Miracle-dz/UniFAR-FTUs huggingface dataset:
USP8 Mutations and Cell Cycle Regulation in Corticotroph Adenomas

Abstract Corticotroph adenomas frequently harbor somatic USP8 mutations. These adenomas also commonly exhibit underexpression of P27, a cell cycle regulator. The present study aimed to determine the influence of USP8 mutations on clinical features of Cushingʼs disease and to elucidate the relationship between USP8 mutations and P27 underexpression in these tumors. Retrospective study with 32 patients with Cushingʼs disease was followed at the Ribeirao Preto Medical School University Hospital. We evaluated the patientsʼ clinical data, the USP8 mutation status and the gene expression of cell cycle regulators P27/CDKN1B, CCNE1, CCND1, CDK2, CDK4, and CDK6 in tumor tissue in addition to the protein expression of P27/CDKN1B. We observed somatic mutations in the exon 14 of USP8 in 31.3% of the patients. Larger tumor size was observed in patients harboring USP8 mutations (p=0.04), with similar rates of remission, age of presentation, salivary cortisol at 23:00 h and after 1 mg dexamethasone, ACTH levels, and early postoperative plasma cortisol. We observed no differences regarding the gene or protein expression of the cell cycle regulators according to USP8 mutation status. In this Brazilian series, the observed frequency of USP8 somatic mutations was similar to that reported in European ancestry populations. Although it was reasonable that USP8 mutations could contribute to cell cycle dysregulation and P27 underexpression in corticotroph adenomas, our data did not confirm this hypothesis. It is possible that increased deubiquitinase activity observed in mutated USP8 might influence other pathways related to cell growth and proliferation.
Current and emerging biologic therapies for allergic rhinitis and chronic rhinosinusitis

ABSTRACT Introduction: Allergic rhinitis and chronic rhinosinusitis, with and without nasal polyps, are the most common chronic inflammatory diseases of the upper airways. They both cause relevant respiratory symptoms and a substantial detriment to patients’ quality of life, mainly in uncontrolled and severe patients. Areas covered: This review aims to present the most recent evidence on current and emerging biologic therapies for allergic rhinitis and chronic rhinosinusitis and discuss their potential implementation in clinical practice. To select relevant literature for inclusion in this review, we conducted a literature search using the PubMed database, using terms ‘biologics OR biological agents’, ‘allergic rhinitis’ and ‘chronic rhinosinusitis’. The literature review was performed for publication years 2009–2019, restricting the articles to humans and English language publications. Expert opinion: Biological therapies represent a potential step forward in providing individualized care for all patients with uncontrolled severe upper airway diseases. Biologics recently showed promising results for the treatment of severe uncontrolled allergic rhinitis and chronic rhinosinusitis with nasal polyps with or without associated asthma. Endotyping inflammatory pathways and identifying related biomarkers remain the major challenge for positioning biologics in the care pathway of chronic respiratory diseases.
GPCR-induced YAP activation sensitizes fibroblasts to profibrotic activity of TGFβ1

Tissue fibrosis is a pathological condition characterized by uncontrolled fibroblast activation that ultimately leads to organ failure. The TGFβ1 pathway, one of the major players in establishment of the disease phenotype, is dependent on the transcriptional co-activators YAP/TAZ. We were interested whether fibroblasts can be sensitized to TGFβ1 by activation of the GPCR/YAP/TAZ axis and whether this mechanism explains the profibrotic properties of diverse GPCR ligands. We found that LPA, S1P and thrombin cooperate in human dermal fibroblasts with TGFβ1 to induce extracellular matrix synthesis, myofibroblast marker expression and cytokine secretion. Whole genome expression profiling identified a YAP/TAZ signature behind the synergistic profibrotic effects of LPA and TGFβ1. LPA, S1P and thrombin stimulation led to activation of the Rho-YAP axis, an increase of nuclear YAP-Smad2 complexes and enhanced expression of profibrotic YAP/Smad2-target genes. More generally, dermal, cardiac and lung fibroblast responses to TGFβ1 could be enhanced by increasing YAP nuclear levels (with GPCR ligands LPA, S1P, thrombin or Rho activator) and inhibited by decreasing nuclear YAP (with Rho inhibitor, forskolin, latrunculin B or 2-deoxy-glucose). Thus, we present here a conceptually interesting finding that fibroblast responses to TGFβ1 can be predicted based on the nuclear levels of YAP and modulated by stimuli/treatments that change YAP nuclear levels. Our study contributes to better understanding of fibrosis as a complex interplay of signalling pathways and proposes YAP/TAZ as promising targets in the treatment of fibrosis.
Clinical spectrum of BICD2 mutations

