Miracle-dz/UniFAR-FTUs huggingface dataset:
Long-term Safety of Secukinumab Over Five Years in Patients with Moderate-to-severe Plaque Psoriasis, Psoriatic Arthritis and Ankylosing Spondylitis: Update on Integrated Pooled Clinical Trial and Post-marketing Surveillance Data

Secukinumab, a selective interleukin (IL)-17A inhibitor, is approved for use in adult and paediatric psoriasis, psoriatic arthritis, ankylosing spondylitis and non-radiographic axial spondyloarthritis. The aim of this study was to report the long-term safety of secukinumab in pooled data from 28 clinical trials and a post-marketing safety surveillance in psoriasis, psoriatic arthritis and ankylosing spondylitis patients. Analyses included 12,637 secukinumab-treated patients, corresponding to 15,063, 5,985 and 3,527 patient-years of exposure in psoriasis, psoriatic arthritis and ankylosing spondylitis patients, respectively. Incidences of serious adverse events were low, with no identifiable patterns across indications. Active tuberculosis or latent tuberculosis infections were rare. The incidence of opportunistic infections was < 0.2/100 patient-years, the incidence of malignancy was ≤ 1/100 patient-years, and the incidence of major adverse cardiovascular events was < 0.7/100 patient-years, with no apparent increases over time. Secukinumab demonstrated a favourable safety profile for up to 5 years of treatment across the 3 indications, and no new safety signals were identified.
Primary Synovial Sarcoma of the Rectum

Synovial sarcoma (SS) is a rare and aggressive subtype of soft tissue sarcomas with an estimated incidence of 1.77 per 1 000 000 in the United States. Synovial sarcoma classically arises in younger patient populations from periarticular tissues, but can theoretically arise anywhere in the body. To our knowledge, only 2 other cases of primary rectal SS have been reported in peer-reviewed literature to date. Herein, we report a unique case of metastatic primary rectal SS and associated clinical findings to advance detection, knowledge, and treatment of this rare neoplasm.
Expression of SOX2OT, DANCR and TINCR long non-coding RNAs in papillary thyroid cancer and its effects on clinicopathological features

Long non-coding RNAs (lncRNAs) are molecules that are >200 base pairs long and do not encode a protein. However, they perform important roles in regulating gene expression. Recent studies have revealed that the changes in the expressions of lncRNAs serve a role in the development and metastases of a number of types of cancer. A number of studies have been published on the association of SOX2 overlapping transcript (SOX2OT), differentiation antagonizing non-protein coding RNA (DANCR) and tissue differentiation-induced non-coding RNA (TINCR) expression with various types of cancer. However, researchers have not yet studied their roles in papillary thyroid cancer or at least, those roles are not clarified. The aim of the present study was to investigate the expression and clinical significance of SOX2OT, DANCR and TINCR in papillary thyroid cancer (PTC). A total of 102 patients with PTC were included in the present study. Reverse transcription-quantitative PCR method was used to determine the relative gene expression levels of lncRNAs and then the relationship between expressions of lncRNAs and clinical characteristics of the subjects was analyzed in detail. Expression levels of SOX2OT (P=0.016) and DANCR (P=0.017) increased in the tumor samples in contrast to the normal tissues. No significant difference was observed in the expression level of TINCR (P=0.298). In addition, SOX2OT expression was associated with micro carcinoma (P<0.001), tumor size (P=0.010) and primary tumor (P=0.006), while DANCR expression was associated with age (P=0.030) and micro carcinoma (P=0.004). The findings of the present study indicated that DANCR may contribute to the development of PTC while SOX2OT may contribute to both the development and progression of PTC.
Nitrate transport via NRT2.1 mediates NIN-LIKE PROTEIN-dependent suppression of root nodulation in Lotus japonicus

