bluuebunny/crossref_metadata_2025 huggingface dataset:
Risk prediction models for endometrial cancer: development and validation in an international consortium
Authors: Shi Joy , Kraft Peter , Rosner Bernard A , Benavente Yolanda , Black Amanda , Brinton Louise A , Chen Chu , Clarke Megan A , Cook Linda S , Costas Laura , Dal Maso Luigino , Freudenheim Jo L , Frias-Gomez Jon , Friedenreich Christine M , Garcia-Closas Montserrat , Goodman Marc T , Johnson Lisa , La Vecchia Carlo , Levi Fabio , Lissowska Jolanta , Lu Lingeng , McCann Susan E , Moysich Kirsten B , Negri Eva , O'Connell Kelli , Parazzini Fabio , Petruzella Stacey , Polesel Jerry , Ponte Jeanette , Rebbeck Timothy R , Reynolds Peggy , Ricceri Fulvio , Risch Harvey A , Sacerdote Carlotta , Setiawan Veronica W , Shu Xiao-Ou , Spurdle Amanda B , Trabert Britton , Webb Penelope M , Wentzensen Nicolas , Wilkens Lynne R , Xu Wang Hong , Yang Hannah P , Yu Herbert , Du Mengmeng , De Vivo Immaculata
Published: January 2023

Background

Endometrial cancer risk stratification may help target interventions, screening, or prophylactic hysterectomy to mitigate the rising burden of this cancer. However, existing prediction models have been developed in select cohorts and have not considered genetic factors.

Methods

We developed endometrial cancer risk prediction models using data on postmenopausal White women aged 45-85 years from 19 case-control studies in the Epidemiology of Endometrial Cancer Consortium (E2C2). Relative risk estimates for predictors were combined with age-specific endometrial cancer incidence rates and estimates for the underlying risk factor distribution. We externally validated the models in 3 cohorts: Nurses’ Health Study (NHS), NHS II, and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.

Results

Area under the receiver operating characteristic curves for the epidemiologic model ranged from 0.64 (95% confidence interval [CI] = 0.62 to 0.67) to 0.69 (95% CI = 0.66 to 0.72). Improvements in discrimination from the addition of genetic factors were modest (no change in area under the receiver operating characteristic curves in NHS; PLCO = 0.64 to 0.66). The epidemiologic model was well calibrated in NHS II (overall expected-to-observed ratio [E/O] = 1.09, 95% CI = 0.98 to 1.22) and PLCO (overall E/O = 1.04, 95% CI = 0.95 to 1.13) but poorly calibrated in NHS (overall E/O = 0.55, 95% CI = 0.51 to 0.59).

Conclusions

Using data from the largest, most heterogeneous study population to date (to our knowledge), prediction models based on epidemiologic factors alone successfully identified women at high risk of endometrial cancer. Genetic factors offered limited improvements in discrimination. Further work is needed to refine this tool for clinical or public health practice and expand these models to multiethnic populations.
Bystander signals from low- and high-dose irradiated human primary fibroblasts and keratinocytes modulate the inflammatory response of peripheral blood mononuclear cells
Authors: Testard Isabelle , Garcia-Chartier Elizabeth , Issa Amani , Collin-Faure Véronique , Aude-Garcia Catherine , Candéias Serge M
Published: January 2023

Irradiated cells can propagate signals to neighboring cells. Manifestations of these so-called bystander effects (BEs) are thought to be relatively more important after exposure to low- vs high-dose radiation and can be mediated via the release of secreted molecules, including inflammatory cytokines, from irradiated cells. Thus, BEs can potentially modify the inflammatory environment of irradiated cells. To determine whether these modifications could affect the functionality of bystander immune cells and their inflammatory response, we analyzed and compared the in vitro response of primary human fibroblasts and keratinocytes to low and high doses of radiation and assessed their ability to modulate the inflammatory activation of peripheral blood mononuclear cells (PBMCs). Only high-dose exposure resulted in either up- or down-regulation of selected inflammatory genes. In conditioned culture media transfer experiments, radiation-induced bystander signals elicited from irradiated fibroblasts and keratinocytes were found to modulate the transcription of inflammatory mediator genes in resting PBMCs, and after activation of PBMCs stimulated with lipopolysaccharide (LPS), a strong inflammatory agent. Radiation-induced BEs induced from skin cells can therefore act as a modifier of the inflammatory response of bystander immune cells and affect their functionality.
Exosome-like vesicles released from ob/ob mouse adipose tissue enhance cell survival of cells with radiation-induced genomic instability
Authors: Ariyoshi Kentaro , Fujishima Yohei , Goh Valerie Swee Ting , Nakata Akifumi , Kasai Kosuke , Yoshida Mitsuaki A , Miura Tomisato
Published: January 2023

Multiple epidemiological studies have shown that obesity is a serious risk factor for cancer development. While the underlying mechanisms between obesity and cancer are still unknown, obesity disrupts the role of adipocytes in energy homeostasis, and the alteration of adipokine, insulin and sex steroid signaling. Recently, it has been identified that adipose tissue-derived exosome-like vesicles (ELVs) regulate metabolic homeostasis. In this study, we collected ELVs from adipose tissue of an obese mouse (ob/ob) strain and control mouse (C57BL/6) strain, and checked whether adipose ELVs influence radiation-induced cell death on mouse fibroblast cells (m5S). Furthermore, we analyzed the micronucleus (MN) frequency in survived cells after radiation exposure to investigate the effect of ELVs on radiation-induced genomic instability. We first observed that ELVs from control and obese mice showed enhanced colony forming ability in un-irradiated m5S cells. However, enhanced survival was observed only in 3 Gy-irradiated m5S cells with obese ELV treatment. Despite no ELV effect on colony size, interestingly, the frequency of MN in survived m5S cells after 3 Gy irradiation was elevated when treated obese ELVs compared to control ELVs. These results suggested that obese mouse adipose ELVs could enhance the survival of irradiated cells harboring increased radiation-induced genomic instability.
Comparison of nutritional value, bioactivity, and volatile compounds of soybean meal–corn bran mixed substrates fermented by different microorganisms
Authors: Huang Jinqing , Dai Yuming , Huang Tao , Du Tonghao , Xiong Tao
Published: January 2023

