bluuebunny/crossref_metadata_2025_split huggingface dataset:
Loss of response to anti‐TNFα agents depends on treatment duration in patients with inflammatory bowel disease
Authors: Schultheiss Johannes P. D. , Mahmoud Remi , Louwers Jonas M. , van der Kaaij Michiel T. , van Hellemondt Boris P. , van Boeckel Petra G. , Mahmmod Nofel , Jharap Bindia , Fidder Herma H. , Oldenburg Bas 
Published: September 2021

SummaryBackgroundInflammatory bowel disease (IBD) is often managed with anti‐tumour necrosis factor‐α therapy (anti‐TNFα), but treatment efficacy is compromised by high annual rates of loss of response (13%‐21% per patient‐year).AimsTo assess whether the incidence of loss of response decreases with longer treatment durationMethodsThis was a multicentre, retrospective cohort study of patients with ulcerative colitis (UC) or Crohn's disease (CD) who received anti‐TNFα for at least 4 months between 2011 and 2019. We studied the incidence of loss of response as a function of treatment duration, employing parametric survival modelling. Predictors of loss of response were identified by Cox regression analysis. Secondary outcomes included overall anti‐TNFα discontinuation and dose escalation.ResultsWe included 844 anti‐TNFα treatment episodes in 708 individuals. Loss of response occurred in 211 (25.0%) episodes, with anti‐drug antibodies detected in 66 (31.3%). During the first year, the incidence of loss of response was three‐fold higher than after four years of treatment (17.2% vs 4.8% per patient‐year, P < 0.001). The incidence of anti‐TNFα discontinuation (28.6% vs 14.0% per patient‐year, P < 0.001) and dose escalations (38.0% vs 6.8% per patient‐year, P < 0.001) also decreased significantly from the first year to after four years, respectively. Predictors of loss of response included UC (vs CD, adjusted hazard ratio [aHR] 1.53, 95% CI 1.10‐2.15) and, among patients with CD, stricturing or penetrating disease (aHR 1.68, 95% CI 1.15‐2.46) and male sex (aHR 0.55, 95% CI 0.38‐0.78). Immunomodulators were protective against loss of response with anti‐drug antibodies (aHR 0.42, 95% CI 0.24‐0.74).ConclusionsPatients with sustained benefit to anti‐TNFα after 2 years are at low risk of subsequent loss of response.
On restricted mean time in favor of treatment
Authors: Mao Lu 
Published: September 2021

AbstractThe restricted mean time in favor (RMT‐IF) of treatment is a nonparametric effect size for complex life history data. It is defined as the net average time the treated spend in a more favorable state than the untreated over a prespecified time window. It generalizes the familiar restricted mean survival time (RMST) from the two‐state life–death model to account for intermediate stages in disease progression. The overall estimand can be additively decomposed into stage‐wise effects, with the standard RMST as a component. Alternate expressions of the overall and stage‐wise estimands as integrals of the marginal survival functions for a sequence of landmark transitioning events allow them to be easily estimated by plug‐in Kaplan–Meier estimators. The dynamic profile of the estimated treatment effects as a function of follow‐up time can be visualized using a multilayer, cone‐shaped “bouquet plot.” Simulation studies under realistic settings show that the RMT‐IF meaningfully and accurately quantifies the treatment effect and outperforms traditional tests on time to the first event in statistical efficiency thanks to its fuller utilization of patient data. The new methods are illustrated on a colon cancer trial with relapse and death as outcomes and a cardiovascular trial with recurrent hospitalizations and death as outcomes. The R‐package rmt implements the proposed methodology and is publicly available from the Comprehensive R Archive Network (CRAN).
Iron parameters in pregnant women with beta‐thalassaemia minor combined with iron deficiency anaemia compared to pregnant women with iron deficiency anaemia alone demonstrate the safety of iron supplementation in beta‐thalassaemia minor during pregnancy
Authors: Chen Niankun , Li Zhongjun , Huang Yingying , Xiao Chaoqun , Shen Xinyang , Pan Shumin , Su Qiongqiong , Wang Zhijian 
Published: September 2021