Mutations in the BICD2 gene cause autosomal dominant lower extremity‐predominant spinal muscular atrophy 2A (SMALED2A), a condition that is associated with a specific pattern of thigh and calf muscle involvement when studied by magnetic resonance imaging (MRI). Patients may present minor clinical sensory impairment, but objective sensory involvement has yet to be demonstrated.
A 70% cut-off for MYC protein expression in diffuse large B cell lymphoma identifies a high-risk group of patients.

Citation: Marita Ziepert, Stefano Lazzi, Raffaella Santi, Federica Vergoni, Massimo Granai, Virginia Mancini, Annette Staiger, Heike Horn, Markus Löffler, Viola Pöschel, Gerhald Held, Gerald Wulf, Lorenz H. Trümper, Norbert Schmitz, Andreas Rosenwald, Elena Sabattini, Kikkeri N. Naresh, Harald Stein, German Ott, and Lorenzo Leoncini. A 70% cut-off for MYC protein expression in diffuse large B cell lymphoma identifies a high-risk group of patients. Haematologica. 2020; 105:xxx doi:10.3324/haematol.2019. 235556
Biomagnification of methylmercury in a marine plankton ecosystem.

Methylmercury is greatly bioconcentrated and biomagnified in marine plankton ecosystems, and these communities form the basis of marine food webs. Therefore, evaluating the potential exposure of methylmercury to higher trophic levels, including humans, requires a better understanding of its distribution in the ocean and the factors that control its biomagnification. In this study, a coupled physical/ecological model is used to simulate the trophic transfer of monomethylmercury (MMHg) in a marine plankton ecosystem. The model includes phytoplankton, a microbial community, herbivorous zooplankton (HZ), and carnivorous zooplankton (CZ). The model captures both shorter food chains in oligotrophic regions, with small HZ feeding on small phytoplankton, and longer chains in higher nutrient conditions, with larger HZ feeding on larger phytoplankton and larger CZ feeding on larger HZ. In the model, trophic dilution occurs in the food webs that involve small zooplankton, as the grazing fluxes of small zooplankton are insufficient to accumulate more MMHg in themselves than in their prey. The model suggests that biomagnification is more prominent in large zooplankton and that the microbial community plays an important role in the trophic transfer of MMHg. Sensitivity analyses show that with increasing body size, the sensitivity of the trophic magnification ratio to grazing, mortality rates, and food assimilation efficiency (AEC) increases, while the sensitivity to excretion rates decreases. More predation or a longer zooplankton lifespan may lead to more prominent biomagnification, especially for large species. Because lower AEC results in more predation, modeled ratios of MMHg concentrations between large plankton are doubled or even tripled when the AEC decreases from 50% to 10%. This suggests that the biomagnification of large zooplankton is particularly sensitive to food assimilation efficiency.
Safety concerns with current treatments for psoriasis in the elderly

ABSTRACT Introduction: The approach to manage psoriasis in the elderly (ages ≥65 years) patients can be challenging. They often suffer from multiple comorbidities and polypharmacy with possible adverse effects and undergo a progressive functional impairment of the immune system that increases susceptibility to infections as well as to auto-reactivity. Despite the increasing aging of the general population and although several therapies are currently available for psoriasis treatment, data regarding their use and tolerability in the elderly are quite limited. Areas covered: This review focuses on topical and systemic therapies that have been investigated in elderly patients in order to provide their safety profile in this population. Expert opinion: Conventional systemic therapies in elderly patients should be carefully dispensed and the correct dosage individually determined, taking into account the metabolism changes, organ impairment, comorbidities, concomitant medications, and contraindications. Apremilast, due to its satisfactory safety profile and low risk of drug interactions, results as an appropriate treatment option for elderly patients. Biologics (TNF-α, IL-12/23, IL-17, and IL-23 inhibitors) come out as safe and long-term options for the management of these patients resulting not associated with a higher risk of adverse events.
Urinary chemical fingerprint left behind by repeated NSAID administration: Discovery of putative biomarkers using artificial intelligence