To evaluate the impact of fermentation with different microorganisms on the nutritional quality and bioactivity of soybean meal–corn bran mixed substrates (MS), five lactic acid bacteria (LAB) strains, two Bacillus, and two yeast strains with excellent probiotics were selected for solid-state fermentation of soybean meal and corn bran MS. The fermented mixed substrate (FMS) inoculated with Lacticaseibacillus casei, Lactobacillus fermentum, Lactiplantibacillus plantarum, and Lactobacillus acidophilus presents lower risk of infection with pathogenic bacteria, probably due to their low pH and high lactate content. Compared to the FMS with LAB and yeast, Bacillus subtilis and B. pumilus showed significant improvements in nutritional quality and bioactivity, including TCA-SP, small peptide, free amino acids, total phenol, and protein digestibility. More than 300 volatile compounds were identified in FMS, including alcohols, ketones, aldehydes, esters, acids, ethers, furans, pyrazines, benzene, phenols, amines, alkanes, and others. FMS with Bacillus was characterized as containing a greater number of compounds such as ketones, aldehydes, and pyrazines. This study showed that microbial fermented feeds differed with various microorganism, and fermentation was an effective way to improve the quality of soybean meal–corn bran mixed feeds. This study might be the basis for excellent strains screening for multi-microbial combined fermentation in the future.
Improving Star Cluster Age Estimates in PHANGS-HST Galaxies and the Impact on Cluster Demographics in NGC 628
Authors: Whitmore Bradley C , Chandar Rupali , Lee Janice C , Floyd Matthew , Deger Sinan , Lilly James , Minsley Rebecca , Thilker David A , Boquien Médéric , Dale Daniel A , Henny Kiana , Scheuermann Fabian , Barnes Ashley T , Bigiel Frank , Emsellem Eric , Glover Simon , Grasha Kathryn , Groves Brent , Hannon Stephen , Klessen Ralf S , Kreckel Kathryn , Kruijssen J M Diederik , Larson Kirsten L , Leroy Adam , Mok Angus , Pan Hsi-An , Pinna Francesca , Sánchez-Blázquez Patricia , Schinnerer Eva , Sormani Mattia C , Watkins Elizabeth , Williams Thomas
Published: January 2023

A long-standing problem when deriving the physical properties of stellar populations is the degeneracy between age, reddening, and metallicity. When a single metallicity is used for all the star clusters in a galaxy, this degeneracy can result in ‘catastrophic’ errors for old globular clusters. Typically, approximately 10–20 per cent of all clusters detected in spiral galaxies can have ages that are incorrect by a factor of 10 or more. In this paper, we present a pilot study for four galaxies (NGC 628, NGC 1433, NGC 1365, and NGC 3351) from the PHANGS-HST survey. We describe methods to correct the age-dating for old globular clusters, by first identifying candidates using their colours, and then reassigning ages and reddening based on a lower metallicity solution. We find that young ‘Interlopers’ can be identified from their Hα flux. CO (2-1) intensity or the presence of dust can also be used, but our tests show that they do not work as well. Improvements in the success fraction are possible at the ≈15 per cent level (reducing the fraction of catastrophic age-estimates from between 13 and 21 per cent, to between 3  and 8 per cent). A large fraction of the incorrectly age-dated globular clusters are systematically given ages around 100 Myr, polluting the younger populations as well. Incorrectly age-dated globular clusters significantly impact the observed cluster age distribution in NGC 628, which affects the physical interpretation of cluster disruption in this galaxy. For NGC 1365, we also demonstrate how to fix a second major age-dating problem, where very dusty young clusters with E(B − V) > 1.5 mag are assigned old, globular-cluster like ages. Finally, we note the discovery of a dense population of ≈300 Myr clusters around the central region of NGC 1365 and discuss how this results naturally from the dynamics in a barred galaxy.
Identifying meteorite droppers among the population of bright ‘sporadic’ bolides imaged by the Spanish Meteor Network during the spring of 2022
Authors: Peña-Asensio E , Trigo-Rodríguez J M , Rimola A , Corretgé-Gilart M , Koschny D
Published: January 2023

The extraordinary weather conditions available between February and March 2022 over Spain have allowed us to analyse the brightest fireballs recorded by the monitoring stations of the Spanish Meteor Network (SPMN). We study the atmospheric flight of 15 large meteoroids to determine if they are meteorite dropper events to prepare campaigns to search for freshly fallen extraterrestrial material. We investigate their origins in the Solar system and their dynamic association with parent bodies and meteoroid streams. Employing our python pipeline 3d-firetoc, we reconstruct the atmospheric trajectory utilizing ground-based multistation observations and compute the heliocentric orbit. In addition, we apply an ablation model to estimate the initial and terminal mass of each event. Using a dissimilarity criterion and propagating backward in time, we check the connection of these meteoroids with known complexes and near-Earth objects. We also calculate if the orbits are compatible with recent meteoroid ejections. We find that ∼27 per cent of these fireballs are dynamically associated with minor meteoroid streams and exhibit physical properties of cometary bodies, as well as one associated with a near-Earth asteroid. We identify two meteorite-producing events; however, the on-site search was unsuccessful. By considering that these fireballs are mostly produced by cm-sized rocks that might be the fragmentation product of much larger meteoroids, our findings emphasize the idea that the population of near-Earth objects is a source of near-term impact hazards, existing large Earth-colliding meteoroids in the known complexes.
A ‘coronal-mass-ejection’ model for flares in Sagittarius A*
Authors: Lin Xi , Li Ya-Ping , Yuan Feng
Published: January 2023