SummaryIn patients with beta‐thalassaemia intermedia or major, hepcidin induces iron overload by continuously promoting iron absorption. There have been no studies in pregnant women with beta‐thalassaemia minor combined with iron deficiency anaemia (IDA), examining whether hepcidin is inhibited by GDF15, as may occur in patients with beta‐thalassaemia intermedia or major, or whether the iron metabolism characteristics and the effect of iron supplementation are consistent with simple IDA in pregnancy. We compared and analysed routine blood parameters, iron metabolism parameters, the GDF15 levels, and the hepcidin levels among four groups, namely the beta‐thalassaemia (β) + IDA, β, IDA, and normal groups. In addition, the β + IDA and IDA groups received iron supplementation for four weeks. We found no statistically significant correlation between hepcidin and GDF15 in any group, but a positive correlation was observed between hepcidin and ferritin. After iron supplementation, the routine blood parameters and iron metabolism parameters in the β + IDA group were improved, and the hepcidin content was significantly increased. These results suggest that in pregnant women with beta‐thalassaemia minor, hepcidin functions normally to maintain iron homeostasis, and that iron supplementation is effective and safe.
A new pancreatic adenocarcinoma‐derived organoid model of acquired chemoresistance to FOLFIRINOX: First insight of the underlying mechanisms
Authors: Hadj Bachir Elsa , Poiraud Charles , Paget Sonia , Stoup Nicolas , El Moghrabi Soumaya , Duchêne Belinda , Jouy Nathalie , Bongiovanni Antonino , Tardivel Meryem , Weiswald Louis‐Bastien , Vandepeutte Marie , Beugniez César , Escande Fabienne , Leteurtre Emmanuelle ,   OrgaRES consortium, Poulain Laurent , Lagadec Chann , Pigny Pascal , Jonckheere Nicolas , Renaud Florence , Truant Stephanie , Van Seuningen Isabelle , Vincent Audrey 
Published: September 2021

AbstractBackground InformationAlthough improvements have been made in the management of pancreatic adenocarcinoma (PDAC) during the past 20 years, the prognosis of this deadly disease remains poor with an overall 5‐year survival under 10%. Treatment with FOLFIRINOX, a combined regimen of 5‐fluorouracil, irinotecan (SN‐38) and oxaliplatin, is nonetheless associated with an excellent initial tumour response and its use has allowed numerous patients to go through surgery while their tumour was initially considered unresectable. These discrepancies between initial tumour response and very low long‐term survival are the consequences of rapidly acquired chemoresistance and represent a major therapeutic frontier. To our knowledge, a model of resistance to the combined three drugs has never been described due to the difficulty of modelling the FOLFIRINOX protocol both in vitro and in vivo. Patient‐derived tumour organoids (PDO) are the missing link that has long been lacking in the wide range of epithelial cancer models between 2D adherent cultures and in vivo xenografts. In this work we sought to set up a model of PDO with resistance to FOLFIRINOX regimen that we could compare to the paired naive PDO.ResultsWe first extrapolated physiological concentrations of the three drugs using previous pharmacodynamics studies and bi‐compartmental elimination models of oxaliplatin and SN‐38. We then treated PaTa‐1818x naive PDAC organoids with six cycles of 72 h‐FOLFIRINOX treatment followed by 96 h interruption. Thereafter, we systematically compared treated organoids to PaTa‐1818x naive organoids in terms of growth, proliferation, viability and expression of genes involved in cancer stemness and aggressiveness.ConclusionsWe reproductively obtained resistant organoids FoxR that significantly showed less sensitivity to FOLFORINOX treatment than the PaTa‐1818x naive organoids from which they were derived. Our resistant model is representative of the sequential steps of chemoresistance observed in patients in terms of growth arrest (proliferation blockade), residual disease (cell quiescence/dormancy) and relapse.SignificanceTo our knowledge, this is the first genuine in vitro model of resistance to the three drugs in combined therapy. This new PDO model will be a great asset for the discovery of acquired chemoresistance mechanisms, knowledge that is mandatory before offering new therapeutic strategies for pancreatic cancer.
Alpha‐arrestins Aly1/Art6 and Aly2/Art3 regulate trafficking of the glycerophosphoinositol transporter Git1 and impact phospholipid homeostasis
Authors: Robinson Benjamin P. , Hawbaker Sarah , Chiang Annette , Jordahl Eric M. , Anaokar Sanket , Nikiforov Alexiy , Bowman Ray W. , Ziegler Philip , McAtee Ceara K. , Patton‐Vogt Jana , O'Donnell Allyson F. 
Published: September 2021

