analyses revealed significant differences between hydrocarbon seep and non-seep locations. Specific bacterial indicators were associated with different sediment depth intervals. Caldatribacteriota and Campilobacterota OTUs were observed in high relative sequence abundance in hydrocarbon seep sediments, particularly in the 20-50 cmbsf interval. Furthermore, these groups were differentially abundant between sites with thermogenic and biogenic hydrocarbons. The patterns revealed here suggest that microbial screening has the potential to play a key role in hydrocarbon seep detection and characterisation in remote deep-sea environments.
Comparison of various transcatheter aortic valves for aortic stenosis – a network meta-analysis of randomized controlled trials
Authors: Hiltner Emily , Shah Monarch , Schwabe-Warf Derek , Haik Bruce , Hakeem Abdul , Russo Mark , Sethi Ankur 
Published: October 2022

AbstractObjectivesOur aim was to compare available transcatheter aortic valve replacement (TAVR) valves using direct and indirect evidence from randomized controlled trials (RCT).BackgroundTAVR is now an established treatment for majority of patients with severe aortic stenosis. However, there is limited data comparing various valves.MethodsWe performed a systematic search of electronic databases for RCT comparing a TAVR valve to a valve or surgery. A Bayesian network meta-analysis was performed to compile evidence from both direct and indirect comparisons at 30 days and at one year.ResultsTwelve studies with 10,307 patients eligible for TAVR met the criteria and were included. Self-expanding valve CoreValve type (SEV_C) is associated with higher risk of pacemaker implantation and use of >1 valve, SEV Accurate type (SEV_A) is associated with higher risk of ≥ moderate aortic regurgitation (AR) and death, and mechanically expandable valve (MEV) is associated with lower risk of ≥ moderate AR but higher risk of pacemaker at 30 days, SEV_C and MEV were associated with higher pacemaker rates compared balloon expandable valve (BEV) at 1 year. There is no difference among the valves in stroke at 30 days and 1 year.ConclusionsAt 30 days, BEV was superior on one or more outcomes of mortality, pacemaker implantation, >1 valve implantation, and ≥ moderate AR compared to other valves except the higher rate ≥?moderate AR compared to MEV. At one year, BEV was associated with lower odds of pacemaker implantation compared to SEV_C and MEV but not different on other end points.
A novel brain penetrant PDGFRα inhibitor HY-008 is effective against glioblastoma
Authors: Xu Chenxin , Feng Haizhong , Sun Weilin 
Published: October 2022

AbstractBackgroundGlioblastoma multiforme (GBM) is the most common primary intracranial malignant tumor in adults, with poor prognosis and high recurrence. Routine treatments of GBM show unsatisfactory efficiency in improving patients’ survival because of limited area of surgical resection and drug resistance. New therapeutic agents are needed to improve GBM treatment efficiency, but the blood-brain barrier (BBB) permeability is a major hurdle. Here, we report HY-008 as a promising therapeutic drug targeting PDGFRα signaling with high BBB permeability and efficient inhibiting effects both in vitro and in vivo.MethodsThrough structural modification and medicinal chemistry efforts, HY-007 and HY-008 were developed. The brain and plasma pharmacokinetic profiles of these two compounds were assessed. The inhibitory efficiency of HY-007 and HY-008 on GBM cell survival and PDGFRα signaling were evaluated. The efficacy of HY-007 and HY-008 as a single agent or HY-008 in combination with temozolomide (TMZ) was investigated using transformed mouse astrocyte and glioma stem-like cell (GSC) orthotopic xenograft models.ResultsHY-007 and HY-008 both had good brain permeability and desirable PK profiles with mild hERG inhibition, while HY-008 is more brain permeable than HY-007. In vitro, HY-007 and HY-008 both significantly inhibited viability of the established GBM cells with PDGF-A overexpression and transformed mouse astrocytes with PDGF-A/PDGFRα overexpression by targeting the PDGFRα signaling activated Erk1/2 and Akt. In vivo, HY-007 and HY-008 both effectively inhibited orthotopic GBM tumor xenograft growth and prolonged the survival of mice, and HY-008 showed less toxicity and better therapeutic effect. In addition, HY-008 increased sensitivity of TMZ, exhibited treatment efficiency both as a single agent and in combination with TMZ, providing significant survival benefits for GBM tumor xenograft-bearing mice.ConclusionsOur data demonstrate that HY-008 is a promising therapeutic agent in GBM treatment and a combination HY-008 with TMZ could serves as a potential efficient therapeutic option for improving GBM clinical treatment.
Functional characterization of a PHF8 processed pseudogene in the mouse genome
Authors: St-Germain Joannie , Khan Muhammad Riaz , Bavykina Viktoriia , Desmarais Rebecka , Scott Micah , Boissonneault Guylain , Brunet Marie A. , Laurent Benoit 
Published: October 2022

