bluuebunny/crossref_metadata_2025_split huggingface dataset:
Paving the road to make chimeric antigen receptor‐T‐cell therapy effective against solid tumors
Authors: Adachi Keishi , Tamada Koji 
Published: September 2022

AbstractThe three major standard therapies, that is, surgery, chemotherapy, and radiation therapy have conventionally been applied to the treatments for cancers and have saved many patients. In addition, for intractable, refractory, or advanced malignancies that cannot be cured by the three standard therapies, immunotherapy is an important subject of basic and clinical researches. Immune checkpoint inhibitor therapy (ICI) has shown significant therapeutic efficacies on some types of tumors in large‐scale randomized clinical trials, making a major impact on clinical oncology by scientifically proving and establishing the effectiveness of an immunotherapy. In 2018, ICI was awarded the Nobel Prize in Physiology or Medicine, and immunotherapy is now becoming the “fourth” standard therapy for cancers. Recently, adoptive cell therapies, in which genetically modified T cells with enhanced reactivity against tumors are infused into the patients, have been attracting considerable attention as a hopeful immunotherapy following ICI. Particularly, chimeric antigen receptor (CAR)‐T‐cell therapies demonstrate marked therapeutic efficacies against some hematologic malignancies, and have been approved in many countries. However, current CAR‐T‐cell therapy is considered to be little effective against solid tumors, which is one of the challenging issues to be overcome in CAR‐T‐cell therapy. In this review, we at first introduce CAR and CAR‐T cell, and then focus on the recent progress of CAR‐T‐cell therapy against solid tumors as well as the novel concept on a role of CAR‐T cells, aiming to further understandings of the novel cancer immunotherapies.
Hereditary spastic paraparesis presenting as cerebral palsy due to ADD3 variant with mechanistic insight provided by a Drosophila γ‐adducin model
Authors: Sanchez Marco Silvia Beatriz , Buhl Edgar , Firth Rose , Zhu Bangfu , Gainsborough Mary , Beleza‐Meireles Ana , Moore Sandra , Caswell Richard , Stals Karen , Ellard Sian , Kennedy Cameron , Hodge James J. L. , Majumdar Anirban 
Published: September 2022

AbstractCerebral palsy (CP) causes neurological disability in early childhood. Hypoxic‐ischaemic injury plays a major role in its aetiology, nevertheless, genetic and epigenetic factors may contribute to the clinical presentation. Mutations in ADD3 (encoding γ‐adducin) gene have been described in a monogenic form of spastic quadriplegic cerebral palsy (OMIM 601568). We studied a 16‐year‐old male with spastic diplegia. Several investigations including neurometabolic testing, brain and spine magnetic resonance imaging (MRI) and CGH‐Array were normal. Further, clinical genetics assessment and whole exome sequencing (WES) gave the diagnosis. We generated an animal model using Drosophila to study the effects of γ‐adducin loss and gain of function. WES revealed a biallelic variant in the ADD3 gene, NM_016824.5(ADD3): c.1100G > A, p.(Gly367Asp). Mutations in this gene have been described as an ultra‐rare autosomal recessive, which is a known form of inherited cerebral palsy. Molecular modelling suggests that this mutation leads to a loss of structural integrity of γ‐adducin and is therefore expected to result in a decreased level of functional protein. Pan‐neuronal over‐expression or knock‐down of the Drosophila ortholog of ADD3 called hts caused a reduction of life span and impaired locomotion thereby phenocopying aspects of the human disease. Our animal experiments present a starting point to understand the biological processes underpinning the clinical phenotype and pathogenic mechanisms, to gain insights into potential future methods for treating or preventing ADD3 related spastic quadriplegic cerebral palsy.
Efficacy and safety of 3‐n‐butylphthalide for the treatment of cognitive impairment: A systematic review and meta‐analysis
Authors: Zhou Qiulu , Han Chao , Xia Yun , Wan Fang , Yin Sijia , Li Yunna , Kou Liang , Chi Xiaosa , Hu Junjie , Sun Yadi , Wu Jiawei , Zou Wenkai , Huang Jinsha , Wang Tao 
Published: September 2022

