bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting KDM4C enhances CD8+ T cell mediated antitumor immunity by activating chemokine CXCL10 transcription in lung cancer
Authors: Jie Xiaohua , Chen Yunshang , Zhao Ye , Yang Xijie , Xu Yingzhuo , Wang Jian , Meng Rui , Zhang Sheng , Dong Xiaorong , Zhang Tao , Yang Kunyu , Xu Shuangbing , Wu Gang 
Published: February 2022

BackgroundAlthough immune checkpoint blockade (ICB) has been proven to achieve a persistent therapeutic response in various tumor types, only 20%–40% of patients benefit from this treatment. Radiotherapy (RT) can enhance tumor immunogenicity and improve the ICB response, but the outcome achieved by combining these two modalities remains clinically unsatisfactory. We previously uncovered that lysine-specific demethylase 4C (KDM4C) is a regulator of radiosensitivity in lung cancer. However, the role of KDM4C in antitumor immunity has not yet been investigated.MethodsInfiltrating immune cells in our mouse tumor model were screened by flow cytometry. An in vivo subcutaneous transplanted tumor model and in vitro conditioned culture model were constructed to detect the quantitative and functional changes in CD8+ T cells. RNA sequencing and chromatin immunoprecipitation-PCR assays were used to explore the downstream regulatory mechanism of KDM4C in antitumor immunity. A C57BL/6 mouse tumor model was developed to evaluate the efficacy and safety of a triple therapy (the KDM4C-specific inhibitor SD70 plus RT and an anti-PD-L1 antibody) in lung cancer in vivo.ResultsGenetical or pharmacological inhibition of KDM4C specifically increased CD8+ T cell infiltration; promoted the proliferation, migration and activation of CD8+ T cells; and alleviated CD8+ T cell exhaustion in mouse tumor tissues. Mechanistically, KDM4C inhibition increased the binding of H3K36me3 to the CXCL10 promoter region, thus inducing CXCL10 transcription and enhancing the CD8+ T cell mediated antitumor immune response. More importantly, among the tested regimens, the triple therapy achieved the best therapeutic efficacy with tolerable toxicity in lung cancer.ConclusionsOur data reveal a crucial role for KDM4C in antitumor immunity in lung cancer and indicate that targeting KDM4C in combination with radioimmunotherapy might be a promising synergistic strategy in lung cancer.
RNA splicing analysis contributes to reclassifying variants of uncertain significance and improves the diagnosis of monogenic disorders
Authors: He Wen-Bin , Xiao Wen-Juan , Dai Cong-Ling , Wang Yu-Rong , Li Xiu-Rong , Gong Fei , Meng Lan-Lan , Tan Chen , Zeng Si-Cong , Lu Guang-Xiu , Lin Ge , Tan Yue-Qiu , Hu Hao , Du Juan 
Published: February 2022

BackgroundNumerous variants of uncertain significance (VUSs) have been identified by whole exome sequencing in clinical practice. However, VUSs are not currently considered medically actionable.ObjectiveTo assess the splicing patterns of 49 VUSs in 48 families identified clinically to improve genetic counselling and family planning.MethodsForty-nine participants with 49 VUSs were recruited from the Reproductive and Genetic Hospital of CITIC-Xiangya. Bioinformatic analysis was performed to preliminarily predict the splicing effects of these VUSs. RT-PCR and minigene analysis were used to assess the splicing patterns of the VUSs. According to the results obtained, couples opted for different methods of reproductive interventions to conceive a child, including prenatal diagnosis and preimplantation genetic testing (PGT).ResultsEleven variants were found to alter pre-mRNA splicing and one variant caused nonsense-mediated mRNA decay, which resulted in the reclassification of these VUSs as likely pathogenic. One couple chose to undergo in vitro fertilisation with PGT treatment; a healthy embryo was transferred and the pregnancy is ongoing. Three couples opted for natural pregnancy with prenatal diagnosis. One couple terminated the pregnancy because the fetus was affected by short-rib thoracic dysplasia and harboured the related variant. The infants of the other two couples were born and were healthy at their last recorded follow-up.ConclusionRNA splicing analysis is an important method to assess the impact of sequence variants on splicing in clinical practice and can contribute to the reclassification of a significant proportion of VUSs. RNA splicing analysis should be considered for genetic disease diagnostics.
Cost-effectiveness model of renal cell carcinoma (RCC) surveillance in hereditary leiomyomatosis and renal cell carcinoma (HLRCC)
Authors: Thompson Alexander J , Alwan Yousef M , Ramani Vijay A C , Evans D Gareth , Maher Eamonn R , Woodward Emma R 
Published: February 2022