Abstract Legumes have adaptive mechanisms that regulate nodulation in response to the amount of nitrogen in the soil. In Lotus japonicus, two NODULE INCEPTION (NIN)-LIKE PROTEIN (NLP) transcription factors, LjNLP4 and LjNLP1, play pivotal roles in the negative regulation of nodulation by controlling the expression of symbiotic genes in high nitrate conditions. Despite an improved understanding of the molecular basis for regulating nodulation, how nitrate plays a role in the signaling pathway to negatively regulate this process is largely unknown. Here, we show that nitrate transport via NITRATE TRANSPORTER 2.1 (LjNRT2.1) is a key step in the NLP signaling pathway to control nodulation. A mutation in the LjNRT2.1 gene attenuates the nitrate-induced control of nodulation. LjNLP1 is necessary and sufficient to induce LjNRT2.1 expression, thereby regulating nitrate uptake/transport. Our data suggest that LjNRT2.1-mediated nitrate uptake/transport is required for LjNLP4 nuclear localization and induction/repression of symbiotic genes. We further show that LjNIN, a positive regulator of nodulation, counteracts the LjNLP1-dependent induction of LjNRT2.1 expression, which is linked to a reduction in nitrate uptake. These findings suggest a plant strategy in which nitrogen acquisition switches from obtaining nitrogen from the soil to symbiotic nitrogen fixation.
Clearance of Maedi-visna infection in a longitudinal study of naturally infected rams is associated with homozygosity for the TMEM154 resistance allele

Maedi-visna (MV) is a lentiviral disease of sheep responsible for severe production losses in affected flocks. There are no vaccination or treatment options with control reliant on test and cull strategies. The most common diagnostic methods used at present are combination ELISAs for Gag and Env proteins with virus variability making PCR diagnostics still largely an experimental tool. To assess variability in viral loads and diagnostic tests results, serology, DNA and RNA viral loads were measured in the blood of 12 naturally infected rams repeatedly blood sampled over 16 months. Six animals tested negative in one or more tests at one or more time points and would have been missed on screening programmes reliant on one test method or a single time point. In addition the one animal homozygous for the ‘K’ allele of the TMEM154 E35K SNP maintained very low viral loads in all assays and apparently cleared infection to below detectable limits at the final time point it was sampled. This adds crucial data to the strong epidemiological evidence that this locus represents a genuine resistance marker for MV infection and is a strong candidate for selective breeding of sheep for resistance to disease.
Comparison of ten predictive equations for estimating lean body mass with dual-energy X-ray absorptiometry in older patients.

OBJECTIVES White fat contributes to body weight (BW) but accumulates very little [18F]fluorodeoxyglucose ([18F]FDG) in the fasting state. As a result, higher standardised uptake values normalised to BW (SUV) are observed in non-fatty tissue in obese patients compared to those in non-obese patients. Therefore, SUV normalised to lean body mass (SUL) that makes tumour uptake values less dependent on patients' body habitus is considered more appropriate. This study aimed to assess ten mathematical equations to predict lean body mass (LBM) by comparison with dual-energy X-ray absorptiometry (DXA) as the reference method. METHODS DXA-based LBM was compared with ten equation-based estimates of LBM in terms of the slope, bias and 95% limits of agreement (LOA) of Bland-Altman plots, and Pearson correlation coefficients (r). Data from 747 men and 811 women aged 60-65 years were included. RESULTS Gallagher's equation was optimal in males (slope = 0.13, bias = -2.4 kg, LOA = 12.8 kg and r = 0.900) while Janmahasatian's equation was optimal in females (slope = 0.14, bias = -0.9 kg, LOA = 10.7 kg and r = 0.876). Janmahasatian's equation performed slightly better than Gallagher's in the pooled male and female data (slope = 0.00, bias = -1.6 kg, LOA = 12.3 kg and r = 0.959). CONCLUSIONS The Gallagher and Janmahasatian equations were optimal and almost indistinguishable in predicting LBM in subjects aged 60-65 years. ADVANCES IN KNOWLEDGE Determination of the optimum equation for predicting lean body mass to improve the calculation of SUL for [18F]FDG PET quantification.
New‐onset lichen planus arising after COVID‐19 vaccination

