Miracle-dz/UniFAR-FTUs huggingface dataset:
European Medicines Agency review of midostaurin (Rydapt) for the treatment of adult patients with acute myeloid leukaemia and systemic mastocytosis

On 18 September 2017, a marketing authorisation valid through the European Union (EU) was issued for midostaurin in combination with standard daunorubicin and cytarabine induction and high-dose cytarabine consolidation chemotherapy and for patients in complete response followed by midostaurin single agent maintenance therapy, for adult patients with newly diagnosed acute myeloid leukaemia (AML) who are Fms-like tyrosine kinase 3 mutation positive and as monotherapy for the treatment of adult patients with aggressive systemic mastocytosis (ASM), systemic mastocytosis with associated haematological neoplasm (SM-AHN) or mast cell leukaemia (MCL). The recommended dose of midostaurin is 50 mg orally twice daily for AML and 100 mg orally twice daily for ASM, SM-AHN and MCL. Midostaurin was evaluated in two pivotal studies. Study A2301 (RATIFY) included 717 patients with AML. Overall survival (OS) was statistically significantly different between the two groups, and the median OS was 74.7 months in the midostaurin+daunorubicin+cytarabine group and 25.6 months in the placebo+daunorubicin+cytarabine group (HR 0.774; 95% CI 0.629 to 0.953; p=0.0078). Study D2201 included 116 patients with ASM, SM-AHN or MCL. An overall response rate, by IWG-MRT/ECNM (international working group – myelofibrosis research and treatment/European competence network on mastocytosis) criteria of 28.3% was observed in all patients and 60.0%, 20.8% and 33.3% in patients with ASM, SM-AHN and MCL respectively. The most common adverse drug reactions (ADRs) with midostaurin treatment in AML were febrile neutropenia, nausea, exfoliative dermatitis, vomiting, headache, petechiae and fever. In ASM, SM-AHN, MCL the most common ADRs were nausea, vomiting, diarrhoea, peripheral oedema and fatigue. The objective of this paper is to summarise the scientific review of the application leading to regulatory approval in the EU.
Retrospective analysis of the efficacy of cytokine‐induced killer cell immunotherapy combined with first‐line chemotherapy in patients with metastatic colorectal cancer

Fluoropyrimidine‐based chemotherapy regimens are the current first‐line treatment for metastatic colorectal cancer (mCRC); however, the outcome is often unsatisfactory. The present study aimed to determine the effect of combined cytokine‐induced killer (CIK) cell immunotherapy and first‐line chemotherapy in patients with mCRC.
Allergen Immunotherapy–Induced Immunoglobulin G4 Reduces Basophil Activation in House Dust Mite–Allergic Asthma Patients

It is unclear if allergen immunotherapy (AIT) can reduce allergy effector cell activation. We evaluated the basophil response during Dermatophagoides pteronyssinus (Der p) subcutaneous immunotherapy (SCIT) and its relationship to allergen-specific immunoglobulin G4 (sIgG4) in allergic rhinitis and/or asthma patients. The study included 55 subjects, of which 35 cases received Der p SCIT and 20 controls received standard medications. Symptom and medication scores (SMSs), sIgG4 levels, specific immunoglobulin E (sIgE) levels, allergen-induced basophil activation tests (BATs) in whole blood, and BAT inhibition assays in serum were determined at weeks 0, 4, 12, 16, 52, and 104 of SCIT. Levels of Der p sIgG4 in SCIT patients significantly increased after 12 weeks of treatment compared to week 0. Serum obtained from SCIT patients significantly inhibited basophil activation after 12 weeks of treatment. Removal of immunoglobulin G4 (IgG4) antibodies at week 104 reduced the ability of serum to block basophil activation. An increase of Der p sIgG4 rather than reduction of Der p sIgE correlated with the reduction of basophil activation during SCIT. The sIgG4 antibodies may compete with sIgE binding to allergens to form an immunoglobulin E (IgE)–allergen complex. SCIT reduced the sensitivity of allergen-triggered basophil activation in Der p allergic rhinitis and/or asthma patients through induction of sIgG4.
Spexin and a Novel Cichlid-Specific Spexin Paralog Both Inhibit FSH and LH Through a Specific Galanin Receptor (Galr2b) in Tilapia