PurposeTo determine the cost-effectiveness of annual renal imaging surveillance (RIS) in hereditary leiomyomatosis and renal cell cancer (HLRCC). HLRCC is associated with a 21% risk to age 70 years of RCC. Presentations with advanced renal cell cancer (RCC) are associated with poor outcomes whereas RIS detects early-stage RCC; however, evidence for the cost-effectiveness of RIS is lacking.MethodsWe developed a decision-analytic model to compare, at different age starting points (11 years, 18 years, 40 years, 60 years), the costs and benefits of lifetime contrast-enhanced renal MRI surveillance (CERMRIS) vs no surveillance in HLRCC. Benefits were measured in life-years gained (LYG), quality-adjusted life years (QALYs) and costs in British Pounds Sterling (GBP). Net monetary benefit (NMB) was calculated using a cost-effectiveness threshold of £20 000/QALY. One-way sensitivity and probabilistic analyses were also performed.ResultsIn the base-case 11-year age cohort, surveillance was cost-effective (Incremental_NMB=£3522 (95% CI −£2747 to £7652); Incremental_LYG=1.25 (95% CI 0.30 to 1.86); Incremental_QALYs=0.29 (95% CI 0.07 to 0.43)] at an additional mean discounted cost of £2185/patient (95% CI £430 to £4144). Surveillance was also cost-effective in other age cohorts and dominated a no surveillance strategy in the 40 year cohort [Incremental_NMB=£12 655 (95% CIs −£709 to £21 134); Incremental_LYG=1.52 (95% CI 0.30 to 2.26); Incremental_QALYs=0.58 (95% CI 0.12 to 0.87) with a cost saving of £965/patient (95% CI −£4202 to £2652).ConclusionAnnual CERMRI in HLRCC is cost-effective across age groups modelled.
Neurofibromatosis type 1 families with first-degree relatives harbouring distinct NF1 pathogenic variants. Genetic counselling and familial diagnosis: what should be offered?
Authors: Garcia Belen , Catasus Nuria , Ros Andrea , Rosas Inma , Negro Alejandro , Guerrero-Murillo Mercedes , Valero Ana Maria , Duat-Rodriguez Anna , Becerra Juan Luis , Bonache Sandra , Lázaro Garcia Conxi , Comas Carmina , Bielsa Isabel , Serra Eduard , Hernández-Chico Concepción , Martin Yolanda , Castellanos Elisabeth , Blanco Ignacio 
Published: February 2022

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by pathogenic variants in NF1. Recently, NF1 testing has been included as a clinical criterion for NF1 diagnosis. Additionally, preconception genetic counselling in patients with NF1 focuses on a 50% risk of transmitting the familial variant as the risk of having a sporadic NF1 is considered the same as the general population.Methods829 individuals, 583 NF1 sporadic cases and 246 patients with NF1 with documented family history, underwent genetic testing for NF1. Genotyping and segregation analysis of NF1 familial variants was determined by microsatellite analysis and NF1 sequencing.ResultsThe mutational analysis of NF1 in 154 families with two or more affected cases studied showed the co-occurrence of two different NF1 germline pathogenic variants in four families. The estimated mutation rate in those families was 3.89×10–3, 20 times higher than the NF1 mutation rate (~2×10−4) (p=0.0008). Furthermore, the co-occurrence of two different NF1 germline pathogenic variants in these families was 1:39, 60 times the frequency of sporadic NF1 (1:2500) (p=0.003). In all cases, the de novo NF1 pathogenic variant was present in a descendant of an affected male. In two cases, variants were detected in the inherited paternal wild-type allele.ConclusionsOur results, together with previous cases reported, suggest that the offspring of male patients with NF1 could have an increased risk of experiencing de novo NF1 pathogenic variants. This observation, if confirmed in additional cohorts, could have relevant implications for NF1 genetic counselling, family planning and NF1 genetic testing.
Asthma in pesticide users: an update from the Great Britain Prospective Investigation of Pesticide Applicators’ Health (PIPAH) cohort study
Authors: Fishwick David , Harding Anne-Helen , Chen Y , Pearce Neil , Frost Gillian 
Published: February 2022