High-resolution near-infrared observations with GRAVITY instrument have revealed rapid orbital motions of a hotspot around Sagittarius A* (Sgr A*), the supermassive black hole in our Galactic Centre, during its three bright flares. The projected distances of the spot to the black hole are measured and seem to increase with time. The values of distance, combined with the measured orbiting time, imply that the spot is rotating with a super-Keplerian velocity. These results are hard to understand if the spot stays within the accretion flow thus provides strong constraints on theoretical models for flares. Previously we have proposed a ‘CME’ model for the flares by analogy with the coronal-mass-ejection model in solar physics. In that model, magnetic reconnection occurred at the surface of the accretion flow results in the formation of flux ropes, which are then ejected out. Energetic electrons accelerated in the current sheet flow into the flux rope region and their radiation is responsible for the flares. In this paper, we apply the model to the interpretation of the GRAVITY results by calculating the dynamics of the ejected flux rope, the evolution of the magnetic field and the energy distribution of accelerated electrons, and the radiation of the system. We find that the model can well explain the observed light curve of the flares, the time-dependent distance, and the super-Keplerian motion of the hotspot. It also explains why the light curve of some flares has double peaks.
Spectrophotometric analysis of magnetic white dwarf – II. Helium-rich compositions
Authors: Hardy François , Dufour Patrick , Jordan Stefan
Published: January 2023

We present an analysis of all single white dwarf stars known to exhibit spectroscopic signatures of neutral helium line splitting due to the presence of a strong magnetic field. Using state-of-the-art models taking into account the effects of magnetic fields on the synthetic spectra, we determine effective temperatures, surface gravities, and masses for the stars in our sample. Our analysis uses data from the second and third Gaia (early) data releases, photometric data from diverse surveys such as the Sloan Digital Sky Survey and Pan-STARRS, and archived spectroscopic data. We are able to successfully reproduce the spectra of eight objects using an offset dipole geometry while several others seem to require either a more complex geometry or a different chemical composition. We also highlight a group of hot featureless white dwarfs that are most probably highly magnetic objects whose spectra are completely smeared due to the field strength distribution across the surface.
The study on transiting systems HAT-P-13, HAT-P-16, and WASP-32 through combining ground-based and TESS photometry
Authors: Sun L , Gu S , Wang X , Bai L , Schmitt J H M M , Perdelwitz V , Ioannidis P
Published: January 2023

High-precision transit photometry supplies ideal opportunities for detecting new exoplanets and characterizing their physical properties, which usually encode valuable information for unveiling the planetary structure, atmosphere, and dynamical history. We present revised properties of three transiting systems (i.e. HAT-P-13, HAT-P-16, and WASP-32) through analyzing TESS photometry and ground-based transit observations, which were obtained at the 1-m and 2.4-m telescopes of Yunnan Observatories, China, and the 1.2-m telescope of Hamburg Observatory, Germany, as well as the data in the literature. During modelling the transit light curves, Gaussian process is employed to account for the potential systematic errors. Through comprehensive timing analysis, we find that both HAT-P-13b and HAT-P-16b show significant timing variations (TTVs) that can be explained by apsidal precession. TTVs of WASP-32b may be led by a decaying orbit due to tidal dissipation or apsidal precession. However, the current observations can not rule out the origins of three systems’ TTVs from gravitational perturbations of close planetary companions conclusively.
The star-formation history in the last 10 billion years from CIB cross-correlations
Authors: Jego Baptiste , Ruiz-Zapatero Jaime , García-García Carlos , Koukoufilippas Nick , Alonso David
Published: January 2023

The cosmic infrared background (CIB) traces the emission of star-forming galaxies throughout all cosmic epochs. Breaking down the contribution from galaxies at different redshifts to the observed CIB maps would allow us to probe the history of star formation. In this paper, we cross-correlate maps of the CIB with galaxy samples covering the range z ≲ 2 to measure the bias-weighted star-formation rate (SFR) density 〈bρSFR〉 as a function of time in a model independent way. This quantity is complementary to direct measurements of the SFR density ρSFR, giving a higher weight to more massive haloes, and thus provides additional information to constrain the physical properties of star formation. Using cross-correlations of the CIB with galaxies from the DESI Legacy Survey and the extended Baryon Oscillation Spectroscopic Survey, we obtain high signal-to-noise ratio measurements of 〈bρSFR〉, which we then use to place constraints on halo-based models of the star-formation history. We fit halo-based SFR models to our data and compare the recovered ρSFR with direct measurements of this quantity. We find a qualitatively good agreement between both independent data sets, although the details depend on the specific halo model assumed. This constitutes a useful robustness test for the physical interpretation of the CIB, and reinforces the role of CIB maps as valuable astrophysical probes of the large-scale structure. We report our measurements of 〈bρSFR〉 as well as a thorough account of their statistical uncertainties, which can be used to constrain star-formation models in combination with other data.
Photometric and structural parameters of newly discovered nuclear star clusters in Local Volume galaxies
Authors: Hoyer Nils , Neumayer Nadine , Seth Anil C , Georgiev Iskren Y , Greene Jenny E
Published: January 2023