AbstractBackgroundCurrent evidence for the efficacy of pharmacological treatment in improving cognitive function is absent. Recent studies have reported that 3‐n‐butylphthalide (NBP) has a positive effect on improving cognitive impairment; however, its clinical efficacy and safety is unclear. Therefore, we conducted a meta‐analysis to assess its efficacy and safety for cognitive impairment.MethodsWe systematically searched the PubMed, EMBASE, Cochrane Library, Web of Science, and Scopus databases, and two reviewers independently screened and extracted the data from included studies. We synthesized the data using the Review Manager Software version 5.3.ResultsWe included six randomized clinical trials (RCTs), encompassing 851 patients with cognitive impairment. The results showed that NBP improved cognitive impairment. Specifically, the clinical efficacy was better than that in the control group, with better performance in improving the Mini‐Mental State Examination and the Montreal Cognitive Assessment scores, while decreasing the Alzheimer's Disease Assessment Scale‐Cognitive subscale and the Clinician's Interview‐Based Impression of Change plus caregiver input scores. There was no significant difference in the incidence of adverse events between both groups.ConclusionThe NBP is effective and safe in improving cognitive impairment; however, more high‐quality RCTs are needed to confirm these findings.
Exploring metapopulation‐scale suppression alternatives for a global invader in a river network experiencing climate change
Authors: Healy Brian D. , Budy Phaedra , Yackulic Charles. B. , Murphy Brendan P. , Schelly Robert C. , McKinstry Mark C. 
Published: September 2022

AbstractInvasive species can dramatically alter ecosystems, but eradication is difficult, and suppression is expensive once they are established. Uncertainties in the potential for expansion and impacts by an invader can lead to delayed and inadequate suppression, allowing for establishment. Metapopulation viability models can aid in planning strategies to improve responses to invaders and lessen invasive species’ impacts, which may be particularly important under climate change. We used a spatially explicit metapopulation viability model to explore suppression strategies for ecologically damaging invasive brown trout (Salmo trutta), established in the Colorado River and a tributary in Grand Canyon National Park. Our goals were to estimate the effectiveness of strategies targeting different life stages and subpopulations within a metapopulation; quantify the effectiveness of a rapid response to a new invasion relative to delaying action until establishment; and estimate whether future hydrology and temperature regimes related to climate change and reservoir management affect metapopulation viability and alter the optimal management response. Our models included scenarios targeting different life stages with spatially varying intensities of electrofishing, redd destruction, incentivized angler harvest, piscicides, and a weir. Quasi‐extinction (QE) was obtainable only with metapopulation‐wide suppression targeting multiple life stages. Brown trout population growth rates were most sensitive to changes in age 0 and large adult mortality. The duration of suppression needed to reach QE for a large established subpopulation was 12 years compared with 4 with a rapid response to a new invasion. Isolated subpopulations were vulnerable to suppression; however, connected tributary subpopulations enhanced metapopulation persistence by serving as climate refuges. Water shortages driving changes in reservoir storage and subsequent warming would cause brown trout declines, but metapopulation QE was achieved only through refocusing and increasing suppression. Our modeling approach improves understanding of invasive brown trout metapopulation dynamics, which could lead to more focused and effective invasive species suppression strategies and, ultimately, maintenance of populations of endemic fishes.
Effects of interactions between anthropogenic stressors and recurring perturbations on ecosystem resilience and collapse
Authors: Keith David A. , Benson Doug H. , Baird Ian R. C. , Watts Laura , Simpson Christopher C. , Krogh Martin , Gorissen Sarsha , Ferrer‐Paris Jose R. , Mason Tanya J. 
Published: September 2022

AbstractInsights into declines in ecosystem resilience and their causes and effects can inform preemptive action to avoid ecosystem collapse and loss of biodiversity, ecosystem services, and human well‐being. Empirical studies of ecosystem collapse are rare and hampered by ecosystem complexity, nonlinear and lagged responses, and interactions across scales. We investigated how an anthropogenic stressor could diminish ecosystem resilience to a recurring perturbation by altering a critical ecosystem driver. We studied groundwater‐dependent, peat‐accumulating, fire‐prone wetlands known as upland swamps in southeastern Australia. We hypothesized that underground mining (stressor) reduces resilience of these wetlands to landscape fires (perturbation) by diminishing groundwater, a key ecosystem driver. We monitored soil moisture as an indicator of ecosystem resilience during and after underground mining. After landscape fire, we compared responses of multiple state variables representing ecosystem structure, composition, and function in swamps within the mining footprint with unmined reference swamps. Soil moisture declined without recovery in swamps with mine subsidence (i.e., undermined), but was maintained in reference swamps over 8 years (effect size 1.8). Relative to burned reference swamps, burned undermined swamps showed greater loss of peat via substrate combustion; reduced cover, height, and biomass of regenerating vegetation; reduced postfire plant species richness and abundance; altered plant species composition; increased mortality rates of woody plants; reduced postfire seedling recruitment; and extirpation of a hydrophilic animal. Undermined swamps therefore showed strong symptoms of postfire ecosystem collapse, whereas reference swamps regenerated vigorously. We found that an anthropogenic stressor diminished the resilience of an ecosystem to recurring perturbations, predisposing it to collapse. Avoidance of ecosystem collapse hinges on early diagnosis of mechanisms and preventative risk reduction. It may be possible to delay or ameliorate symptoms of collapse or to restore resilience, but the latter appears unlikely in our study system due to fundamental alteration of a critical ecosystem driver.Efectos de las interacciones entre los estresantes antropogénicos y las perturbaciones recurrentes sobre la resiliencia y el colapso de los ecosistemas
Learning from perpetrator replacement to remove crime opportunities and prevent poaching of the Sundarbans tiger
Authors: Uddin Nasir , Enoch Sam , Harihar Abishek , Pickles Rob S. A. , Ara Tasnim , Hughes Alice C. 
Published: September 2022