ObjectivesTo define the prevalence and incidence of asthma in a large working population of pesticide workers and to assess which exposures are potentially of relevance to causing or aggravating this condition.MethodsA baseline cross-sectional study at recruitment (2013–2017, n=5817), with follow-up in 2018 (n=2578), was carried out in predominantly Great Britain based pesticide workers. At baseline, participants completed a health and work questionnaire which included questions on demographic, lifestyle, socioeconomic and work-related factors, pesticide use and doctor diagnosed health conditions. In January 2018, a follow-up questionnaire focused on respiratory ill health, with questions covering self-reported respiratory symptoms and doctor diagnosed respiratory conditions. The associations of various exposures with asthma were estimated using logistic regression adjusting for age as a continuous variable, and for sex where possible. An estimate of hours worked with pesticides in the previous year was calculated for each participant.ResultsAt baseline, 608 (10.4%) had doctor diagnosed asthma. In 2018 the figure was 297 (11.5% of the follow-up population); the incidence of new asthma cases between surveys was 1.7 cases per 1000 participants per year. At follow-up, 18.1% reported wheeze in the last 12 months, 73.2% of those with self-reported asthma noted it to be persistent and using a more specific definition of asthma (doctor diagnosed asthma with at least one asthma-related symptom in the last year); 6.8% (95% CI 5.9% to 7.9%) fulfilled this definition. At follow-up, 127 participants felt that their asthma was caused or made worse by their work, with 77 (63.6%) nominating organic dust, 13 (10.7%) unspecified dust, 12 (9.9%) chemicals, 9 (7.4%) mixed exposures, 7 (5.8%) physical agents and 3 (2.5%) fumes or other irritants. There was little or no association between high pesticide exposure and doctor diagnosed asthma or self-reported recent wheeze, although there was an elevated risk for work-related wheeze (OR for high exposure=2.67; 95% CI 1.16 to 6.18). High pesticide exposure (high vs low exposure category OR 2.68, 95% CI 1.28 to 5.60) was also associated with work-related chest tightness. Exposure to organic dusts was associated (significantly, p=0.026) with persistent asthma when adjusted for the effects of age and smoking.ConclusionsThis large study of pesticide workers has identified expected levels of doctor diagnosed asthma, and high levels of self-reported respiratory symptoms. Pesticide exposure was associated with an increased risk of self-reported work-related wheeze, but not with asthma or wheeze in general. Further work is needed to identify more clearly which exposures within a complex mixed exposure profile are likely causative in order to best focus interventions to reduce work-related asthma and related conditions.
Factors associated with low levels of HIV testing among young men who have sex with men (MSM) participating in EMIS-2017 in Spain
Authors: Gallego Nuria , Diaz Asuncion , Folch Cinta , Meyer Sebastian , Vazquez Maria , Casabona Jordi , Hernando Victoria 
Published: February 2022

PurposeThe European Men who have sex with men Internet Survey looked over the characteristics and needs of men who have sex with men (MSM) across Europe. Our objective was to estimate the prevalence of HIV testing and its associated factors among MSM younger than 25 years old participating in the EMIS-2017 in Spain.MethodsMultivariable regression model was used to compare those who had been tested for HIV within the last 12 months and those that had not.ResultsOf 2313 participants, 1070 (46.3%) had been tested for HIV in the past 12 months. Increased age (age 19–21 years, aOR=3.38 (95% CI 2.57 to 4.44); age 22–24 years, aOR=5.26 (4.06 to 6.92) compared with age 16–18 years); being migrant (Latin America: aOR=1.34 (0.98 to 1.84); Europe, North America and Mediterranean countries (aOR=1.56 (0.98 to 2.51) compared with those from Spain); living more openly with one’s sexuality (out to some people (aOR=1.53 (1.19 to 1.96)); out to all or almost all people (aOR=2.24 (1.75 to 2.87) compared with those out to none or a few people); having had one condomless steady partners in the las year ((aOR=1.59 (1.26 to 2.02)); having had condomless non-steady partners in the last year (one: aOR=1.76 (1.35 to 2.29)); two or more partners: aOR=2.37 (1.84 to 3.04)); and having practised sex work in the past year (aOR=1.52 (1.07 to 2.13)) were associated with increased odds of HIV testing. Living in a smaller city was associated with less likelihood of HIV testing (<1 00 000 inhabitants: aOR=0.51 (95% CI 0.41 to 0.64); 100 000–500 000: aOR=0.68 (95% CI 0.54 to 0.86) compared with more than 500 000).ConclusionYoung MSM showed low HIV testing rate. Future programming specifically targeting this population, especially those middle adolescents, living in a medium-small city and having less ‘outness’, can help increase HIV testing and prevent access barriers.
Provincial-scale digital soil mapping using a random forest approach for British Columbia
Authors: Heung Brandon , Bulmer Chuck E. , Schmidt Margaret G. , Zhang Jin 
Published: February 2022