Prediction and early detection of kidney damage induced by nonsteroidal anti-inflammatories (NSAIDs) would provide the best chances of maximizing the anti-inflammatory effects while minimizing the risk of kidney damage. Unfortunately, biomarkers for detecting NSAID-induced kidney damage in cats remain to be discovered. To identify potential urinary biomarkers for monitoring NSAID-based treatments, we applied an untargeted metabolomics approach to urine collected from cats treated repeatedly with meloxicam or saline for up to 17 days. Applying multivariate analysis, this study identified a panel of seven metabolites that discriminate meloxicam treated from saline treated cats. Combining artificial intelligence machine learning algorithms and an independent testing urinary metabolome data set from cats with meloxicam-induced kidney damage, a panel of metabolites was identified and validated. The panel of metabolites including tryptophan, tyrosine, taurine, threonic acid, pseudouridine, xylitol and lyxitol, successfully distinguish meloxicam-treated and saline-treated cats with up to 75–100% sensitivity and specificity. This panel of urinary metabolites may prove a useful and non-invasive diagnostic tool for monitoring potential NSAID induced kidney injury in feline patients and may act as the framework for identifying urine biomarkers of NSAID induced injury in other species.
Somatic mutations and copy number variations in breast cancers with heterogeneous HER2 amplification

Intratumour heterogeneity fuels carcinogenesis and allows circumventing specific targeted therapies. HER2 gene amplification is associated with poor outcome in invasive breast cancer. Heterogeneous HER2 amplification has been described in 5–41% of breast cancers. Here, we investigated the genetic differences between HER2‐positive and HER2‐negative admixed breast cancer components. We performed an in‐depth analysis to explore the potential heterogeneity in the somatic mutational landscape of each individual tumour component. Formalin‐fixed, paraffin‐embedded breast cancer tissue of ten patients with at least one HER2‐negative and at least one HER2‐positive component was microdissected. Targeted next‐generation sequencing was performed using a customized 53‐gene panel. Somatic mutations and copy number variations were analysed. Overall, the tumours showed a heterogeneous distribution of 12 deletions, 9 insertions, 32 missense variants and 7 nonsense variants in 26 different genes, which are (likely) pathogenic. Three splice site alterations were identified. One patient had an EGFR copy number gain restricted to a HER2‐negative in situ component, resulting in EGFR protein overexpression. Two patients had FGFR1 copy number gains in at least one tumour component. Two patients had an 8q24 gain in at least one tumour component, resulting in a copy number increase in MYC and PVT1. One patient had a CCND1 copy number gain restricted to a HER2‐negative tumour component. No common alternative drivers were identified in the HER2‐negative tumour components. This series of 10 breast cancers with heterogeneous HER2 gene amplification illustrates that HER2 positivity is not an unconditional prerequisite for the maintenance of tumour growth. Many other molecular aberrations are likely to act as alternative or collaborative drivers. This study demonstrates that breast carcinogenesis is a dynamically evolving process characterized by a versatile somatic mutational profile, of which some genetic aberrations will be crucial for cancer progression, and others will be mere ‘passenger’ molecular anomalies.
Enhancement of antioxidant activity of well-dispersed core–shell structured CeO2 coating Au nanorods under visible light irradiation