Dear Editor, COVID-19 pandemic vaccination campaign is the main weapon to overcome this global emergency. Several cutaneous reactions related to COVID-19 vaccination have been reported. Herein, we report the case of a 54 year-old male patient referring at our outpatient clinic for widespread pruritic lesions appeared 10 days after the first dose of Pfizer mRNABNT162b2 vaccine. Dermatological examination revealed small, polygonal, erythematous papules that coalesced into brownish plaques in trunk, upper and lower limbs. Moreover, nail involvement was observed showing a thinned, grooved, and ridged nail plate, particularly in the second nail of the right hand (Figure 1A–D). No mucosal involvement was assessed. The patient referred that these manifestations started as pruritic papules localized at the lower limbs subsequently spreading to the trunk and the upper limbs. The patient had no relevant medical history. Standard blood examinations, as well as C hepatitis markers were all within normal ranges. Finally, RT-PCR was performed to rule out an active COVID-19 infection. Hence, in the suspicious of lichen planus (LP), an incisional biopsy of a lesion of the left foot was performed. Reflectance confocal microscopy (RCM) exam facilitated a more precise real-time diagnosis, guiding the biopsy (Figure 1E). Histological examination, conducted after hematoxylin and eosin staining, confirmed the clinical suspect of cutaneous LP showing the degeneration of the basal layer of the epidermis, epidermal hyperplasia, hypergranulosis and a band like lymphocytic infiltrate obscuring the dermo-epidermal junction. Treatment was started following current guidelines with daily oral prednisolone 25 mg for 7 days, tapering the dose up to 4 weeks with a rapid resolution of the disease. No side effects connected to the therapy and no recurrence of LP were reported. LP is a chronic, autoinflammatory, autoimmune disease with an unknown pathogenesis. In literature, there are several studies reporting lichenoid reactions potentially related to vaccination, particularly against hepatitis B and influenza vaccines. However, there are
Alternative to animal experimentation in pharmacology teaching: Development and validation of an equivalent digital learning tool

Regarding animal experiments in pharmacology teaching, ethical considerations led us to examine an alternative approach to the use of living animals. This study aimed to assess whether digital tools could replace live animal experiments in terms of motivation and knowledge acquisition. The study was carried out with students enrolled in the 5th year of the industry/research stream at the Faculty of Pharmacy of the University of Limoges. The participants were randomly assigned to groups of traditional or digital teaching methods, with the common theme of the class being the effect of a diuretic agent (furosemide) in rats. The scenario and learning objectives were identical for the two groups. Before the class and after randomization, the acceptance of the digital educational material was assessed with a scale, which predicts the acceptability of users according to individual dimensions and social representations, followed by the assessment of the motivation by a situational motivation scale (SIMS) for both groups. After the class, the students’ motivation was assessed by a questionnaire based on Deci and Ryan's self‐determination theory. In the end, the participants were evaluated for homogeneity, based on general knowledge of renal pharmacology, and for knowledge acquisition concerning specific knowledge related to this teaching session. This study revealed a good acceptance of the digital tool and a good motivation toward the digital method among all the students. It found the two teaching methods (digital and traditional) to be equivalent in terms of motivation and knowledge acquisition. In our study, digital pedagogical tools as an alternative to live animals did not affect students’ motivation and knowledge acquisition.
The Toggle Switch Model for Gene Expression Change during the Prenatal-to-Postnatal Transition in Mammals

Abstract The prenatal-to-postnatal transition is a pivotal process in the life cycle whereby an organism shifts from responding to intrauterine cues to undergoing extrauterine stresses with many physiological adaptations. However, the molecular basis underlying the evolutionarily conserved physiological adaptations remains elusive. Here, we analyze the transcriptomes of seven organs across developmental time points from five mammalian species by constructing computational coexpression networks and report a developmental shift of gene expression at the perinatal stage. The low-to-high and high-to-low expressed genes tightly coalesce in the functional categories and gene regulatory pathways that implicate the physiological adaptions during the prenatal-to-postnatal transition, including lipid metabolism, circadian rhythm, immune response, cell cycle, and cell division. The low-to-high and high-to-low expressed genes around the perinatal stage tend to form the mutually inhibitory toggle switch gene pairs linking the gene regulatory networks in response to the environmental changes. We thus propose the toggle switch model for the developmental shift of gene expression as a mechanic framework to investigate how the physiological adaptations occur during the prenatal-to-postnatal transition.
Distinct structural bases for sequence-specific DNA binding by mammalian BEN domain proteins