AbstractBackground informationPhosphatidylinositol (PI) is an essential phospholipid, critical to membrane bilayers. The complete deacylation of PI by B‐type phospholipases produces intracellular and extracellular glycerophosphoinositol (GPI). Extracellular GPI is transported into the cell via Git1, a member of the Major Facilitator Superfamily of transporters at the yeast plasma membrane. Internalized GPI is degraded to produce inositol, phosphate and glycerol, thereby contributing to these pools. GIT1 gene expression is controlled by nutrient balance, with phosphate or inositol starvation increasing GIT1 expression to stimulate GPI uptake. However, less is known about control of Git1 protein levels or localization.ResultsWe find that the α‐arrestins, an important class of protein trafficking adaptor, regulate Git1 localization and this is dependent upon their interaction with the ubiquitin ligase Rsp5. Specifically, α‐arrestin Aly2 stimulates Git1 trafficking to the vacuole under basal conditions, but in response to GPI‐treatment, either Aly1 or Aly2 promote Git1 vacuole trafficking. Cell surface retention of Git1, as occurs in aly1∆ aly2∆ cells, is linked to impaired growth in the presence of exogenous GPI and results in increased uptake of radiolabeled GPI, suggesting that accumulation of GPI somehow causes cellular toxicity. Regulation of α‐arrestin Aly1 by the protein phosphatase calcineurin improves steady‐state and substrate‐induced trafficking of Git1, however, calcineurin plays a larger role in Git1 trafficking beyond regulation of α‐arrestins. Interestingly, loss of Aly1 and Aly2 increased phosphatidylinositol‐3‐phosphate on the limiting membrane of the vacuole, and this was further exacerbated by GPI addition, suggesting that the effect is partially linked to Git1. Loss of Aly1 and Aly2 leads to increased incorporation of inositol label from [3H]‐inositol‐labelled GPI into PI, confirming that internalized GPI influences PI balance and indicating a role for the a‐arrestins in this regulation.ConclusionsThe α‐arrestins Aly1 and Aly2 are novel regulators of Git1 trafficking with previously unanticipated roles in controlling phospholipid distribution and balance.SignificanceTo our knowledge, this is the first example of α‐arrestin regulation of phosphatidyliniositol‐3‐phosphate levels. In future studies it will be exciting to determine if other α‐arrestins similarly alter PI and PIPs to change the cellular landscape.
Effect of oral health literacy on self‐reported tooth loss: A multiple mediation analysis
Authors: Ju Xiangqun , Jamieson Lisa M. , Mejia Gloria C. , Mittinty Murthy N. 
Published: September 2021

AbstractBackgroundThis study aims to investigate the mediating pathways of oral health literacy (OHL) and oral health‐related behaviours on the relationship between education and self‐reported tooth loss among Australian adults.MethodsData used for studying the effects of mediating pathways are from the National Dental Telephone Interview Survey 2013, a random sample survey of Australian adults aged 18+ years. To study the mediating effects, we use counterfactual‐based analysis. To decompose the effect of multiple mediator’s alternate, to natural effect, methods such as interventional effects have been proposed. In this paper, we use these approaches to decompose the effect between education, OHL and oral health‐related behaviours on self‐reported tooth loss. Sensitivity analysis was performed for unmeasured confounding with multiple mediators.ResultsData were available for 2936 Australian adults. The prevalence of persons with ≥12 self‐reported tooth loss was approximately 15%. The average total causal effect from the low education group was nearly 150%, and the interventional indirect effect through OHL and the dependence of oral health‐related behaviours on OHL to more than 12 missing teeth were 20% and 120%, respectively, higher than in the high education group. Sensitivity analysis indicated if the difference in the prevalence of unmeasured confounder is as big as 6% the direct effect and the indirect effect remains as observed.ConclusionsAn additional two‐fifths reduction on having more than 12 missing teeth for Australian adults with lower education level could be achieved if the proportion of lower OHL was decreased and optimal dental behaviours were increased.
Down-regulation of PR/SET domain 10 underlies natural killer cell dysfunction in hepatocellular carcinoma
Authors: Han Jiantao , Ke Chao , Jiang Bin , Zhou Hongjian , Xu Hanbin , Xie Xingwang 
Published: September 2021