Gold nanoparticle (AuNP) modification shows great advantages in improving the antioxidant activity of nanoCeO2. However, the improved effect of AuNP modification becomes smaller and even results in the decrease of antioxidant ability due to severe aggregation with increasing nanomaterial concentration. Additionally, the effects of photo-properties of AuNPs on the antioxidant activity of nanoCeO2 have not been studied. In response to these problems, core–shell-shaped Au@CeO2 was synthesized which took Au nanorods (AuNRs) as carriers and had a layer of CeO2 NP coating. The antioxidant activity of Au@CeO2 was evaluated by the UV–vis method in the methyl violet–Fenton system. Results showed that AuNRs could improve the antioxidant activity of nanoCeO2 due to the increase in the amount of Ce3+ on the surface of nanoCeO2, and the enhancing effect remained across the whole experimental concentration range due to the good dispersibility of AuNRs. Additionally, a further increase in the antioxidant ability of Au@CeO2 was found with 5 min visible light irradiation, and continuous irradiation during a 25 min time reaction, which resulted in more obvious enhanced antioxidant ability. This phenomenon was attributed to the localized surface plasmon resonance of AuNRs triggered by photons which induced charge transfer from AuNRs to nanoCeO2, thus making the cyclic transformation between Ce3+ and Ce4+ easier.
Risk Factors and Trends Associated With Mortality Among Adults With Hip Fracture in Singapore.

Importance Examining trends in mortality following hip fracture and its associated factors is important for population health surveillance and for developing preventive interventions. Objective To examine temporal trends in, and risk factors associated with, mortality following hip fracture over 18 years in Singapore. Design, Setting, and Participants This retrospective, population-based cohort study included men and women aged 50 years and older admitted to Singapore hospitals for first hip fracture identified and followed up from 2000 to 2017. Demographic information, fracture type, and Charlson Comorbidity Index (CCI) score were retrieved from nationwide claims data, and mortality data were from the National Death Registry. Data were analyzed from August 2018 to December 2019. Main Outcomes and Measures Adjusted hazard ratios (aHRs) and their 95% confidence intervals were estimated using Cox proportional hazards regression. Kaplan-Meier life table methods were used to calculate survival following the hip fracture on a cohort basis. The crude survival over time since fracture was compared by sex, age group, ethnicity, CCI, and fracture type. Standardized mortality ratios (SMRs) were calculated using all-cause mortality obtained from Singapore population life tables. Results Among 36 082 first inpatient admissions for hip fractures (mean [SD] patient age, 78.2 [10.1] years; 24 902 [69.0%] female; 30 348 [84.1%] Chinese, 2863 [7.9%] Malay, 1778 [4.9%] Indian, and 1093 [3.0%] other ethnicity), elevated rates of mortality were observed for male sex (aHR, 1.46; 95% CI, 1.41-1.52), Malay ethnicity (aHR, 1.23; 95% CI, 1.15-1.30 vs Chinese ethnicity), older age (aHR, 5.20; 95% CI, 4.27-6.34 for age ≥85 years vs 50-54 years), high CCI score (aHR, 3.62; 95% CI, 3.42-3.84 for CCI ≥6 vs CCI of 0), trochanteric fractures (aHR, 1.11; 95% CI, 1.06-1.16 vs cervical fractures), and earlier cohorts (aHR, 0.59; 95% CI, 0.56-0.62 for 2012-2017 vs 2000-2005). Absolute mortality decreased significantly over time: by 21% in 2006 to 2011 and by 40% in 2012 to 2017, compared with 2000 to 2005. On long-term follow-up, differences in survival associated with sex and ethnicity tended to diminish, whereas differences associated with older age, higher CCI score, and trochanteric fractures increased. In the first year after fracture, reductions in SMR were observed comparing the periods 2013 to 2016 with 2003 to 2007 in women (SMR, 2.05; 95% CI, 1.91-2.20 vs SMR, 2.54; 95% CI, 2.39-2.70, respectively) but not among men (SMR, 3.28; 95% CI, 3.04-3.54 vs SMR, 3.42; 95% CI, 3.18-3.68, respectively). Conclusions and Relevance Malay ethnicity, older age, male sex, prefracture comorbidity, and trochanteric fractures were independently associated with increased risk of death, identifying population groups that could be targeted for intervention strategies. The improvement in relative mortality for women but not men suggests the need to develop interventions that improve mortality outcomes for men.
A Multicenter, Comparative Study of Two Pressure-Redistribution Mattresses with Repositioning Intervals for Critical Care Patients.