In this study, Zheng et al. investigated how BEN factors, a recently recognized DNA binding module, identify their targets in humans. They characterize several mammalian BEN domain (BD) factors, including from two NACC family BTB-BEN proteins and from BEND3, which has four BDs, and provide structural insights into sequence-specific DNA binding by mammalian BEN proteins.
Evaluation of marketing authorization and clinical implementation of ulipristal acetate for uterine fibroids

ABSTRACT Ulipristal acetate (UPA) is a medical treatment for uterine fibroids and was authorized for surgical pre-treatment in 2012 after the conduct of the PEARL I and II randomized controlled trials and for intermittent treatment after the observational PEARL III and IV trials. However, UPA came into disrepute due to its temporary suspension in 2017 and 2020 because of an apparent association with liver injury. This clinical opinion paper aims to review the process of marketing authorization and implementation of UPA, in order to provide all involved stakeholders with recommendations for the introduction of future drugs. Before marketing authorization, the European Medicines Agency (EMA) states that Phase III registration trials should evaluate relevant outcomes in a representative population, while comparing to gold-standard treatment. This review shows that the representativeness of the study populations in all PEARL trials was limited, surgical outcomes were not evaluated and intermittent treatment was assessed without comparative groups. Implementation into clinical practice was extensive, with 900 000 prescribed treatment cycles in 5 years in Europe and Canada combined. Extremely high costs are involved in developing and evaluating pre-marketing studies in new drugs, influencing trial design and relevance of chosen outcomes, thereby impeding clinical applicability. It is vitally important that the marketing implementation after authorization is regulated in such way that necessary evidence is generated before widespread prescription of a new drug. All stakeholders, from pharmaceutical companies to authorizing bodies, governmental funding bodies and medical professionals should be aware of their role and take responsibility for their part in this process.
High-Lift Enhancement using Fluidic Actuation

The performance of an airfoil equipped with a high-lift system based on a single-element flap configuration is enhanced by the manipulation of vorticity concentrations near the airfoil surface using fluidic actuation. The actuation, which is effected downstream of the juncture between the main airfoil body and the flap, leads to a significant extension of the attached flow domain along the flap. Consequently, a substantial increase in lift at large flap deflections is produced (at δ = 40o and α = 4o, the lift is increased by 49% relative to baseline). Actuation is effected using spanwise arrays of fluidic oscillators consisting of jets oscillating in the spanwise direction. It is shown that the momentum coefficient Cµ required for a given lift increment can be significantly reduced through appropriate design of the interface geometry between the jet and the boundary layer. I. INTRODUCTION The performance of high-lift systems has a significant impact on the design and performance of transport aircraft. Maximum takeoff weight, required runway length and stall speeds are some of the parameters influenced by high-lift system performance. Historically, high-lift systems have consisted of complex, multi-element designs with intricate positioning mechanisms to derive maximum performance and efficiency. While high-lift systems have been simplified significantly on modern transport aircraft, there remains room for improvement in terms of weight, parts, fabrication costs and cruise efficiency. Active flow control provides an avenue for such improvements and creates the potential for high-lift performance beyond what is possible for conventional systems. A study conducted in 1999 by Boeing and NASA (McLean et al. 1 ) estimates that, among other things, a simplified high-lift system using unsteady flow control can reduce the empty weight of a 737-class aircraft by 3.3%. This weight reduction, along with the aerodynamic advantages of a simplified high-lift design, such as the removal of fairings required for the external mechanisms of conventional high-lift systems, equate to a bestcase cruise drag reduction of 3.2%. The authors also conclude that a further study is required to define the aerodynamic performance of high-lift systems using unsteady flow control. Gomes et al. 2 have concluded that it is possible to design a practical AFC highlift system based on synthetic jets. However, the performance benefits of such a system still remained to be established and would determine whether or not the technology could be integrated on an aircraft. They have also suggested that the application of AFC to the trailing-edge flap would yield the greatest benefit to the airplane as far as high-lift system application was concerned. Strategies for active flow control on lifting surfaces have primarily focused on mitigation of partial or complete flow separation over stalled flaps or wing sections, where the separating shear layer is dominated by a strong coupling to the instability of the wake that
A review of design considerations for light-duty diesel combustion systems