Abstract
Hepatocellular carcinoma (HCC) is the world's leading cause of tumor-related mortalities. Natural killer (NK) cells play a critical role at the first immunological defense line against HCC initiation and progression. NK cell dysfunction is therefore an important mechanism for immune evasion of HCC cells. In the present study using a murine HCC model, we revealed the down-regulation of PR/SET Domain 10 (PRDM10) in hepatic NK cells that were phenotypically and functionally exhausted. PRDM10 silencing diminished the expression of natural killer group 2 member D (NKG2D) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), augmented T cell immunoglobulin and ITIM domain (TIGIT) expression, and decreased the expression of interferon (IFN)-γ, perforin and granzyme B in normal hepatic NK cells in vitro. Consistently, PRDM10-deficient NK cells exhibited impaired cytotoxicity on target cells. In contrast, PRDM10 over-expression promoted NKG2D and Fas ligand (FasL) expression, reduced CD96 expression and enhanced transcripts of IFN-γ, perforin and granzyme B in NK cells in vivo. Moreover, PRDM10 silencing and PRDM10 over-expression down-regulated and up-regulated Eomesodermin (Eomes) expression, respectively. In summary, this study reveals PRDM10 down-regulation as a novel mechanism underlying NK cell dysfunction and identifies PRDM10 as a supporting factor of NK cell function.
Identification of embolic stroke in patients with large vessel occlusion: The Chinese embolic stroke score, CHESS
Authors: Hong Lan , Lin Longting , Li Gang , Yang Jianhong , Geng Yu , Lou Min , Parsons Mark , Cheng Xin , Dong Qiang 
Published: September 2021

AbstractAimsThe aim of the study was to develop a simple and objective score using clinical variables and quantified perfusion measures to identify embolic stroke with large vessel occlusions.MethodsEligible patients from five centers participating in the International Stroke Perfusion Imaging Registry were included in this study. Patients were split into a derivation cohort (n = 213) and a validation cohort (n = 116). A score was developed according to the coefficients of independent predictors of embolic stroke from stepwise logistic regression model in the derivation cohort. The performance of the score was validated by assessing its discrimination and calibration.ResultsThe independent predictors of embolic stroke made up the Chinese Embolic Stroke Score (CHESS). There were: history of atrial fibrillation (3 points), non‐hypertension history (2 points), and delay time>6 s volume/delay time>3 s volume on perfusion imaging ≥0.23 (2 points). The AUC of CHESS in the derivation cohort and validation cohort were 0.87 and 0.79, respectively. Patients with a CHESS of 0 could be identified as low‐risk of embolic stroke, with a CHESS of 2–4 could be identified as medium‐risk and with a CHESS of 5–7 could be regarded as high‐risk. The observed rate of embolic stroke of each risk group was well‐calibrated with the predicted rate.ConclusionCHESS could reliably and independently identify embolic stroke as the cause of large vessel occlusion.
Morinda officinalis oligosaccharides alleviate depressive‐like behaviors in post‐stroke rats via suppressing NLRP3 inflammasome to inhibit hippocampal inflammation
Authors: Li Zhifang , Xu Hexiang , Xu Yi , Lu Guanfeng , Peng Qiwei , Chen Jiefang , Bi Rentang , Li Jianzhuang , Chen Shengcai , Li Hongkai , Jin Huijuan , Hu Bo 
Published: September 2021

