bluuebunny/crossref_metadata_2025_split huggingface dataset:
Machine learning-based detection of sleep-disordered breathing in hypertrophic cardiomyopathy
Authors: Akita Keitaro , Kageyama Shigetaka , Suzuki Sayumi , Ohno Kazuto , Kamakura Masamitsu , Nawada Ryuzo , Takanaka Chiei , Wakabayashi Yasushi , Kanda Takahiro , Tawarahara Kei , Mutoh Masahiro , Matsunaga Masaki , Suwa Satoru , Takeuchi Yasuyo , Sakamoto Hiroki , Saito Hideki , Hayashi Kazusa , Wakahara Nobuyuki , Unno Kyoko , Ikoma Takenori , Sato Ryota , Iguchi Keisuke , Satoh Terumori , Sano Makoto , Suwa Kenichiro , Naruse Yoshihisa , Ohtani Hayato , Saotome Masao , Maekawa Yuichiro 
Published: April 2024

BackgroundHypertrophic cardiomyopathy (HCM) is often concomitant with sleep-disordered breathing (SDB), which can cause adverse cardiovascular events. Although an appropriate approach to SDB prevents cardiac remodelling, detection of concomitant SDB in patients with HCM remains suboptimal. Thus, we aimed to develop a machine learning-based discriminant model for SDB in HCM.MethodsIn the present multicentre study, we consecutively registered patients with HCM and performed nocturnal oximetry. The outcome was a high Oxygen Desaturation Index (ODI), defined as 3% ODI >10, which significantly correlated with the presence of moderate or severe SDB. We randomly divided the whole participants into a training set (80%) and a test set (20%). With data from the training set, we developed a random forest discriminant model for high ODI based on clinical parameters. We tested the ability of the discriminant model on the test set and compared it with a previous logistic regression model for distinguishing SDB in patients with HCM.ResultsAmong 369 patients with HCM, 228 (61.8%) had high ODI. In the test set, the area under the receiver operating characteristic curve of the discriminant model was 0.86 (95% CI 0.77 to 0.94). The sensitivity was 0.91 (95% CI 0.79 to 0.98) and specificity was 0.68 (95% CI 0.48 to 0.84). When the test set was divided into low-probability and high-probability groups, the high-probability group had a higher prevalence of high ODI than the low-probability group (82.4% vs 17.4%, OR 20.9 (95% CI 5.3 to 105.8), Fisher’s exact test p<0.001). The discriminant model significantly outperformed the previous logistic regression model (DeLong test p=0.03).ConclusionsOur study serves as the first to develop a machine learning-based discriminant model for the concomitance of SDB in patients with HCM. The discriminant model may facilitate cost-effective screening tests and treatments for SDB in the population with HCM.
SLESIS-R: an improved score for prediction of serious infection in patients with systemic lupus erythematosus based on the RELESSER prospective cohort
Authors: Rua-Figueroa Iñigo , García de Yébenes M Jesus , Martinez-Barrio Julia , Galindo Izquierdo Maria , Calvo Alén Jaime , Fernandez-Nebro Antonio , Menor-Almagro Raúl , Carmona Loreto , Tejera Segura Beatriz , Tomero Eva , Freire-González Mercedes , Sangüesa Clara , Horcada Loreto , Blanco Ricardo , Uriarte Itzazelaia Esther , Narváez Javier , Rosas Gómez de Salazar José Carlos , Gómez-Sabater Silvia , Morales Claudia Moriano , Andreu Jose L , Segarra Vicente Torrente , Aurrecoechea Elena , Perez Ana , Nóvoa Medina Javier , Salgado Eva , Lozano-Rivas Nuria , Montilla Carlos , Ruiz-Lucea Esther , Arevalo Marta , Iñiguez Carlota , García-Villanueva María Jesús , Exposito Lorena , Ibáñez-Barceló Mónica , Bonilla Gema , Carrión-Barberà Irene , Erausquin Celia , Fragio Gil Jorge Juan , Pecondón Angela , Toyos Francisco J , Cobo Tatiana , Muñoz-Jiménez Alejandro , Oller Jose , Nolla Joan M , Pego-Reigosa J M 
Published: April 2024