AbstractIllegal wildlife trade (IWT) is one of the leading causes of the decline in high‐value species. Crime‐reduction strategies to counter IWT can have unintended effects, with crime displacement occurring when offenders react to such interventions. Despite the value of understanding how and why displacement occurs for informing conservation strategies, few examples are published. We explored a case of perpetrator replacement following an intervention and drew lessons for conservation strategies for high‐value species. Poaching and subsequent trade threaten the Sundarbans tiger (Panthera tigris). Pirate gangs were the dominant poachers from 1980 to 2017, but following an extensive campaign, the Sundarbans was declared pirate free in 2018. We interviewed 280 individuals, including 100 tiger poachers, from 26 administrative unions bordering the Sundarbans and used interviewee responses to compare the poaching situation during and after the pirate era. We analyzed the spatial distribution of tiger poachers among the unions and used crime script analysis of the dominant poacher type to identify intervention. Because pirates opportunistically poached tigers, the government's successful counter‐pirate campaign inadvertently removed the dominant tiger poaching type. However, a temporary reduction in poaching was rapidly cancelled out by the emergence of at least 32 specialist tiger‐poaching teams. With the risk of extortion and robbery from pirates gone, other groups increased the frequency of opportunistic and targeted tiger poaching. Based on expert interviews, we estimated that 341 tiger poachers of all types are active throughout the unions, with 79% of specialists concentrated in 27% of unions. The highly focused counter‐pirate campaign reduced motivations and opportunities for piracy but left intact the opportunity structure and trade connections for tiger poaching, and with insufficient enforcement officers trading has flourished. Interventions targeting opportunities for poaching by specialist tiger poachers include heightened surveillance and reporting mechanisms and alternative livelihood provision to disincentivize poaching.
A phase I, randomized, placebo‐controlled study of molnupiravir in healthy Japanese to support special approval in Japan to treat COVID‐19
Authors: Nakamura Keisuke , Fujimoto Katsukuni , Hasegawa Chihiro , Aoki Ikuo , Yoshitsugu Hiroyuki , Ugai Hiroyuki , Yatsuzuka Naoyoshi , Tanaka Yoshiyuki , Furihata Kenichi , Maas Brian M. , Wickremasingha Prachi K. , Duncan Kelly E. , Iwamoto Marian , Stoch Selwyn A. , Uemura Naoto 
Published: September 2022