We use high-resolution Hubble Space Telescope imaging data of dwarf galaxies in the Local Volume ($\lesssim {11}\, \mathrm{Mpc}$) to parameterize 19 newly discovered nuclear star clusters (NSCs). Most of the clusters have stellar masses of $M_{\star }^{\mathrm{nsc}} \lesssim 10^{6}{\, {\rm M}_{\odot }}$ and compare to Galactic globular clusters in terms of ellipticity, effective radius, stellar mass, and surface density. The clusters are modelled with a Sérsic profile and their surface brightness evaluated at the effective radius reveals a tight positive correlation to the host galaxy stellar mass. Our data also indicate an increase in slope of the density profiles with increasing mass, perhaps indicating an increasing role for in situ star formation in more massive hosts. We evaluate the scaling relation between the clusters and their host galaxy stellar mass to find an environmental dependence: for NSCs in field galaxies, the slope of the relation is $\alpha = 0.82^{+0.08}_{-0.08}$ whereas $\alpha = 0.55^{+0.06}_{-0.05}$ for dwarfs in the core of the Virgo cluster. Restricting the fit for the cluster to $M_{\star }^{\mathrm{gal}} \ge 10^{6.5}{\, {\rm M}_{\odot }}$ yields $\alpha = 0.70^{+0.08}_{-0.07}$, in agreement with the field environment within the 1σ interval. The environmental dependence is due to the lowest-mass nucleated galaxies and we speculate that this is either due to an increased number of progenitor globular clusters merging to become an NSC, or due to the formation of more massive globular clusters in dense environments, depending on the initial globular cluster mass function. Our results clearly corroborate recent results in that there exists a tight connection between NSCs and globular clusters in dwarf galaxies.
The SOUX AGN sample: SDSS–XMM-Newton optical, ultraviolet, and X-ray selected active galactic nuclei spanning a wide range of parameter space – sample definition
Authors: Kynoch Daniel , Mitchell Jake A J , Ward Martin J , Done Chris , Lusso Elisabeta , Landt Hermine
Published: January 2023

We assemble a sample of 696 type 1 active galactic nuclei (AGN) up to a redshift of z = 2.5, all of which have an SDSS spectrum containing at least one broad emission line (H α, H β, or Mg ii) and an XMM-Newton X-ray spectrum containing at least 250 counts in addition to simultaneous optical/ultraviolet photometry from the XMM Optical Monitor. Our sample includes quasars and narrow-line Seyfert 1s: thus our AGN span a wide range in luminosity, black hole mass, and accretion rate. We determine single-epoch black hole mass relations for the three emission lines and find that they provide broadly consistent mass estimates whether the continuum or emission line luminosity is used as the proxy for the broad emission line region radius. We explore variations of the UV/X-ray energy index αox with the UV continuum luminosity and with black hole mass and accretion rate, and make comparisons to the physical quasar spectral energy distribution model qsosed. The majority of the AGN in our sample lie in a region of parameter space with 0.02 < L/LEdd < 2 as defined by this model, with narrow-line type 1 AGN offset to lower masses and higher accretion rates than typical broad-line quasars. We find differences in the dependence of αox on UV luminosity between both narrow/broad-line and radio-loud/quiet subsets of AGN: αox has a slightly weaker dependence on UV luminosity for broad-line AGN and radio-loud AGN have systematically harder αox.
Determining satellite infall times using machine learning
Authors: Barmentloo Stan , Cautun Marius
Published: January 2023

A key unknown of the Milky Way (MW) satellites is their orbital history, and, in particular, the time they were accreted onto the MW system since it marks the point where they experience a multitude of environmental processes. We present a new methodology for determining infall times, namely using a neural network (NN) algorithm. The NN is trained on MW-analogues in the EAGLE hydrodynamical simulation to predict if a dwarf galaxy is at first infall or a backsplash galaxy and to infer its infall time. The resulting NN predicts with 85-per cent accuracy if a galaxy currently outside the virial radius is a backsplash satellite and determines the infall times with a typical 68-per cent confidence interval of 4.4 Gyr. Applying the NN to MW dwarfs with Gaia EDR3 proper motions, we find that all of the dwarfs within 300 kpc had been inside the Galactic halo. The overall MW satellite accretion rate agrees well with the theoretical prediction except for late times when the MW shows a second peak at a lookback time of 1.5 Gyr corresponding to the infall of the LMC and its satellites. We also find that the quenching times for ultrafaint dwarfs show no significant correlation with infall time and thus supporting the hypothesis that they were quenched during reionization. In contrast, dwarfs with stellar masses above 105 M⊙ are found to be consistent with environmental quenching inside the Galactic halo, with star-formation ceasing on average at $0.5^{+0.9}_{-1.2}$ Gyr after infall.
MOCCA-Survey Database: extra galactic globular clusters – III. The population of black holes in Milky Way and Andromeda-like galaxies
Authors: Leveque A , Giersz M , Askar Abbas , Arca-Sedda M , Olejak A
Published: January 2023