ObjectiveTo develop an improved score for prediction of severe infection in patients with systemic lupus erythematosus (SLE), namely, the SLE Severe Infection Score-Revised (SLESIS-R) and to validate it in a large multicentre lupus cohort.MethodsWe used data from the prospective phase of RELESSER (RELESSER-PROS), the SLE register of the Spanish Society of Rheumatology. A multivariable logistic model was constructed taking into account the variables already forming the SLESIS score, plus all other potential predictors identified in a literature review. Performance was analysed using the C-statistic and the area under the receiver operating characteristic curve (AUROC). Internal validation was carried out using a 100-sample bootstrapping procedure. ORs were transformed into score items, and the AUROC was used to determine performance.ResultsA total of 1459 patients who had completed 1 year of follow-up were included in the development cohort (mean age, 49±13 years; 90% women). Twenty-five (1.7%) had experienced ≥1 severe infection. According to the adjusted multivariate model, severe infection could be predicted from four variables: age (years) ≥60, previous SLE-related hospitalisation, previous serious infection and glucocorticoid dose. A score was built from the best model, taking values from 0 to 17. The AUROC was 0.861 (0.777–0.946). The cut-off chosen was ≥6, which exhibited an accuracy of 85.9% and a positive likelihood ratio of 5.48.ConclusionsSLESIS-R is an accurate and feasible instrument for predicting infections in patients with SLE. SLESIS-R could help to make informed decisions on the use of immunosuppressants and the implementation of preventive measures.
Fast neutron production at the LNL Tandem from the $$^7$$Li($$^{14}$$N,xn)X reaction
Authors: Torres-Sánchez Pablo , Steiger Hans Th. J. , Mastinu Pierfrancesco , Wyss Jeffery L. , Kayser Lennard , Silvestrin Luca , Musacchio-González Elizabeth , Stock Matthias Raphael , Dörflinger David , Fahrendholz Ulrike , Prete Gianfranco , Carletto Osvaldo , Oberauer Lothar , Porras Ignacio 
Published: April 2024

AbstractFast neutron beams (E$$_n > $$

n

>

1 MeV) are of relevance for many scientific and industrial applications. This paper explores fast neutron production using a TANDEM accelerator at the Legnaro National Laboratories, via an energetic ion beam (90 MeV $$^{14}N$$

14

N

) onto a lithium target. The high energy models for nuclear collision of FLUKA foresee large neutron yields for reactions of this kind. The experiment aimed at validating the expected neutron yields from FLUKA simulations, using two separate and independent set-ups: one based on the multi-foil activation technique, and the other on the time of flight technique, by using liquid scintillator detectors. The results of the experiment show clear agreement of the measured spectra with the FLUKA simulations, both in the shape and the magnitude of the neutron flux at the measured positions. The neutron spectrum is centered around the 8 MeV range with mild tails, and a maximum neutron energy spanning up to 50 MeV. These advantageous results provide a starting point in the development of fast neutron beams based on high energy ion beams from medium-sized accelerator facilities.
The CompactLight Design Study
Authors: D’Auria G. , Adli E. , Aicheler M. , Aksoy A. , Alesini D. , Apsimon R. , Arnsberg J. , Auchettl R. , Bainbridge A. , Balazs K. , Bantekas D. , Bedolla J. , Behtouei M. , Bellaveglia M. , vd Berg M. , Bernhard A. , Bignami A. , Breitenbach M. , Breukers M. , Burt G. , Cai J. , Calvi M. , Cardelli F. , Carpanese M. , Cortes H. M. Castaneda , Castilla A. , Cianchi A. , Clarke J. , Cowie L. , Croia M. , Cross A. , Danailov M. , Dattoli G. , Deleval S. , Mitri S. Di , Diomede M. , Dowd R. , Dunning D. , Easton J. , Fang W. , Fatehi S. , Faus-Golfe A. , Ferianis M. , Ferrario M. , Ficcadenti L. , Gallo A. , Gazis E. , Gazis N. , Geometrante R. , Gethmann J. , Gioppo R. , Giribono A. , González-Iglesias D. , Goryashko V. , Grohmann S. , Gu Q. , Han Y. , Hinton A. , Hobi A. , Hoekstra R. , Huang X. , Jacewicz M. , Jones J. , Kaertner F. , Karagiannaki A. , Kokole M. , Kotitsa R. , Kotsopoulos D. , Krasch B. , Latina A. , Lepercq P. , Liu X. , Lucas T. G. , Luiten O. J. , Maheshwari M. , Mahnic J. , Mak A. , Marcos J. , Marin E. , Marinov K. , Martínez B. G. , Mercier B. , Migliorati M. , Milharcic T. , Mostacci A. , Mu noz R. , Musat V. , Mutsaers P. H. A. , Nergiz Z. , Nguyen F. , Nix L. , Palumbo L. , Parodi M. , Pavlica R. , Pellegrino L. , Pereira D. E. , Perez F. , Petralia A. , Piersanti L. , Pockar J. , Pramatari K. , Priem H. , Primozic U. , Rassool R. , Reiche S. , Revilak P. , Richter S. C. , Rochow R. , Rossi C. , Salén P. , Schmidt T. , Schoerling D. , Schulte D. , Scifo J. , Sheehy S. , Shepherd B. , Spataro B. , Stapnes S. , Stragier X. F. D. , Syratchev I. , Tabacco C. , Tan J. , Tanke E. , Taylor G. , Telahi I. , Thompson N. , Trachanas E. , Tzanetou K. S. , Vaccarezza C. , Vainola J. , Vannozzi A. , Volpi M. , Wang C. , Williams P. , Wu X. , Wuensch W. , Yap J. , Zangrando M. , Zhang K. , Zhang L. , Zhao Y. , Zhao Z. , Zhu D. 
Published: April 2024