AbstractThe majority of pseudogenes are generated when an RNA transcript is reverse-transcribed and integrated into the genome at a new location. Pseudogenes are often considered as an imperfect and silent copy of a functional gene because of the accumulation of numerous mutations in their sequence. Here we report the presence ofPHF8-ps, aPHF8retrotransposed pseudogene in the mouse genome, which has no disruptions in its coding sequence. We showed that this pseudogene was specifically transcribed in testis and can produce a Phf8-ps protein in vivo. As Phf8-ps protein has a well-conserved JmjC domain, we characterized its enzymatic activity and showed that Phf8-ps did not have the intrinsic capability to demethylate H3K9me2 in vitro compared to the parental Phf8 protein. Surprisingly, Phf8-ps did not localize in the nucleus like Phf8 but rather was mostly located at the cytoplasm. Finally, our proteomic analysis of Phf8-ps associated proteins revealed that Phf8-ps interacted with mitochondrial proteins but also with prefoldin subunits (PFDN proteins) that deliver unfolded proteins to the cytosolic chaperonin complex implicated the folding of cytosolic proteins. Together, our findings highlighted Phf8-ps as a new pseudogene-derived protein with distinct molecular functions from Phf8.
COVID-19 among adults living with HIV: Correlates of mortality in a general population in a resource-limited setting
Authors: Kassanjee Reshma , Davies Mary-Ann , Ngwenya Olina , Osei-Yeboah Richard , Jacobs Theuns , Morden Erna , Timmerman Venessa , Britz Stefan , Mendelson Marc , Taljaard Jantjie , Riou Julien , Boulle Andrew , Tiffin Nicki , Zinyakatira Nesbert 
Published: October 2022

AbstractIntroductionWhile a large proportion of people with HIV (PWH) have experienced SARS-CoV-2 infections, there is uncertainty about the role of HIV disease severity on COVID-19 outcomes, especially in lower income settings. We studied the association between mortality and characteristics of HIV severity and management, and vaccination, among adult PWH.MethodsWe analysed observational cohort data on all PWH aged ≥15 years experiencing a diagnosed SARS-CoV-2 infection (until March 2022), who accessed public sector healthcare in the Western Cape province of South Africa. Logistic regression was used to study the association of mortality with CD4 cell count, viral load, evidence of ART, time since first HIV evidence, and vaccination, adjusting for demographic characteristics, comorbidities, admission pressure, location and time period.ResultsMortality occurred in 5.7% (95% CI: 5.3,6.0) of 17 831 first diagnosed infections. Higher mortality was associated with lower recent CD4, no evidence of ART collection, high or unknown recent viral load (among those with ART evidence), and recent first HIV evidence, differentially by age. Vaccination was protective. The burden of comorbidities was high, and tuberculosis, chronic kidney disease, diabetes and hypertension were associated with higher mortality, more strongly in younger adults.ConclusionsMortality was strongly associated with suboptimal HIV control, and prevalence of these risk factors increased in later COVID-19 waves. It remains a public health priority to ensure PWH are on suppressive ART and vaccinated, and manage any disruptions in care that occurred during the pandemic. The diagnosis and management of comorbidities, including for tuberculosis, should be optimised.
Synthetic electronic health records generated with variational graph autoencoders
Authors: Nikolentzos Giannis , Vazirgiannis Michalis , Xypolopoulos Christos , Lingman Markus , Brandt Erik G. 
Published: October 2022