Spexin (SPX) is a 14 amino acid peptide hormone that has pleiotropic functions across vertebrates, one of which is involvement in the brain-pituitary-gonad axis of fish. SPX(1) has been identified in each class of vertebrates, and a second SPX (named SPX2) has been found in some non-mammalian species. We have cloned two spexin paralogs, designated as Spx1a and Spx1b, from Nile tilapia (Oreochromis niloticus) that have varying tissue distribution patterns. Spx1b is a novel peptide only identified in cichlid fish, and is more closely related to Spx1 than Spx2 homologs as supported by phylogenetic, synteny, and functional analyses. Kisspeptin, Spx, and galanin (Gal) peptides and their corresponding kiss receptors and Gal receptors (Galrs), respectively, are evolutionarily related. Cloning of six tilapia Galrs (Galr1a, Galr1b, Galr2a, Galr2b, Galr type 1, and Galr type 2) and subsequent in vitro second-messenger reporter assays for Gαs, Gαq, and Gαi suggests that Gal and Spx activate Galr1a/Galr2a and Galr2b, respectively. A decrease in plasma follicle stimulating hormone and luteinizing hormone concentrations was observed with injections of Spx1a or Spx1b in vivo. Additionally, application of Spx1a to pituitary slices decreased the firing rate of LH cells, suggesting direct inhibition at the pituitary level. These data collectively suggest an inhibitory mechanism of action against the secretion of gonadotropins for a traditional and a novel spexin paralog in cichlid species.
Causal Structure Learning in Continuous Systems

Real causal systems are complicated. Despite this, causal learning research has traditionally emphasized how causal relations can be induced on the basis of idealized events, i.e., those that have been mapped to binary variables and abstracted from time. For example, participants may be asked to assess the efficacy of a headache-relief pill on the basis of multiple patients who take the pill (or not) and find their headache relieved (or not). In contrast, the current study examines learning via interactions with continuous dynamic systems, systems that include continuous variables that interact over time (and that can be continuously observed in real time by the learner). To explore such systems, we develop a new framework that represents a causal system as a network of stationary Gauss–Markov (“Ornstein–Uhlenbeck”) processes and show how such OU networks can express complex dynamic phenomena, such as feedback loops and oscillations. To assess adult's abilities to learn such systems, we conducted an experiment in which participants were asked to identify the causal relationships of a number of OU networks, potentially carrying out multiple, temporally-extended interventions. We compared their judgments to a normative model for learning OU networks as well as a range of alternative and heuristic learning models from the literature. We found that, although participants exhibited substantial learning of such systems, they committed certain systematic errors. These successes and failures were best accounted for by a model that describes people as focusing on pairs of variables, rather than evaluating the evidence with respect to the full space of possible structural models. We argue that our approach provides both a principled framework for exploring the space of dynamic learning environments as well as new algorithmic insights into how people interact successfully with a continuous causal world.
Implementation of Key Components of Evidence-Based Family Therapy for Eating Disorders in Child and Adolescent Psychiatric Outpatient Care

Background Restrictive eating disorders with pronounced starvation are serious psychiatric conditions that often begin during childhood or adolescence. An early and efficient intervention is crucial to minimize the risk of the illness becoming longstanding and to limit the consequences. There is good evidence that weight gain during the first month of treatment provides a better prognosis. Only a limited amount of young people suffering from severe restrictive eating disorder receive an evidence-based treatment at present in Sweden. The ROCKETLAUNCH project intends to implement key components of the evidence-based family therapy during the first month of treatment in child and adolescent psychiatric outpatient care. Methods From the southern part of Sweden, 12 local child and adolescent psychiatric outpatient services will take part. All patients with a restrictive eating disorder and pronounced starvation together with their families will be asked to take part in the study. We expect that one hundred 50 patients will be assessed every year. The patients and their families will receive 1 month of intense manualized treatment. Body weight, days in inpatient care, eating disorder, and other psychopathology-related symptoms, will be evaluated after one month and at 12-month follow-up. Economic evaluation of ROCKETLAUNCH will also be carried out alongside the intervention. At each outpatient clinic, data from the 10 previous patients will be gathered to compare the treatment provided at ROCKETLAUNCH with the standard treatment in Sweden. Discussion We expect that by implementing the key components of the evidence-based family therapy during the first month of treatment, the prognosis of young newly diagnosed patients with severe restrictive eating disorders, primarily anorexia nervosa will improve, which, in turn, will reduce the need for psychiatric inpatient care. Clinical Trial Registration www.ClinicalTrials. gov, identifier NCT04060433.
Host identification for the deep-sea snail genus Haliella with description of a new species (Caenogastropoda, Eulimidae)