AbstractMolnupiravir (MK‐4482) is an oral prodrug of the antiviral ribonucleoside analog, N‐hydroxycytidine (NHC), which has activity against RNA viruses, including severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2). We conducted a phase I safety and pharmacokinetic study of molnupiravir in healthy Japanese adult participants. A sample size larger than typically used in pharmacokinetic studies was implemented to collect additional safety data in the Japanese population to support special approval for emergency use in Japan. Single doses of molnupiravir up to 1600 mg and multiple doses of 400 and 800 mg administered every 12 h (q12h) for 5.5 days were generally well‐tolerated. NHC appeared rapidly in plasma and reached maximum concentration (Cmax), with a median time to Cmax (Tmax) between 1.00 and 2.00 h. Area under the concentration versus time curve from zero to infinity (AUC0–inf), area under the concentration versus time curve from zero to 12 h (AUC0–12), and Cmax of plasma NHC increased approximately dose proportionally. With q12h dosing, the geometric mean (GM) accumulation ratios for NHC AUC0–12 and Cmax were ~1 for 400 and 800 mg. Pharmacokinetics of NHC triphosphate (NHC‐TP), the active metabolite of NHC was assessed in peripheral blood mononuclear cells and also demonstrated roughly dose proportional pharmacokinetics. The GM accumulation ratios for NHC‐TP AUC0–12 and Cmax were ~2.5 for 400 and 800 mg. Following administration with food, only a modest reduction (24%) in plasma NHC Cmax with comparable AUC0–inf was seen, supporting administration without regard to food.
Interleukin‐1α and tumor necrosis factor α as an inducer for reactive‐oxygen‐species‐mediated NOD‐like receptor protein 1/NOD‐like receptor protein 3 inflammasome activation in mononuclear blood cells from individuals with chronic insomnia disorder
Authors: Aghelan Zahra , Karima Saeed , Khazaie Habibolah , Abtahi Seyed Hosein , Farokhi Ali Reza , Rostampour Masoumeh , Bahrehmand Fariborz , Khodarahmi Reza 
Published: September 2022

AbstractBackground and purposeThere is some evidence that cytokines may play an important role in sleep deprivation; however, the underlying mechanisms are still unknown. So, the present study aimed to evaluate the relationship between NOD‐like receptor protein 1 (NLRP1) and NOD‐like receptor protein 3 (NLRP3) inflammasome activation of blood cells and serum levels of cytokines in individuals with chronic insomnia disorder (CID).MethodsBlood samples were collected from 24 individuals with CID and 24 healthy volunteers. The inflammasome activation was evaluated using real‐time polymerase chain reaction of NLRP1, NLRP3, apoptosis‐associated speck‐like protein containing a caspase‐recruitment domain (ASC) and caspase‐1; western blot of NLRP1 and NLRP3; caspase‐1 activity assay; and serum levels of interleukin‐1β (IL‐1β), IL‐18 and other cytokines using enzyme‐linked immunosorbent assay. Reactive oxygen species generation in blood cells were detected by flow cytometry assay. Also, magnetic resonance imaging scans were obtained on a Siemens Magnetom Avanto 1.5 T MRI whole‐body scanner using an eight‐channel head coil.ResultsIncreased activity of NLRP1 and NLRP3 inflammasomes in blood cells, increased serum levels of pro‐inflammatory cytokines and decreased serum levels of IL‐10 and transforming growth factor β in individuals with CID were found. Significant correlation was observed between increased serum concentration of IL‐1β and the severity of insomnia in individuals with CID. The levels of reactive oxygen species in blood cells were found to be correlated with IL‐1α and tumor necrosis factor α concentrations in sera from individuals with CID. Moreover, the individuals with CID demonstrated increased right cerebellum cortex and lateral ventricle mean diffusivity bilaterally compared to controls.ConclusionsThis study provided new insights on the pathogenesis of CID and the effects of cytokines on inflammasome activation.
Validation of motor and functional scales for the evaluation of adult patients with 5q spinal muscular atrophy
Authors: Vázquez‐Costa Juan F. , Povedano Mónica , Nascimiento‐Osorio Andrés E. , Moreno Escribano Antonio , Kapetanovic Garcia Solange , Dominguez Raul , Exposito Jessica M. , González Laura , Marco Carla , Medina Castillo Julita , Muelas Nuria , Natera de Benito Daniel , Ñungo Garzón Nancy Carolina , Pitarch Castellano Inmaculada , Sevilla Teresa , Hervás David 
Published: September 2022

AbstractBackground and purposeMos scales currently used to evaluate spinal muscular atrophy (SMA) patients have only been validated in children. The aim of this study was to assess the construct validity and responsiveness of several outcome measures in adult SMA patients.MethodsPatients older than 15 years and followed up in five referral centres for at least 6 months, between October 2015 and August 2020, with a motor function scale score (Hammersmith Functional Motor Scale Expanded [HFMSE], Revised Upper Limb module [RULM]) were included. Bedside functional scales (Egen Klassification [EK2], Revised Amyotrophic Lateral Sclerosis Functional Rating Scale [ALSFRS‐R]) were also collected when available. Spearman's rho correlations (rs) and Bangdiwala's concordance test (B) were used to evaluate the scales' construct validity. Monthly slopes of change were used to calculate their responsiveness of the scales.ResultsThe study included 79 SMA patients, followed up for a mean of 16 months. All scales showed strong correlations with each other (rs > 0.70). A floor effect in motor function scales was found in the weakest patients (HFMSE < 5 and RULM < 10), and a ceiling effect was found in stronger patients (HFMSE > 60 and RULM > 35). The ALSFRS‐R (B = 0.72) showed a strong ability to discriminate between walkers, sitters and non‐sitters, and the HFMSE (B = 0.86) between walkers and sitters. The responsiveness was low overall, although in treated patients a moderate responsiveness was found for the ALSFRS‐R and HFMSE in walkers (0.69 and 0.61, respectively) and for EK2 in sitters (0.65) and non‐sitters (0.60).ConclusionsThis study shows the validity and limitations of the scales most frequently used to assess adult SMA patients. Overall, bedside functional scales showed some advantages over motor scales, although all showed limited responsiveness.
The coordination of green–brown food webs and their disruption by anthropogenic nutrient inputs
Authors: Zelnik Yuval R. , Manzoni Stefano , Bommarco Riccardo 
Published: September 2022