AbstractCompactLight is a Design Study funded by the European Union under the
Horizon 2020 research and innovation funding programme, with Grant Agreement No. 777431.
CompactLight was conducted by an International Collaboration of 23 international
laboratories and academic institutions, three private companies, and five third parties.
The project, which started in January 2018 with a duration of 48 months, aimed to design
an innovative, compact, and cost-effective hard X-ray FEL facility complemented by a
soft X-ray source to pave the road for future compact accelerator-based facilities. The
result is an accelerator that can be operated at up to 1 kHz pulse repetition rate,
beyond today’s state of the art, using the latest concepts for high brightness electron
photoinjectors, very high gradient accelerating structures in X-band, and novel
short-period undulators. In this report, we summarize the main deliverable of the
project: the CompactLight Conceptual Design Report, which overviews the current status
of the design and addresses the main technological challenges.
SARDINE: Simulator for Automated Recommendation in Dynamic and Interactive Environments
Authors: Deffayet Romain , Thonet Thibaut , Hwang Dongyoon , Lehoux Vassilissa , Renders Jean-Michel , de Rijke Maarten 
Published: April 2024

Simulators can provide valuable insights for researchers and practitioners who wish to improve recommender systems, because they allow one to easily tweak the experimental setup in which recommender systems operate, and as a result lower the cost of identifying general trends and uncovering novel findings about the candidate methods. A key requirement to enable this accelerated improvement cycle is that the simulator is able to span the various sources of complexity that can be found in the real recommendation environment that it simulates.
With the emergence of interactive and data-driven methods—e.g., reinforcement learning or online and counterfactual learning-to-rank—that aim to achieve user-related goals beyond the traditional accuracy-centric objectives, adequate simulators are needed. In particular, such simulators must model the various mechanisms that render the recommendation environment dynamic and interactive, e.g., the effect of recommendations on the user or the effect of biased data on subsequent iterations of the recommender system. We therefore propose SARDINE, a flexible and interpretable recommendation simulator that can help accelerate research in interactive and data-driven recommender systems. We demonstrate its usefulness by studying existing methods within nine diverse environments derived from SARDINE, and even uncover novel insights about them.
Comprehensive Transcriptomic Analysis of EWSR1::WT1 Targets Identifies CDK4/6 Inhibitors as an Effective Therapy for Desmoplastic Small Round Cell Tumors
Authors: Magrath Justin W. , Sampath Shruthi Sanjitha , Flinchum Dane A. , Hartono Alifiani B. , Goldberg Ilon N. , Boehling Julia R. , Savkovic Suzana D. , Lee Sean B. 
Published: April 2024