AbstractData-driven medical care delivery must always respect patient privacy – a requirement that is not easily met. This issue have impeded improvements to healthcare software and have delayed the long-predicted prevalence of artificial intelligence in healthcare. Until now, it has been very difficult to share data between healthcare organizations, resulting in poor statistical models due to unrepresentative patient cohorts. Synthetic data, i. e., artificial but realistic electronic health records, could overcome the drought that is troubling the healthcare sector. Deep neural network architectures in particular have shown an incredible ability to learn from complex data sets, and generate large amounts of unseen data points with the same statistical properties as the training data. Here, we present a generative neural network model that can create synthetic health records with realistic timelines. These clinical trajectories are generated on a per-patient basis and are represented as linear-sequence graphs of clinical events over time. We use a variational graph autoencoder (VGAE) to generate synthetic samples from real-world electronic health records. Our approach generates health records not seen in the training data. We show that these artificial patient trajectories are realistic and preserve patient privacy, and can therefore support safe sharing of data across organizations.
A systematic review on outbreaks of COVID-19 among children within households in the European region
Authors: Vardavas Constantine I. , Nikitara Katerina , Aslanoglou Katerina , Kamekis Apostolos , Ramesh Nithya , Symvoulakis Emmanouil , Agaku Israel , Phalkey Revati , Leonardi-Bee Jo , Fernandez Esteve , Condell Orla , Lamb Favelle , Deogan Charlotte , Suk Jonathan E. 
Published: October 2022

ABSTRACTObjectivesThis systematic review aims to identify the secondary attack rates (SAR) to adults and other children when children are the index cases within household settings.MethodsThis literature review assessed European-based studies published in Medline and Embase between January 2020 and January 2022 that assessed the secondary transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within household settings. The inclusion criteria were based on the PEO framework (P-Population, E-Exposure, O-Outcome) for systematic reviews. Thus, the study population was restricted to humans within the household setting in Europe (population), in contact with pediatric index cases 1–17 years old (exposure) that led to the transmission of SARS-CoV-2 reported as either a SAR or the probability of onward infection (outcome).ResultsOf 1,819 studies originally identified, 25 met the inclusion criteria. Overall, the SAR ranged from 13% to 75% in 23 studies, while there was no evidence of secondary transmission from children to other household members in two studies. Evidence indicated that asymptomatic SARS-CoV-2 index cases also have a lower SAR than those with symptoms and that younger children may have a lower SAR than adolescents (>12 years old) within household settings.ConclusionsSARS-CoV-2 secondary transmission from paediatric index cases ranged from 0% to 75%, within household settings between January 2020 and January 2022, with differences noted by age and by symptomatic/asymptomatic status of the index case. Given the anticipated endemic circulation of SARS-CoV-2, continued monitoring and assessment of household transmission is necessary.
FGFR1 governs iron metabolism via regulating post-translational modification of IRP2 in prostate cancer cells
Authors: Lin Hui , Shi Liuhong , Zhou Dongyan , Chen Shuangya , He Ping , Zheng Xiaolu , Qiu Feng , Yuan Yuying , Lin Shuaijun , Li Xiaokun , Wang Fen , Wang Cong 
Published: October 2022

AbstractThe acquisition of ectopic fibroblast growth factor receptor 1 (FGFR1) expression is well documented in prostate cancer (PCa) progression. However, how FGFR1 facilitates PCa progression is not fully revealed, although it is known to confer tumor growth advantage and metastasis. Here we report that FGFR1 deletion in DU145 human PCa cells retards the iron metabolism and reduces transferrin receptor 1 (TFR1), which synergistically enhances the anti-cancer effect of iron chelator. FGFR1 and TFR1 are highly expressed in PCa, and FGFR1 overexpression increased TFR1 in PCa cell lines. Furthermore, we first time demonstrate that FGFR1 deletion boosts and shifts the degradation of iron regulatory proteins 2 (IRP2) to downregulate TFR1. Detailed characterization revealed that based on FGFR1 deletion the stability of IRP2 is broken, whose degradation is accelerated, which can be not observed without FGFR1 deletion. In addition, IRP2 overexpression rescue the malignancy degree of DU145 cells. Our results here unravel a novel mechanism by which FGFR1 promotes PCa progression by upregulating iron metabolism, and that the FGFR1/IRP2/TFR1 axis can be a potential target for managing PCa progression.