AbstractAimOur goal was to quantify nitrogen flows and stocks in green–brown food webs in different ecosystems, how they differ across ecosystems and how they respond to nutrient enrichment.LocationGlobal.Time periodContemporary.Major taxa studiedPlants, phytoplankton, macroalgae, invertebrates, vertebrates and zooplankton.MethodsData from >500 studies were combined to estimate nitrogen stocks and fluxes in green–brown food webs in forests, grasslands, brackish environments, seagrass meadows, lakes and oceans. We compared the stocks, fluxes and metabolic rates of different functional groups within each food web. We also used these estimates to build a dynamical model to test the response of the ecosystems to nutrient enrichment.ResultsWe found surprising symmetries between the green and brown channels across ecosystems, in their stocks, fluxes and consumption coefficients and mortality rates. We also found that nitrogen enrichment, either organic or inorganic, can disrupt this balance between the green and brown channels.Main conclusionsLinking green and brown food webs reveals a previously hidden symmetry between herbivory and detritivory, which appears to be a widespread property of natural ecosystems but can be disrupted by anthropogenic nitrogen additions.
Factors associated with patient empowerment in Spanish adults with type 2 diabetes: A cross‐sectional analysis
Authors: Duarte‐Díaz Andrea , González‐Pacheco Himar , Rivero‐Santana Amado , Ramallo‐Fariña Yolanda , Perestelo‐Pérez Lilisbeth , Peñate Wenceslao , Carrion Carme , Serrano‐Aguilar Pedro ,   INDICA Team
Published: September 2022

AbstractObjectiveThe aim of the present study is to identify factors associated with patient empowerment in people living with type 2 diabetes mellitus (T2DM) in the Canary Islands (Spain).MethodsSecondary cross‐sectional analysis was carried out of data obtained in the INDICA study: A 24‐month cluster randomized‐controlled trial evaluating the effectiveness of educational interventions supported by new technology decision tools for T2DM patients. Sociodemographic variables, clinical data (years since diagnosis, glycated haemoglobin level, creatine, triglycerides, waist hip index, body mass index and number of comorbidities), diabetes knowledge (DIATEK), affective outcomes (Beck Depression Inventory‐II, the State subscale of the State‐Trait Anxiety Inventory and The Diabetes Distress Scale) and diabetes‐related quality of life (The Audit of Diabetes‐Dependent Quality of life) were assessed as potential correlates of patient empowerment, assessed using the Diabetes Empowerment Scale‐Short Form. Multilevel mixed linear regression models on patient empowerment were developed.ResultsThe analysis included the baseline data of 2334 patients. Results showed that age (B = −0.14; p < .001), diabetes knowledge (B = 0.61; p < .001) and state‐anxiety (B = −0.09; p < .001) are significantly associated with patient empowerment. Sex, education level, living alone, employment status, country of birth, time since diagnosis, number of comorbidities, glycated haemoglobin level, depression and distress were not independently associated with patient empowerment in the multivariate analyses.ConclusionYounger age, lower state‐anxiety and greater diabetes‐specific knowledge are important correlates of patient empowerment. In line with the results of the INDICA study, interventions based on patient‐centred care might be effective in improving patient empowerment in adults with T2DM. Understanding the factors associated with empowerment may help clinicians and policymakers to identify high‐risk groups, prioritize resources and target evidence‐based interventions to better support people with T2DM to be actively involved in their own care.Patient or Public ContributionPatients with T2DM were actively involved in the design of the INDICA study. Two patient associations were included as part of the research team and actively participated in designing the interventions and selecting outcome measures.