Abstract

Desmoplastic small round cell tumors (DSRCT) are a type of aggressive, pediatric sarcoma characterized by the EWSR1::WT1 fusion oncogene. Targeted therapies for DSRCT have not been developed, and standard multimodal therapy is insufficient, leading to a 5-year survival rate of only 15% to 25%. Here, we depleted EWSR1::WT1 in DSRCT and established its essentiality in vivo. Transcriptomic analysis revealed that EWSR1::WT1 induces unique transcriptional alterations compared with WT1 and other fusion oncoproteins and that EWSR1::WT1 binding directly mediates gene upregulation. The E-KTS isoform of EWSR1::WT1 played a dominant role in transcription, and it bound to the CCND1 promoter and stimulated DSRCT growth through the cyclin D–CDK4/6–RB axis. Treatment with the CDK4/6 inhibitor palbociclib successfully reduced growth in two DSRCT xenograft models. As palbociclib has been approved by the FDA for the treatment of breast cancer, these findings demonstrate the sensitivity of DSRCT to palbociclib and support immediate clinical investigation of palbociclib for treating this aggressive pediatric cancer.

Significance:
EWSR1::WT1 is essential for desmoplastic small round cell tumors and upregulates the cyclin D–CDK4/6–RB axis that can be targeted with palbociclib, providing a targeted therapeutic strategy for treating this deadly tumor type.
Racial Disparities in Early-Stage NSCLC Treatment: A Call for Action
Authors: Pellini Bruna , Chaudhuri Aadel A. 
Published: April 2024

Abstract
Non–small cell lung cancer (NSCLC) is associated with a 5-year survival rate of only 28%; however, when caught at an early stage, it can be cured with surgery or stereotactic body radiotherapy (SBRT). Unfortunately, racial disparities may result in limited access to care for some patients. Liu and colleagues analyzed 64,999 cases of early-stage NSCLC treated between 2005 and 2017 from the Florida Cancer Registry and showed that Black patients had 36% lower odds of receiving curative-intent surgery compared with their White counterparts. This study highlights significant racial disparities in treatment patterns that must be addressed urgently.
See related article by Liu and colleagues, Cancer Epidemiol Biomarkers Prev 2024;33:489–99
Novel WRN Helicase Inhibitors Selectively Target Microsatellite-Unstable Cancer Cells
Authors: Picco Gabriele , Rao Yanhua , Al Saedi Angham , Lee Yang , Vieira Sara F. , Bhosle Shriram , May Kieron , Herranz-Ors Carmen , Walker Samantha J. , Shenje Raynold , Dincer Cansu , Gibson Freddy , Banerjee Ruby , Hewitson Zoe , Werner Thilo , Cottom Joshua E. , Peng Yang , Deng Nanhua , Zhang Youyou , Nartey Eldridge N. , Nickels Leng , Landis Philip , Conticelli Daniela , McCarten Katrina , Bush Jacob , Sharma Mamta , Lightfoot Howard , House David , Milford Emma , Grant Emma K. , Glogowski Michal P. , Wagner Craig D. , Bantscheff Marcus , Rutkowska-Klute Anna ,   Cell Model Network UK Group, Zappacosta Francesca , Pettinger Jonathan , Barthorpe Syd , Eberl H. Christian , Jones Brian T. , Schneck Jessica L. , Murphy Dennis J. , Voest Emile E. , Taygerly Joshua P. , DeMartino Michael P. , Coelho Matthew A. , Houseley Jonathan , Sharma Geeta , Schwartz Benjamin , Garnett Mathew J. 
Published: April 2024