Abstract A new parasitic species of eulimid gastropod, Haliella seisuimaruaesp. nov., is described from bathyal (728–978 m) waters off the Pacific coasts of Japan. It shows the closest resemblance to the type species H. stenostoma from the North Atlantic and Barents Sea in having a tall shell with an almost straight outer lip, but differs in having a junction of the parietal wall and columellar lip at 38% of the aperture height from the suture (33% in H. stenostoma), a slightly wider aperture and a more curved and extended columellar lip. The holotype of H. seisuimaruaesp. nov. was found attached to an irregular sea urchin, Brissopsis sp. cf. luzonica (Spatangoida: Brissidae). This represents the first direct observation of parasitic ecology and echinoderm host for the genus Haliella. A new replacement name, Eulima tsushimensisnom. nov., is proposed here for Eulima stenostoma A. Adams, 1861, which is preoccupied by Eulima stenostoma Jeffreys, 1858 (type of Haliella).
Optimization of leaf morphology in relation to leaf water status: A theory

Abstract The leaf economic traits such as leaf area, maximum carbon assimilation rate, and venation are all correlated and related to water availability. Furthermore, leaves are often broad and large in humid areas and narrower in arid/semiarid and hot and cold areas. We use optimization theory to explain these patterns. We have created a constrained optimization leaf model linking leaf shape to vein structure that is integrated into coupled transpiration and carbon assimilation processes. The model maximizes net leaf carbon gain (NPPleaf) over the loss of xylem water potential. Modeled relations between leaf traits are consistent with empirically observed patterns. As the results of the leaf shape–venation relation, our model further predicts that a broadleaf has overall higher NPPleaf compared to a narrowleaf. In addition, a broadleaf has a lower stomatal resistance compared to a narrowleaf under the same level of constraint. With the same leaf area, a broadleaf will have, on average, larger conduits and lower total leaf xylem resistance and thus be more efficient in water transportation but less resistant to cavitation. By linking venation structure to leaf shape and using water potential as the constraint, our model provides a physical explanation for the general pattern of the covariance of leaf traits through the safety–efficiency trade‐off of leaf hydraulic design.
RAPTURE (RAD capture) panel facilitates analyses characterizing sea lamprey reproductive ecology and movement dynamics

Abstract Genomic tools are lacking for invasive and native populations of sea lamprey (Petromyzon marinus). Our objective was to discover single nucleotide polymorphism (SNP) loci to conduct pedigree analyses to quantify reproductive contributions of adult sea lampreys and dispersion of sibling larval sea lampreys of different ages in Great Lakes tributaries. Additional applications of data were explored using additional geographically expansive samples. We used restriction site‐associated DNA sequencing (RAD‐Seq) to discover genetic variation in Duffins Creek (DC), Ontario, Canada, and the St. Clair River (SCR), Michigan, USA. We subsequently developed RAD capture baits to genotype 3,446 RAD loci that contained 11,970 SNPs. Based on RAD capture assays, estimates of variance in SNP allele frequency among five Great Lakes tributary populations (mean F ST 0.008; range 0.00–0.018) were concordant with previous microsatellite‐based studies; however, outlier loci were identified that contributed substantially to spatial population genetic structure. At finer scales within streams, simulations indicated that accuracy in genetic pedigree reconstruction was high when 200 or 500 independent loci were used, even in situations of high spawner abundance (e.g., 1,000 adults). Based on empirical collections of larval sea lamprey genotypes, we found that age‐1 and age‐2 families of full and half‐siblings were widely but nonrandomly distributed within stream reaches sampled. Using the genomic scale set of SNP loci developed in this study, biologists can rapidly genotype sea lamprey in non‐native and native ranges to investigate questions pertaining to population structuring and reproductive ecology at previously unattainable scales.
Effective preparation of magnetic molecularly imprinted polymer nanoparticle for the rapid and selective extraction of cyfluthrin from honeysuckle