This work investigates the black hole (BH) population of globular clusters (GCs) in Milky Way- and Andromeda-like galaxies. We combine the population synthesis code MASinGa and the MOCCA-Survey Database I to infer the properties of GCs harbouring a stellar-mass BH subsystem (BHS), an intermediate-mass BH (IMBH), or neither of those. We find that the typical number of GCs with a BHS, an IMBH, or none become comparable in the galactic outskirts, whilst the inner galactic regions are dominated by GCs without a significant dark component. We retrieve the properties of binary BHs (BBHs) that have either merged in the last 3 Gyr or survived in their parent cluster until present-day. We find that around 80 per cent of the merging BBHs form due to dynamical interactions while the remaining originate from evolution of primordial binaries. The inferred merger rate for both in-cluster and ejected mergers is $1.0\!-\!23\, \, \rm {yr^{-1}\, Gpc^{-3}}$ in the local Universe, depending on the adopted assumptions. We find around 100–240 BBHs survive in GCs until present-day and are mostly concentrated in the inner few kpc of the galaxy. When compared with the field, GCs are at least two times more efficient in the formation of BHs and binaries containing at least one BH. Around 1000–3000 single BHs and 100–200 BBHs are transported into the galactic nucleus from infalling clusters over a time span of 12 Gyr. We estimate that the number of BHs and BBHs lurking in the star cluster to be about 1.4–2.2 × 104 and 700–1100, respectively.
Multiomics approach to profiling Sertoli cell maturation during development of the spermatogonial stem cell niche
Authors: Voigt A L , Dardari R , Lara N L M , He T , Steele H , Dufour A , Orwig K E , Dobrinski I
Published: January 2023

Spermatogonial stem cells (SSCs) are the basis of spermatogenesis, a complex process supported by a specialized microenvironment, called the SSC niche. Postnatal development of SSCs is characterized by distinct metabolic transitions from prepubertal to adult stages. An understanding of the niche factors that regulate these maturational events is critical for the clinical application of SSCs in fertility preservation. To investigate the niche maturation events that take place during SSC maturation, we combined different ‘-omics’ technologies. Serial single cell RNA sequencing analysis revealed changes in the transcriptomes indicative of niche maturation that was initiated at 11 years of age in humans and at 8 weeks of age in pigs, as evident by Monocle analysis of Sertoli cells and peritubular myoid cell (PMC) development in humans and Sertoli cell analysis in pigs. Morphological niche maturation was associated with lipid droplet accumulation, a characteristic that was conserved between species. Lipidomic profiling revealed an increase in triglycerides and a decrease in sphingolipids with Sertoli cell maturation in the pig model. Quantitative (phospho-) proteomics analysis detected the activation of distinct pathways with porcine Sertoli cell maturation. We show here that the main aspects of niche maturation coincide with the morphological maturation of SSCs, which is followed by their metabolic maturation. The main aspects are also conserved between the species and can be predicted by changes in the niche lipidome. Overall, this knowledge is pivotal to establishing cell/tissue-based biomarkers that could gauge stem cell maturation to facilitate laboratory techniques that allow for SSC transplantation for restoration of fertility.
Long-term safety and efficacy of E6011, an anti-fractalkine monoclonal antibody, in patients with rheumatoid arthritis inadequately responding to methotrexate
Authors: Tanaka Yoshiya , Takeuchi Tsutomu , Yamanaka Hisashi , Nanki Toshihiro , Umehara Hisanori , Yasuda Nobuyuki , Tago Fumitoshi , Kitahara Yasumi , Kawakubo Makoto , Torii Kentaro , Hojo Seiichiro , Kawano Tetsu , Imai Toshio
Published: January 2023

Objectives

To evaluate the long-term safety and efficacy of E6011, a humanized anti-fractalkine monoclonal antibody, in patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX).

Methods

Active RA patients with an inadequate response to MTX were randomly assigned to the E6011 or placebo group and received the study drug subcutaneously every 2 weeks during a 24-week double-blind study period. Subjects who completed evaluations at Week 24 were rolled over into the extension phase and received open-label E6011 (200 or 400 mg) every 2 weeks until Week 102. The safety analysis was conducted up to Week 104, and the efficacy analysis was conducted up to Week 84.

Results

A total of 169 subjects completed the double-blind treatment phase and were rolled over into the extension phase. In total, 167 (98.8%) subjects experienced any adverse events, and the incidence of treatment-related adverse events was 56.2%. The American College of Rheumatology 20 response rates were observed between 40 and 70% during the extension phase.

Conclusions

E6011 was safe and well tolerated with no notable safety concerns up to 102 weeks in RA patients with an inadequate response to MTX.
PREDICT-crFMF score: A novel model for predicting colchicine resistance in children with familial Mediterranean fever
Authors: Aktay Ayaz Nuray , Demirkan Fatma Gül , Coşkuner Taner , Demir Ferhat , Tanatar Ayşe , Çakan Mustafa , Karadağ Şerife Gül , Yener Gülçin Otar , Öztürk Kübra , Bağlan Esra , Çakmak Figen , Çağlayan Şengül , Özdel Semanur , Ulu Kadir , Sözeri Betül , Sönmez Hafize Emine
Published: January 2023

Objectives

To develop a novel scoring system to predict colchicine resistance in Familial Mediterranean fever (FMF) based on the initial features of the patients.

Methods

The medical records of patients were analyzed prior to the initiation of colchicine. After generating a predictive score in the initial cohort, it was applied to an independent cohort for external validation of effectiveness and reliability.