Abstract
Microsatellite-unstable (MSI) cancers require WRN helicase to resolve replication stress due to expanded DNA (TA)n dinucleotide repeats. WRN is a promising synthetic lethal target for MSI tumors, and WRN inhibitors are in development. In this study, we used CRISPR–Cas9 base editing to map WRN residues critical for MSI cells, validating the helicase domain as the primary drug target. Fragment-based screening led to the development of potent and highly selective WRN helicase covalent inhibitors. These compounds selectively suppressed MSI model growth in vitro and in vivo by mimicking WRN loss, inducing DNA double-strand breaks at expanded TA repeats and DNA damage. Assessment of biomarkers in preclinical models linked TA-repeat expansions and mismatch repair alterations to compound activity. Efficacy was confirmed in immunotherapy-resistant organoids and patient-derived xenograft models. The discovery of potent, selective covalent WRN inhibitors provides proof of concept for synthetic lethal targeting of WRN in MSI cancer and tools to dissect WRN biology.
Significance: We report the discovery and characterization of potent, selective WRN helicase inhibitors for MSI cancer treatment, with biomarker analysis and evaluation of efficacy in vivo and in immunotherapy-refractory preclinical models. These findings pave the way to translate WRN inhibition into MSI cancer therapies and provide tools to investigate WRN biology.
See related commentary by Wainberg, p. 1369
Randomized Placebo-Controlled, Biomarker-Stratified Phase Ib Microbiome Modulation in Melanoma: Impact of Antibiotic Preconditioning on Microbiome and Immunity
Authors: Glitza Isabella C. , Seo Yongwoo David , Spencer Christine N. , Wortman Jennifer R. , Burton Elizabeth M. , Alayli Farah A. , Loo Christopher P. , Gautam Shikha , Damania Ashish , Densmore Julie , Fairchild Justin , Cabanski Christopher R. , Wong Matthew C. , Peterson Christine B. , Weiner Brian , Hicks Nathan , Aunins John , McChalicher Christopher , Walsh Emily , Tetzlaff Michael T. , Hamid Omid , Ott Patrick A. , Boland Genevieve M. , Sullivan Ryan J. , Grossmann Kenneth F. , Ajami Nadim J. , LaVallee Theresa , Henn Matthew R. , Tawbi Hussein A. , Wargo Jennifer A. 
Published: April 2024

Abstract
Gut-microbiota modulation shows promise in improving immune-checkpoint blockade (ICB) response; however, precision biomarker-driven, placebo-controlled trials are lacking. We performed a multicenter, randomized placebo-controlled, biomarker-stratified phase I trial in patients with ICB-naïve metastatic melanoma using SER-401, an orally delivered Firmicutesenriched spore formulation. Fecal microbiota signatures were characterized at baseline; patients were stratified by high versus low Ruminococcaceae abundance prior to randomization to the SER-401 arm (oral vancomycin-preconditioning/SER-401 alone/nivolumab + SER-401), versus the placebo arm [placebo antibiotic/placebo microbiome modulation (PMM)/nivolumab + PMM (NCT03817125)]. Analysis of 14 accrued patients demonstrated that treatment with SER-401 + nivolumab was safe, with an overall response rate of 25% in the SER-401 arm and 67% in the placebo arm (though the study was underpowered related to poor accrual during the COVID-19 pandemic). Translational analyses demonstrated that vancomycin preconditioning was associated with the disruption of the gut microbiota and impaired immunity, with incomplete recovery at ICB administration (particularly in patients with high baseline Ruminococcaceae). These results have important implications for future microbiome modulation trials.
Significance: This first-of-its-kind, placebo-controlled, randomized biomarker-driven microbiome modulation trial demonstrated that vancomycin + SER-401 and anti–PD-1 are safe in melanoma patients. Although limited by poor accrual during the pandemic, important insights were gained via translational analyses, suggesting that antibiotic preconditioning and interventional drug dosing regimens should be carefully considered when designing such trials.
See author Yongwoo David Seo discuss this research brief, published simultaneously at the AACR Annual Meeting 2024: https://vimeo.com/932607668/63addff7fc
Efficacy and Safety of Adagrasib plus Cetuximab in Patients with KRASG12C-Mutated Metastatic Colorectal Cancer
Authors: Yaeger Rona , Uboha Nataliya V. , Pelster Meredith S. , Bekaii-Saab Tanios S. , Barve Minal , Saltzman Joel , Sabari Joshua K. , Peguero Julio A. , Paulson Andrew Scott , Jänne Pasi A. , Cruz-Correa Marcia , Anderes Kenna , Velastegui Karen , Yan Xiaohong , Der-Torossian Hirak , Klempner Samuel J. , Kopetz Scott E. 
Published: April 2024