Abstract Cyfluthrin is a widely used pesticide. In this study, a sensitive and efficient magnetic molecularly imprinted polymer (MMIP) was prepared by surface molecular imprinting, which used functionalized Fe3O4 particles as magnetic cores. Cyfluthrin was extracted and enriched using magnetic molecularly polymer for analyzing pesticide residue of Chinese herbal medicines. The crystal type, microstructure, particle size, saturation magnetization, and characteristic functional groups of the synthesized MMIPs were analyzed by analysis equipment. The results of isothermal adsorption and kinetic adsorption indicated that MMIPs reached adsorption equilibrium at 30 min, with a maximum capacity of 4.9 mg g−1, which had good adsorption performance, while selective adsorption experiments showed that MMIPs had higher affinity for cyfluthrin. Under the optimized conditions, the limit of detection (LOD) and the limit of quantification (LOQ) were 32.987 ng ml−1 and 109.955 ng ml−1, respectively. And linear range (30–3000ng ml−1) of cyfluthrin with correlation coefficient R2=0.9979, and MMIPs were used in honeysuckle, the recoveries were 91.5%∼97.2%, and RSD was 5.35%∼8.32% (n = 3). It is indicated that the magnetic molecularly imprinted polymer can be used as an effective material for the specific separation of cyfluthrin from honeysuckle.
Evidences for Expression and Location of ANGPTL8 in Human Adipose Tissue

The metabolism of triglycerides (TGs) is regulated, among others, by the lipoprotein lipase (LPL) that hydrolyses the TGs on endothelial cells. In turn, LPL is inhibited by the ANGPTLs family of proteins, such as ANGPTL3, 4, and, 8; the latter is the least known. In this work, we have tried to establish the expression and localisation of the Angiopoietin-like 8 (ANGPTL8) protein in the visceral adipose tissue (VAT) of morbid-obese and non-obese patients. 109 subjects (66 women and 43 men) undergoing laparoscopic surgery participated in this study. A blood sample and a portion of the VAT were obtained, and the patients were classified according to their Body Mass Index (BMI) as non-obese (19.5–30 kg/m2) and morbid-obese (40–50 kg/m2). No significant changes in ANGPTL8 plasma levels were determined by EIA in obese patients. The immunocytochemistry and Western blotting showed the presence of increased ANGPTL8 in morbid-obese patients (p < 0.05). In-situ hybridisation and a real time polymerase chain reaction (RT-PCR) confirmed that the mRNA that encodes ANGPTL8 was present in adipocytes, without differences in their nutritional state (p = 0.89), and even in the endothelial cells. Our data suggests that ANGPT8 plasmatic levels do not change significantly in patients with morbid obesity, although there is a modest difference related to gender. Besides, we demonstrate that in visceral adipose tissue, ANGPTL8 is well defined in the cytoplasm of adipocytes coexisting with perilipin-1 and its mRNA, also is present in endothelial cells. These findings suggest the possibility that among other functions, ANGPTL8 could perform either a paracrine and/or an endocrine role in the adipose tissue.
Association of Urinary Levels of Bisphenols A, F, and S with Endometriosis Risk: Preliminary Results of the EndEA Study