AbstractAimsMorinda officinalis oligosaccharides (MOOs), a traditional Chinese medicine, have been used to treat mild and moderate depressive episodes. In this study, we investigated whether MOOs can ameliorate depressive‐like behaviors in post‐stroke depression (PSD) rats and further explored its mechanism by suppressing microglial NLRP3 inflammasome activation to inhibit hippocampal inflammation.MethodsBehavioral tests were performed to evaluate the effect of MOOs on depressive‐like behaviors in PSD rats. The effects of MOOs on the expression of IL‐18, IL‐1β, and nucleotide‐binding domain leucine‐rich repeat (NLR) family pyrin domain containing 3 (NLRP3) inflammasome were measured in both PSD rats and lipopolysaccharide (LPS) and adenosine triphosphate (ATP) stimulated primary rat microglia by reverse transcription polymerase chain reaction (RT‐PCR), immunofluorescence and Western blot analysis. Adeno‐associated virus (AAV) was injected into the hippocampus to regulate NLRP3 inflammasome expression. The detailed molecular mechanism underlying the effects of MOOs was analyzed by Western blot and immunofluorescence.ResultsMOOs can alleviate depressive‐like behaviors in PSD rats. PSD rats showed increased expression of IL‐18, IL‐1β, and NLRP3 inflammasome in the ischemic hippocampus, while MOOs reversed the elevation. NLRP3 downregulation ameliorated depressive‐like behaviors and hippocampal inflammation response in PSD rats, while NLRP3 upregulation inhibited the effect of MOOs on depressive‐like behaviors and hippocampal inflammation response in PSD rats. Moreover, we found that NLRP3 was mainly expressed on microglia. In vitro, MOOs effectively inhibited the expression of IL‐18, IL‐1β, and NLRP3 inflammasome in LPS + ATP treated primary rat microglia. We also showed that modulation of NLRP3 inflammasome by MOOs was associated with the IκB/NF‐κB p65 signaling pathway.ConclusionOverall, our study reveals the antidepressive effect of MOOs on PSD rats through modulation of microglial NLRP3 inflammasome. We also provide a novel insight into hippocampal inflammation response in PSD pathology and put forward NLRP3 inflammasome as a potential therapeutic target for PSD.
Arid1a regulates neural stem/progenitor cell proliferation and differentiation during cortical development
Authors: Liu Xiao , Dai Shang‐Kun , Liu Pei‐Pei , Liu Chang‐Mei 
Published: September 2021

AbstractObjectiveNeurodevelopmental diseases are common disorders caused by the disruption of essential neurodevelopmental processes. Recent human exome sequencing and genome‐wide association studies have shown that mutations in the subunits of the SWI/SNF (BAF) complex are risk factors for neurodevelopmental diseases. Clinical studies have found that ARID1A (BAF250a) is the most frequently mutated SWI/SNF gene and its mutations lead to mental retardation and microcephaly. However, the function of ARID1A in brain development and its underlying mechanisms still remain elusive.MethodsThe present study used Cre/loxP system to generate an Arid1a conditional knockout mouse line. Cell proliferation, cell apoptosis and cell differentiation of NSPCs were studied by immunofluorescence staining. In addition, RNA‐seq and RT‐PCR were performed to dissect the molecular mechanisms of Arid1a underlying cortical neurogenesis. Finally, rescue experiments were conducted to evaluate the effects of Neurod1 or Fezf2 overexpression on the differentiation of NSPCs in vitro.ResultsConditional knockout of Arid1a reduces cortical thickness in the developing cortex. Arid1a loss of function inhibits the proliferation of radial glial cells, and increases cell death during late cortical development, and leads to dysregulated expression of genes associated with proliferation and differentiation. Overexpression of Neurod1 or Fezf2 in Arid1a cKO NSPCs rescues their neural differentiation defect in vitro.ConclusionsThis study demonstrates for the first time that Arid1a plays an important role in regulating the proliferation and differentiation of NSPCs during cortical development, and proposes several gene candidates that are worth to understand the pathological mechanisms and to develop novel interventions of neurodevelopment disorders caused by Arid1a mutations.
Examining stakeholder perceptions of oyster ecosystem services using fuzzy cognitive mapping
Authors: Drew Joshua , Kahn Beryl , Locatelli Nicolas , Airey Montana , Humphries Austin 
Published: September 2021

AbstractNature provides numerous ecosystem services to people, yet the prioritization of these services often depends on the goals of various stakeholder groups. The eastern oyster (Crassostrea virginica) is an ecologically important species along the Gulf and Atlantic coasts of the United States, where it provides essential fish habitat and may mitigate against climatic variations in urban areas. The eastern oyster also supports a multimillion dollar aquaculture industry in coastal communities. Recent declines in eastern oyster populations, however, have spurred widespread restoration activities. Here, we look at three expert stakeholder groups (academics, nongovernmental organizations, and governmental agencies) in Rhode Island (United States) to understand how stakeholder perceptions of oyster ecosystem services differ. Stakeholders' mental models showed differences among the groups' topologies and components, although the terms “Water Quality” and “Habitat/Structural Complexity” were prioritized in all the groups. Our results suggest that there is substantial intergroup variation, but that there are common threads around which future oyster restoration and management programs can be designed. By making these mental models of ecosystem services explicit, we illuminate tacit assumptions held by different stakeholders of the oyster stakeholder community in Rhode Island. In doing so, we highlight opportunities for more efficient collaboration around commonly shared goals for sustainable social and ecological management.