Although British Columbia (BC), Canada, has a rich history of producing conventional soil maps (CSMs) between 1925 and 2000, the province still lacks a detailed soil map with a comprehensive coverage due to the cost and time required to develop such a product. This study builds on previous digital soil mapping (DSM) research in BC and develops provincial-scale maps. Soil taxonomic classes (e.g., great groups and order) and parent material classes were mapped at a 100 m spatial resolution for BC (944 735 km2). Training points were generated from detailed and semi-detailed soil survey maps. The training points were intersected with 26 topographic indices for mapping parent materials with an additional 9 climatic and vegetation indices for mapping soil classes. The soil–environmental relationships were inferred using the random forest (RF) classifier. The fitted models were used to predict 23 soil great groups, 9 soil orders, and 10 parent material classes. Accuracy assessments were performed using n = 14 570 validation points for parent material classes and n = 14 316 validation points for soil classes, acquired from the BC Soil Information System. The accuracy rates for soil great groups, orders, and parent material classes were 55%, 62%, and 69%, respectively, and kappa coefficients were 0.37, 0.41, and 0.59, respectively. This study demonstrated that when RF was trained using CSMs, the accuracy for the resulting DSM was higher than the original CSM. To assess prediction uncertainties, ignorance uncertainty maps were developed using class-probability layers generated by the RF models.
Perturbative structure of two- and four-point functions of color charge in a non-Gaussian small-x action
Authors: Giannini Andre V. , Nara Yasushi 
Published: February 2022

AbstractWe compute the perturbative expansion of the two- and four-point functions of color charges in the Color Glass Condensate framework considering the quartic correction to the McLerran–Venugopalan (MV) model of Gaussian color charge fluctuations. Expressions for these correlators in the perturbative expansion for small and large non-Gaussian color charge fluctuations are derived for arbitrary orders in perturbation theory. We explicitly show that the perturbative series does not converge at higher orders as expected. We apply the Borel–Padé resummation method to our problem to construct a convergent series. It is shown that the fully non-perturbative solution can be described by the Borel–Padé approximants constructed from the first few terms of the perturbative series for small non-Gaussian fluctuations.
The COX-2–PGE2 Pathway Promotes Tumor Evasion in Colorectal Adenomas
Authors: Wei Jie , Zhang Jinyu , Wang Dingzhi , Cen Bo , Lang Jessica D. , DuBois Raymond N. 
Published: February 2022

Abstract

The mechanisms underlying the regulation of a checkpoint receptor, PD-1, in tumor-infiltrating immune cells during the development of colorectal cancer are not fully understood. Here we demonstrate that COX-2–derived PGE2, an inflammatory mediator and tumor promoter, induces PD-1 expression by enhancing NFκB's binding to the PD-1 promoter via an EP4–PI3K–Akt signaling pathway in both CD8+ T cells and macrophages. Moreover, PGE2 suppresses CD8+ T-cell proliferation and cytotoxicity against tumor cells and impairs macrophage phagocytosis of cancer cells via an EP4–PI3K–Akt–NFκB–PD-1 signaling pathway. In contrast, inhibiting the COX-2–PGE2–EP4 pathway increases intestinal CD8+ T-cell activation and proliferation and enhances intestinal macrophage phagocytosis of carcinoma cells accompanied by reduction of PD-1 expression in intestinal CD8+ T cells and macrophages in ApcMin/+ mice. PD-1 expression correlates well with COX-2 levels in human colorectal cancer specimens. Both elevated PD-1 and COX-2 are associated with poorer overall survival in patients with colorectal cancer. Our results uncover a novel role of PGE2 in tumor immune evasion. They may provide the rationale for developing new therapeutic approaches to subvert this process by targeting immune checkpoint pathways using EP4 antagonists. In addition, our findings reveal a novel mechanism explaining how NSAIDs reduce colorectal cancer risk by suppressing tumor immune evasion.