Results

Among 1418 patients with FMF, 56 (3.9%) were colchicine resistant (cr) and 1312 (96.1%) were colchicine responsive. Recurrent arthritis (4 points), protracted febrile myalgia (8 points), erysipelas-like erythema (2 points), exertional leg pain (2 points), and carrying M694V homozygous mutation (4 points) were determined as the parameters for predicting cr-FMF in the logistic regression model. The cut-off value of 9 was 87% sensitive and 82% specific to foresee the risk of cr-FMF in the receiver operating characteristic. Validation of the scoring system with an independent group (cr-FMF = 107, colchicine responsive = 1935) revealed that the cut-off value was 82% sensitive and 79% specific to identify the risk of cr-FMF.

Conclusions

By constructing this reliable and predictor tool, we enunciate that predicting cr-FMF at the initiation of the disease and interfering timely before the emergence of complications will be possible.
H2O-Controlled Eruptive Filtering on the Bimodality of Continental Volcanism Across Tectonic Settings
Authors: Zhao Kai , Xu Xisheng , Bachmann Olivier , Nan Tongchao , Xia Yan
Published: January 2023

The contemporary basaltic and rhyolitic volcanism with a dearth of intermediate compositions creates a compositional gap (‘Daly gap’), which is known to be pronounced in continental rifts/hotspots but absent in continental arcs. The intrinsic mechanism(s) producing the Daly gap remain poorly understood. Similar bimodal spectra recorded in melt inclusions from continental rifts/hotspots and arcs suggest that similar processes modulate the bulk composition of erupted magmas. A compiled data set of melt inclusion composition, phenocryst fraction, pre-eruptive temperature and melt H2O content enables precise calculations of melt viscosities and bulk magma viscosities for >100 eruptions of global volcanoes in various tectonic settings. Analyses of the data set suggest lower viscosities of rhyolitic melts in arcs than in rifts/hotspots (~104.5 ± 0.2 versus ~105.5 ± 0.2 Pa·s, respectively), at comparable temperatures, because of ~1.5 wt % higher melt H2O contents in arcs. Combining numerical constraints on ascent dynamics and data set observations, our study defines an eruption threshold of ~106.0 ± 0.3 Pa·s at the base of a volcanic conduit rooted in the subvolcanic reservoir. The lower viscosities of rhyolitic melts in arcs facilitate stirring/re-homogenization of upper crustal reservoirs upon recharge and accommodation of more phenocrysts in erupted products, leading to the common appearance of crystal-rich (30–50%) andesites and dacites (with rhyolitic interstitial melts) with mixing signatures in magmatic provinces of continental arcs. In contrast, the lower mixing efficiency and eruptibility of the more viscous magmas present in continental rifts/hotspots lead to preferential eruption of crystal-poor (<~30%) rhyolites, enhancing compositional bimodality in the erupted records. This H2O-controlled eruptive filter modulates the presence versus absence of the Daly gap and is key to the distinct differentiation patterns across tectonic settings.
Mechanisms of pathogenicity in the hypertrophic cardiomyopathy-associated TPM1 variant S215L
Authors: Halder Saiti S , Rynkiewicz Michael J , Creso Jenette G , Sewanan Lorenzo R , Howland Lindsey , Moore Jeffrey R , Lehman William , Campbell Stuart G
Published: January 2023

Hypertrophic cardiomyopathy (HCM) is an inherited disorder often caused by mutations to sarcomeric genes. Many different HCM-associated TPM1 mutations have been identified but they vary in their degrees of severity, prevalence, and rate of disease progression. The pathogenicity of many TPM1 variants detected in the clinical population remains unknown. Our objective was to employ a computational modeling pipeline to assess pathogenicity of one such variant of unknown significance, TPM1 S215L, and validate predictions using experimental methods. Molecular dynamic simulations of tropomyosin on actin suggest that the S215L significantly destabilizes the blocked regulatory state while increasing flexibility of the tropomyosin chain. These changes were quantitatively represented in a Markov model of thin-filament activation to infer the impacts of S215L on myofilament function. Simulations of in vitro motility and isometric twitch force predicted that the mutation would increase Ca2+ sensitivity and twitch force while slowing twitch relaxation. In vitro motility experiments with thin filaments containing TPM1 S215L revealed higher Ca2+ sensitivity compared with wild type. Three-dimensional genetically engineered heart tissues expressing TPM1 S215L exhibited hypercontractility, upregulation of hypertrophic gene markers, and diastolic dysfunction. These data form a mechanistic description of TPM1 S215L pathogenicity that starts with disruption of the mechanical and regulatory properties of tropomyosin, leading thereafter to hypercontractility and finally induction of a hypertrophic phenotype. These simulations and experiments support the classification of S215L as a pathogenic mutation and support the hypothesis that an inability to adequately inhibit actomyosin interactions is the mechanism whereby thin-filament mutations cause HCM.
Metaverse, mental health and museums in post-COVID-19
Authors: Kahambing Jan Gresil
Published: January 2023

In this article, I extend the modalities of mental health integration to the metaverse further toward the alternative case of museums. Some countries have modeled health facilitations of psychological nature to museums either physically or virtually. The metaverse as the incorporation of digital and actual bodies poses a further philosophical question of addressing the network of institutional and personal somatic modifications in the post-COVID-19 era.
Effects of faecal microbiota transplantation on the small intestinal mucosa in systemic sclerosis
Authors: Strahm Noemi , Didriksen Henriette , Fretheim Håvard , Molberg Øyvind , Midtvedt Øyvind , Farstad Inger Nina , Midtvedt Tore , Lundin Knut E A , Aabakken Lars , Błyszczuk Przemysław , Distler Oliver , Kania Gabriela , Hoffmann-Vold Anna-Maria
Published: January 2023

Objectives

In SSc, gastrointestinal tract (GIT) involvement is a major concern, with no disease-modifying and limited symptomatic therapies available. Faecal microbiota transplantation (FMT) represents a new therapeutic option for GIT-affliction in SSc, showing clinical promise in a recent controlled pilot trial. Here, we aim to investigate effects of FMT on duodenal biopsies collected from SSc patients by immunohistochemistry and transcriptome profiling.