Abstract

Adagrasib, an irreversible, selective KRASG12C inhibitor, may be an effective treatment in KRASG12C-mutated colorectal cancer, particularly when combined with an anti-EGFR antibody. In this analysis of the KRYSTAL-1 trial, patients with previously treated KRASG12C-mutated unresectable or metastatic colorectal cancer received adagrasib (600 mg twice daily) plus cetuximab. The primary endpoint was objective response rate (ORR) by blinded independent central review. Ninety-four patients received adagrasib plus cetuximab. With a median follow-up of 11.9 months, ORR was 34.0%, disease control rate was 85.1%, and median duration of response was 5.8 months (95% confidence interval [CI], 4.2–7.6). Median progression-free survival was 6.9 months (95% CI, 5.7–7.4) and median overall survival was 15.9 months (95% CI, 11.8–18.8). Treatment-related adverse events (TRAEs) occurred in all patients; grade 3–4 in 27.7% and no grade 5. No TRAEs led to adagrasib discontinuation. Exploratory analyses suggest circulating tumor DNA may identify features of response and acquired resistance.

Significance:
Adagrasib plus cetuximab demonstrates promising clinical activity and tolerable safety in heavily pretreated patients with unresectable or metastatic KRASG12C-mutated colorectal cancer. These data support a potential new standard of care and highlight the significance of testing and identification of KRASG12C mutations in patients with colorectal cancer.
This article is featured in Selected Articles from This Issue, p. 897
See co-corresponding author Rona Yaeger discuss this research article, published simultaneously at the AACR Annual Meeting 2024: https://vimeo.com/932606282/f27a6e46f4
Low Exposures to Amphibole or Serpentine Asbestos in Germline Bap1-mutant Mice Induce Mesothelioma Characterized by an Immunosuppressive Tumor Microenvironment
Authors: Kadariya Yuwaraj , Sementino Eleonora , Ruan Maggie , Cheung Mitchell , Hadikhani Parham , Osmanbeyoglu Hatice U. , Klein-Szanto Andres J. , Cai Kathy , Testa Joseph R. 
Published: April 2024

Abstract

Asbestos and BAP1 germline mutations are risk factors for malignant mesothelioma (MM). While it is well accepted that amphibole asbestos is carcinogenic, the role of serpentine (chrysotile) asbestos in MM has been debated. To address this controversy, we assessed whether minimal exposure to chrysotile could significantly increase the incidence and rate of MM onset in germline Bap1-mutant mice. With either crocidolite or chrysotile, and at each dose tested, MMs occurred at a significantly higher rate and earlier onset time in Bap1-mutant mice than in wild-type littermates. To explore the role of gene–environment interactions in MMs from Bap1-mutant mice, we investigated proinflammatory and protumorigenic factors and the tumor immune microenvironment (TIME). IHC and immunofluorescence staining showed an increased number of macrophages in granulomatous lesions and MMs. The relative number of CD163-positive (CD163+) M2 macrophages in chrysotile-induced MMs was consistently greater than in crocidolite-induced MMs, suggesting that chrysotile induces a more profound immunosuppressive response that creates favorable conditions for evading immune surveillance. MMs from Bap1-mutant mice showed upregulation of CD39/CD73-adenosine and C-C motif chemokine ligand 2 (Ccl2)/C-C motif chemokine receptor 2 (Ccr2) pathways, which together with upregulation of IL6 and IL10, promoted an immunosuppressive TIME, partly by attracting M2 macrophages. Interrogation of published human MM RNA sequencing (RNA-seq) data implicated these same immunosuppressive pathways and connections with CD163+ M2 macrophages. These findings indicate that increased M2 macrophages, along with upregulated CD39/CD73-adenosine and Ccl2/Ccr2 pathways, contribute to an immunosuppressive TIME in chrysotile-induced MMs of Bap1-mutant mice, suggesting that immunotherapeutic strategies targeting protumorigenic immune pathways could be beneficial in human BAP1 mutation carriers who develop MM.

Significance:
We show that germline Bap1-mutant mice have enhanced susceptibility to MM upon minimal exposure to chrysotile asbestos, not only amphibole fibers. Chrysotile induced a more profound immune tumor response than crocidolite in Bap1-mutant mice by upregulating CD39/CD73-adenosine and Ccl2/Ccr2 pathways and recruiting more M2 macrophages, which together contributed to an immunosuppressive tumor microenvironment. Interrogation of human MM RNA-seq data revealed interconnected immunosuppressive pathways consistent with our mouse findings.