OBJECTIVE To compare the effectiveness of two protocols for preventing pressure injuries (PIs) in Chinese hospitals. DESIGN AND SETTING A multicenter, open-label, comparative study conducted in seven Chinese acute care hospitals. PATIENTS AND INTERVENTION In total, 1,654 eligible patients were identified, and 1,204 were enrolled in the study. Enrolled patients were randomly assigned into the trial group (4-hour repositioning combined with a viscoelastic foam mattress; n = 602) or the control group (2-hour repositioning combined with a powered air pressure redistribution mattress; n = 602). Participants received their respective protocols until they were discharged, died, or for at least 7 days. MAIN OUTCOME MEASURES The incidence of PIs, Braden Scale scores, and the time to development of PIs. MAIN RESULTS Ultimately, 596 trial group patients and 598 control group patients were analyzed. Thirteen patients had single new stage 2 or worse PIs. The total incidence of PIs was 1.1%. The difference between the two groups was significant (0.3% vs 1.8%). However, the difference between the groups' Braden Scale score median during the intervention was not significant (13 vs 13.5). CONCLUSIONS The 4-hour repositioning interval combined with a viscoelastic foam mattress did not increase PI incidence or risk. These findings could help providers select the right pressure redistribution mattresses and repositioning intervals for critical care patients.
Deciphering the miRNA transcriptome of Rongchang pig longissimus dorsi at weaning and slaughter time points.

MicroRNA (miRNA) is essential for the process of gene posttranscriptional regulation in skeletal muscle of many species, such as mice, cattle and so on. However, a little number of miRNAs have been reported in the muscle development of Chinese native pig breeds. In this study, the longissimus dorsi transcripts of Chinese native Rongchang pig at weaning and slaughter time points were analysed for miRNA-seq. The results showed that 19 novel and 186 known miRNAs involved in the Rongchang pig skeletal muscle development were identified. Based on these findings, we further confirmed that porcine miR-127, miR-299 and miR-432-5p were obviously down-expressed in adult pig (287 days of age), while miR-7134-3p and 664-5p were significantly up-expressed in weaning pig (35 days of age). In other words, these miRNAs could be the potential molecular markers and play vital roles in the muscle development process. Moreover, we found miR-127 could inhibit the proliferation and myogenesis of porcine satellite cells in longissimus dorsi muscle. Our findings will provide deep insight into miRNA function for pork quality research with Chinese indigenous pig breeds.
Molecular Detection and Genetic Characteristics of Equine Herpesvirus in Korea

Respiratory diseases cause significant economic losses (especially in the horse racing industry). The present study describes the detection and genetic characteristics of equine herpesvirus (EHV) from a total of 1497 samples from clinically healthy horses in Korea, including 926 blood samples, 187 lung tissues, and 384 nasal swabs. EHV-2 and EHV-5 were detected in 386 (41.7%; 95% CI: 38.5–44.9) and 201 (21.7%; 95% CI: 19.1–24.4) blood samples, respectively, and in 25 (13.4%; 95% CI: 8.5–18.2) and 35 (18.7%; 95% CI: 13.1–24.3) lung tissues, respectively. EHV-1 and EHV-4 were not detected in either blood or lung tissues. EHV-1, EHV-2, and EHV-5 were detected in 46 (12.0%; 95% CI: 8.7–15.2), 21 (5.5%; 95% CI: 3.2–7.7), and 43 (11.2%; 95% CI: 8.0–14.4) nasal swabs, respectively. EHV-4 was not detected in nasal swabs. Co-infection with EHV-2 and EHV-5 was detected in 11.6% (107/926) of the blood samples and 6.4% (12/187) of lung tissues. In nasal swabs, co-infection with EHV-1, EHV-2, and EHV-5 was detected in 0.8% (3/384) of samples. Phylogenetic analysis of the glycoprotein B gene showed that EHV-1, EHV-2, and EHV-5 strains demonstrated significant genetic diversity in Korea, with a nucleotide sequence identity among them that ranged from 95.7% to 100% for EHV-1, 96.2–100% for EHV-2, and 93.8–99.3% for EHV-5. These results are the first phylogenetic analyses of EHV-1 in Korea in nasal swabs from a nationwide population of clinically healthy horses. Both EHV-2 and EHV-5 from blood, lung tissues, and nasal swabs were also detected.