Methods

We analysed duodenal biopsies obtained pre-intervention (week 0) and post-intervention (weeks 2 and 16) from nine SSc patients receiving an intestinal infusion of FMT (n = 5) or placebo (n = 4). The analysis included immunohistochemistry (IHC) with a selected immune function and fibrosis markers, and whole biopsy transcriptome profiling.

Results

In patients receiving FMT, the number of podoplanin- and CD64-expressing cells in the mucosa were lower at week 2 compared with baseline. This decline in podoplanin- (r = 0.94) and CD64-positive (r = 0.89) cells correlated with improved patient-reported lower GIT symptoms. Whole biopsy transcriptome profiling from week 2 showed significant enrichment of pathways critical for cellular and endoplasmic reticulum stress responses, microvillus and secretory vesicles, vascular and sodium-dependent transport, and circadian rhythm. At week 16, we found enrichment of pathways mandatory for binding activity of immunoglobulin receptors, T cell receptor complexes, and chemokine receptors, as well as response to zinc-ions. We found that 25 genes, including Matrix metalloproteinase-1 were upregulated at both week 2 and week 16.

Conclusion

Combining selective IHC and unbiased gene expression analyses, this exploratory study highlights the potential for disease-relevant organ effects of FMT in SSc patients with GIT involvement.

Trial registration

ClinicalTrials.gov, http://clinicaltrials.gov, NCT03444220.
Classification of patients with osteoarthritis through clusters of comorbidities using 633 330 individuals from Spain
Authors: Pineda-Moncusí Marta , Dernie Francesco , Dell’Isola Andrea , Kamps Anne , Runhaar Jos , Swain Subhashisa , Zhang Weiya , Englund Martin , Pitsillidou Irene , Strauss Victoria Y , Robinson Danielle E , Prieto-Alhambra Daniel , Khalid Sara
Published: January 2023

Objectives

To explore clustering of comorbidities among patients with a new diagnosis of OA and estimate the 10-year mortality risk for each identified cluster.

Methods

This is a population-based cohort study of individuals with first incident diagnosis of OA of the hip, knee, ankle/foot, wrist/hand or ‘unspecified’ site between 2006 and 2020, using SIDIAP (a primary care database representative of Catalonia, Spain). At the time of OA diagnosis, conditions associated with OA in the literature that were found in ≥1% of the individuals (n = 35) were fitted into two cluster algorithms, k-means and latent class analysis. Models were assessed using a range of internal and external evaluation procedures. Mortality risk of the obtained clusters was assessed by survival analysis using Cox proportional hazards.

Results

We identified 633 330 patients with a diagnosis of OA. Our proposed best solution used latent class analysis to identify four clusters: ‘low-morbidity’ (relatively low number of comorbidities), ‘back/neck pain plus mental health’, ‘metabolic syndrome’ and ‘multimorbidity’ (higher prevalence of all studied comorbidities). Compared with the ‘low-morbidity’ cluster, the ‘multimorbidity’ cluster had the highest risk of 10-year mortality (adjusted hazard ratio [HR]: 2.19 [95% CI: 2.15, 2.23]), followed by the ‘metabolic syndrome’ cluster (adjusted HR: 1.24 [95% CI: 1.22, 1.27]) and the ‘back/neck pain plus mental health’ cluster (adjusted HR: 1.12 [95% CI: 1.09, 1.15]).

Conclusion

Patients with a new diagnosis of OA can be clustered into groups based on their comorbidity profile, with significant differences in 10-year mortality risk. Further research is required to understand the interplay between OA and particular comorbidity groups, and the clinical significance of such results.
Lagrange-NG: The next generation of Lagrange
Authors: Bettisworth Ben , Smith Stephen A , Stamatakis Alexandros
Published: January 2023

Computing ancestral ranges via the Dispersion Extinction and Cladogensis (DEC) model of biogeography is characterized by an exponential number of states relative to the number of regions considered. This is because the DEC model requires computing a large matrix exponential, which typically accounts for up to 80% of overall runtime. Therefore, the kinds of biogeographical analyses that can be conducted under the DEC model are limited by the number of regions under consideration. In this work, we present a completely redesigned efficient version of the popular tool Lagrange which is up to 49 times faster with multithreading enabled, and is also 26 times faster when using only one thread. We call this new version Lagrange-NG (Lagrange-Next Generation). The increased computational efficiency allows Lagrange-NG to analyze datasets with a large number of regions in a reasonable amount of time, up to 12 regions in approximately 18 min. We achieve these speedups using a relatively new method of computing the matrix exponential based on Krylov subspaces. In order to validate the correctness of Lagrange-NG, we also introduce a novel metric on range distributions for trees so that researchers can assess the difference between any two range inferences. Finally, Lagrange-NG exhibits substantially higher adherence to coding quality standards. It improves a respective software quality indicator as implemented in the SoftWipe tool from average (5.5; Lagrange) to high (7.8; Lagrange-NG). Lagrange-NG is freely available under GPL2. [Biogeography; Phylogenetics; DEC Model.]
Epidermotropic B-Cell Lymphoma: A Case of Secondary Cutaneous Splenic Marginal Zone B-Cell Lymphoma With Autoinvolutive and Recurrent Cutaneous Lesions
Authors: Rovira-López Roger , Gallardo Fernando , Salar Antonio , Colomo Lluis , Pujol Ramon M.
Published: January 2023