Practical aspects of light-duty diesel combustion system design are reviewed, with an emphasis on design considerations reported by manufacturers and engine design consultancies. The factors driving the selection of compression ratio, stroke-to-bore ratio, and various aspects of combustion chamber geometry are examined, along with the trends observed in these parameters in recently released engines. The interactions among geometric characteristics, swirl ratio, and the fuel injection nozzle parameters are also reviewed.
Phase II randomised trial of type I interferon inhibitor anifrolumab in patients with active lupus nephritis

Objective To assess the efficacy and safety of the type I interferon receptor antibody, anifrolumab, in patients with active, biopsy-proven, Class III/IV lupus nephritis. Methods This phase II double-blinded study randomised 147 patients (1:1:1) to receive monthly intravenous anifrolumab basic regimen (BR, 300 mg), intensified regimen (IR, 900 mg ×3, 300 mg thereafter) or placebo, alongside standard therapy (oral glucocorticoids, mycophenolate mofetil). The primary endpoint was change in baseline 24-hour urine protein–creatinine ratio (UPCR) at week (W) 52 for combined anifrolumab versus placebo groups. The secondary endpoint was complete renal response (CRR) at W52. Exploratory endpoints included more stringent CRR definitions and sustained glucocorticoid reductions (≤7.5 mg/day, W24–52). Safety was analysed descriptively. Results Patients received anifrolumab BR (n=45), IR (n=51), or placebo (n=49). At W52, 24-hour UPCR improved by 69% and 70% for combined anifrolumab and placebo groups, respectively (geometric mean ratio=1.03; 95% CI 0.62 to 1.71; p=0.905). Serum concentrations were higher with anifrolumab IR versus anifrolumab BR, which provided suboptimal exposure. Numerically more patients treated with anifrolumab IR vs placebo attained CRR (45.5% vs 31.1%), CRR with UPCR ≤0.5 mg/mg (40.9% vs 26.7%), CRR with inactive urinary sediment (40.9% vs 13.3%) and sustained glucocorticoid reductions (55.6% vs 33.3%). Incidence of herpes zoster was higher with combined anifrolumab vs placebo (16.7% vs 8.2%). Incidence of serious adverse events was similar across groups. Conclusion Although the primary endpoint was not met, anifrolumab IR was associated with numerical improvements over placebo across endpoints, including CRR, in patients with active lupus nephritis. Trial registration number NCT02547922.
δ-Tocotrienol is the most potent vitamin E form in inhibiting prostate cancer cell growth and inhibits prostate carcinogenesis in Ptenp-/- mice.

Vitamin E compounds, consisting of α, β, γ, and δ forms of tocopherols and tocotrienols, display different cancer preventive activities in experimental models. Tocotrienols may have higher potential for clinical use due to their lower effective doses in laboratory studies. However, most studies on tocotrienols have been carried out using cancer cell lines. Strong data from animal studies may encourage the use of tocotrienols for human cancer prevention research. To examine the cancer inhibitory activity of different vitamin E forms, we first investigated their inhibitory activities of different vitamin E forms in prostate cancer cell lines. We found that δ-tocotrienol (δT3) was the most effective form in inhibiting cell growth at equivalent doses. Because of this in vitro potency, δT3 was further studied using prostate specific Pten-/- (Ptenp-/-) mice. We found that 0.05% δT3 in diet reduced prostate adenocarcinoma multiplicity by 32.7%, featuring increased apoptosis and reduced cell proliferation. The inhibitory effect of 0.05% δT3 in diet was similar to that of 0.2% δ-tocopherol (δT) in diet reported previously. Our further study on the δT3-induced transcriptome changes indicated that δT3 inhibited genes in blood vessel development in the prostate of Ptenp-/- mice, which was confirmed by immunohistochemistry. Together, our results demonstrate that δT3 effectively inhibits the development of prostate adenocarcinoma in Ptenp-/- mice, which involves inhibition of proliferation and angiogenesis and promotion of apoptosis.