Prevention Relevance:
These findings provide a potential explanation underlying the chemopreventive effect of NSAIDs on reducing colorectal cancer incidence during premalignancy and provide a rationale for developing EP4 antagonists for colorectal cancer prevention and treatment. Simply targeting PGE2 signaling alone may be efficacious in colorectal cancer prevention and treatment, avoiding side effects associated with NSAIDs.
Transnational Terrorist Recruitment: Evidence from Daesh Personnel Records
Authors: Brockmeyer Anne , Do Quy-Toan , Joubert Clément , Bhatia Kartika , Jelil Mohamed Abdel 
Published: February 2022

Abstract
Global terrorist organizations attract radicalized individuals across borders and constitute a threat for both sending and receiving countries. We use unique personnel records from the Islamic State in Iraq and the Levant (Daesh) to show that unemployment in sending countries is associated with the number of transnational terrorist recruits from these countries. The relationship is spatially heterogeneous, which is most plausibly attributable to travel costs. We argue that poor labor market opportunities generally push more individuals to join terrorist organizations, but at the same time, limit their ability to do so when longer travel distances imply higher travel costs.
Playing Hide and Seek: How Lenders Respond to Borrower Protection
Authors: Benzarti Youssef 
Published: February 2022

Abstract
This paper uses the universe of mortgage contracts to estimate the response of high-interest lenders to borrower protection regulations aimed at simplifying and making loan terms more transparent. Using a quasi-experimental design, I find that lenders substantially reduce interest rates—by an average of 10%—in order to avoid being subject to borrower protection, without reducing amounts loaned or the number of loans approved. This finding is consistent with high-interest lenders preferring to issue obfuscatory mortgage contracts with lower interest rates rather than more transparent and regulated mortgages with higher interest rates.
Effective ENSO Amplitude Forecasts Based on Oceanic and Atmospheric Preconditions
Authors: Xuan Zhuolin , Zhang Wenjun , Jiang Feng , Jin Fei-Fei 
Published: February 2022

AbstractCurrent climate models have relatively high skills in predicting El Niño–Southern Oscillation (ENSO) phase (i.e., El Niño, neutral, and La Niña), once leaping over the spring predictability barrier. However, it is still a big challenge to realistically forecast the ENSO amplitude, for instance, whether a predicted event will be strong, moderate, or weak. Here we demonstrate that the accumulated westerly wind events (WWEs)/easterly wind surges (EWSs) and oceanic recharged/discharged states are both of importance in accurate ENSO amplitude forecasts. El Niño and La Niña events exhibit asymmetric temporal and spatial features in the atmospheric and oceanic preconditions. El Niño amplitude at the peak season is closely associated with the accumulated WWEs over the eastern equatorial Pacific from the previous December to May and the recharged state in the western equatorial Pacific during February. In contrast, the amplitude of La Niña events is sensitive to the accumulated EWSs over the equatorial western Pacific from the previous November to April and the discharged state extending from the equatorial western to central Pacific during February. Considering these asymmetric atmospheric and oceanic preconditions of El Niño and La Niña cases, a statistical model is established to accurately forecast the ENSO amplitude at its mature phase during 1982–2018, which is validated to be robust based on a 1-yr cross-validation and independent sample tests. The feasibility and the limitation of the established statistical model are also discussed by examining its practical utility.
Marijuana Use Associated with Decreased Mortality in Trauma Patients
Authors: Bloom Samuel R. , Grigorian Areg , Schubl Sebastian , Thangathurai Duraiyah , Kuza Catherine M. , Swentek Lourdes , Nahmias Jeffry 
Published: February 2022

BackgroundThe incidence of trauma patients with a positive marijuana screen (pMS) is increasing but the effects of marijuana on outcomes have varied in previous studies. A recent statewide analysis demonstrated decreased mortality for intensive care unit (ICU) trauma patients with pMS. Thus, we hypothesized a pMS to be associated with a decreased risk of mortality for all trauma patients.MethodsThe 2017 Trauma Quality Improvement Program (TQIP) database was queried for adult (≥18 years-old) pMS patients, who were compared to patients negative for all drugs and alcohol (nDS). Patients not drug tested or testing positive for drug(s)/alcohol other than marijuana were excluded. Multivariable logistic regression was used to evaluate risk of mortality after controlling for known predictors of mortality including age, sex, injury severity, vital signs, and comorbidities. Additional subgroup analyses were performed for ICU patients and younger adults (<40 years-old).ResultsFrom 141 737 tested patients, 23 310 (16.4%) had an isolated pMS. Patients with pMS were younger ( P < .001) but had a similar median injury severity score (ISS) (9, P = .42) compared to nDS patients. On multivariable analysis the associated risk of mortality was lower for pMS (OR .79, .71-.87, P < .001) compared to nDS patients. Subgroups analyses also demonstrated decreased associated risk of mortality for ICU and younger patients (both P < .05).DiscussionPatients with a pMS had decreased associated risk of mortality compared to nDS patients, including subgroups of ICU and younger patients. These findings require corroboration with future prospective clinical study and basic science evaluation to ascertain the exact pathophysiologic basis and thereby target potential interventions.