An 84-year-old woman presented with a 3-month history of a papular rash on the trunk, abdomen, and back. Histopathological examination revealed atypical lymphoid deep and band-like dermal infiltrates with marked epidermotropism. Neoplastic cells expressed B-cell markers (CD20), and clonal immunoglobulin gene rearrangement was observed. A complete peripheral blood study revealed aberrant circulating villous lymphocytes with the expression of B-cell markers (CD20, CD22, and CD79a) and aberrant expression of CD5. A staging workup revealed discrete splenic enlargement and bone marrow and gastrointestinal tract involvement. Skin lesions regressed spontaneously several weeks after diagnosis. Throughout evolution, the patient developed scattered cutaneous nodules and generalized papulo-nodules showing either epidermotropic or nonepidermotropic atypical dermal lymphoid infiltrates. This case illustrates the observation of autoinvolutive and recurrent epidermotropic B-cell atypical cutaneous infiltrates as a characteristic feature of secondary cutaneous involvement in splenic marginal B-cell lymphoma. Previously reported cases of epidermotropic B-cell lymphoma have been reviewed. Concurrent and simultaneous observation of epidermotropic and nonepidermotropic lesions seems to indicate that epidermotropism is an important but nonconstant diagnostic feature of splenic marginal B-cell lymphoma.
Trichoepithelioma on the Finger: A Rare Location and Dermoscopic–Histopathologic Correlation
Authors: Mayo-Martínez Fátima , Moro Ruggero , Traves Victor , Llombart Beatriz , Requena Celia
Published: January 2023

Trichoepithelioma is a benign adnexal neoplasm of follicular germinative cells, with bulbs, papillae, and sheaths of perifollicular connective tissue as signs of follicular differentiation. Accordingly, trichoepithelioma may arise in any hair-bearing location, mostly on the face. That is why trichoepithelioma cannot appear in glabrous skin, and, although the dorsum of the hands and feet are a hair-bearing area, acral location is exceptional. We report the first case of trichoepithelioma localized in the finger of a 79-year-old man. It was a brown-pink, firm, 7-mm diameter, solid papule on the dorsal aspect of his left index finger. The lesion was completely asymptomatic, and he remembered to have it for many years. We describe this case highlighting its rare anatomical location and correlate its dermoscopic features with the histopathological appearance.
Reactive Eccrine Syringofibroadenoma (ESFA) in Association With a Merkel Cell Carcinoma Excision Scar
Authors: Salah Haneen T. , Czelusta Adam J. , Sanchez Ramon L.
Published: January 2023

Eccrine syringofibroadenoma (ESFA) is a rare benign skin adnexal lesion of the acrosyringium of eccrine sweat ducts. Reactive ESFA, a subtype of ESFA, is usually associated with non-neoplastic cutaneous dermatoses or neoplastic skin tumors. Clinically, the lesions can be solitary or multiple, pink, or skin-colored coalescing papules or nodules of variable sizes. Histopathologically, this tumor is composed of numerous anastomosing cords of monomorphic cuboidal epithelial cells with eccrine duct formation. The association of reactive ESFA with benign conditions, such as psoriasis, diabetic polyneuropathy, scars, and leprosy, has been reported. However, the association of reactive ESFA with malignant tumors is extremely rare, with very few cases reported in the literature. We present a case of a 72-year-old woman who developed reactive ESFA associated with Merkel cell carcinoma excision scar. The ESFA tumors developed in the area of the surgical graft 10 months after the Merkel cell carcinoma had been excised. New ESFA tumors have continued to appear in the scar on a yearly basis while, so far, has been no recurrence of the original tumor. However, the presence of new tumor growths in the area suggested the possibility of recurrence of the Merkel cell carcinoma. That possibility was enhanced by the fact that PET scans revealed hypermetabolic activity in the ESFA papules.
Transcription Factor HES-1: How Is the Expression of This Transcriptional Factor in Paucibacillary Leprosy Patients?
Authors: Serrano-Coll Héctor , Ospina-Gómez Juan Pablo , Salamanca Carolina , Restrepo Lina , Berbeo Katerine , Olarte Graciela , Cardona-Castro Nora
Published: January 2023

Introduction:

Leprosy is an ancient and chronic infectious disease caused by 2 mycobacteria (Mycobacterium leprae and Mycobacterium lepromatosis). Recently, our research group observed that HES-1, an innate cellular component of the Notch signaling pathway, is related to the pathogenesis of leprosy. Therefore, it could be helpful in its detection.

Objective:

To determine the expression of HES-1 in the skin of patients with paucibacillary (PB) leprosy.

Methods:

A cross-sectional, descriptive, observational study was conducted. Forty-five skin samples from patients with leprosy were evaluated (30 samples from MB leprosy and 15 from PB leprosy) using immunohistochemistry of HES-1 and S-100.

Results:

PB leprosy biopsies revealed a reduction of HES-1 in 66.7% of the epidermis, 80% of the eccrine glands, and 62.5% of the hair follicles of these patients, with statistical differences in the control group (P < 0.0001). Besides, HES-1 showed similar utility to S-100 immunostaining in detecting the MB and PB leprosy.

Conclusions:

HES-1 is a transcriptional factor also reduced in PB patients' epidermis and skin appendages. Finally, our data show that HES-1 could be a biomarker in diagnosing PB and MB leprosy.