Aim: The aim of this study was to explore associations of urinary concentrations of bisphenols A (BPA), S (BPS), and F (BPF) and of thiobarbituric acid reactive substances (TBARS) with the risk of endometriosis in women of childbearing age. Methods: This case–control study enrolled 124 women between January 2018 and July 2019: 35 women with endometriosis (cases) and 89 women without endometriosis undergoing abdominal surgery for other reasons (controls). Endometriosis was diagnosed (cases) or ruled out (controls) by laparoscopic inspection of the pelvis and the biopsy of suspected lesions (histological diagnosis). Fasting urine samples were collected before surgery to determine concentrations of BPA, BPS, BPF, and TBARS. Associations of bisphenol and TBARS concentrations with endometriosis risk were explored with multivariate logistic and linear regression analyses. Results: After adjustment for urinary creatinine, age, BMI, parity, and residence, endometriosis risk was increased with each 1 log unit of BPA [OR 1.5; 95%CI 1.0–2.3] and Σbisphenols [OR 1.5; 95%CI 0.9–2.3] but was not associated with the presence of BPS and BPF. Classification of the women by tertiles of exposure revealed statistically significant associations between endometriosis risk and the second tertile of exposure to BPA [OR 3.7; 95%CI 1.3–10.3] and Σbisphenols [OR 5.4; 95%CI 1.9–15.6]. In addition, TBARS concentrations showed a close-to-significant relationship with increased endometriosis risk [OR 1.6; 95%CI 1.0–2.8], and classification by TBARS concentration tertile revealed that the association between endometriosis risk and concentrations of BPA [OR 2.0; 95%CI 1.0–4.1] and Σbisphenols [OR 2.2; 95%CI 1.0–4.6] was only statistically significant for women in the highest TBARS tertile (>4.23 μM). Conclusion: Exposure to bisphenols may increase the risk of endometriosis, and oxidative stress may play a crucial role in this association. Further studies are warranted to verify these findings.
The cognitive costs, contraindications and complications of epilepsy surgery in adults.

PURPOSE OF REVIEW Access to epilepsy surgery is rapidly growing throughout the world. While it is an established and effective treatment for seizures, epilepsy surgery has the potential to exacerbate cognitive comorbidities of the condition. RECENT FINDINGS Not all surgical patients experience a postoperative decline in cognitive function. Postoperative cognitive function depends upon the functional integrity of the tissue to be removed and the functional reserve of the structures that remain in situ. While developments in surgical technique can reduce the cognitive morbidity of epilepsy surgery, the same procedure may result in different cognitive outcomes for different candidates, depending on their preoperative characteristics and postoperative trajectories. Multivariate models can be used to identify those most at risk of cognitive decline. There remains a significant lack of research into clinical interventions aimed at reducing the impact of surgically induced cognitive deficits on the lives of the patients who experience them. SUMMARY Accurate identification of the cognitive risks associated with surgery, based on an individual's personal risk profile rather than the generic risks associated with the procedure, is now recognized as a mandatory part of the preoperative evaluation and is one of the pillars of informed consent for the procedure.
GARP is a key molecule for mesenchymal stromal cell responses to TGF‐β and fundamental to control mitochondrial ROS levels

Multipotent mesenchymal stromal cells (MSCs) have emerged as a promising cell therapy in regenerative medicine and for autoimmune/inflammatory diseases. However, a main hurdle for MSCs‐based therapies is the loss of their proliferative potential in vitro. Here we report that glycoprotein A repetitions predominant (GARP) is required for the proliferation and survival of adipose‐derived MSCs (ASCs) via its regulation of transforming growth factor‐β (TGF‐β) activation. Silencing of GARP in human ASCs increased their activation of TGF‐β which augmented the levels of mitochondrial reactive oxygen species (mtROS), resulting in DNA damage, a block in proliferation and apoptosis. Inhibition of TGF‐β signaling reduced the levels of mtROS and DNA damage and restored the ability of GARP−/lowASCs to proliferate. In contrast, overexpression of GARP in ASCs increased their proliferative capacity and rendered them more resistant to etoposide‐induced DNA damage and apoptosis, in a TGF‐β‐dependent manner. In summary, our data show that the presence or absence of GARP on ASCs gives rise to distinct TGF‐β responses with diametrically opposing effects on ASC proliferation and survival.
Cross-Modal Attention With Semantic Consistence for Image–Text Matching

The task of image–text matching refers to measuring the visual-semantic similarity between an image and a sentence. Recently, the fine-grained matching methods that explore the local alignment between the image regions and the sentence words have shown advance in inferring the image–text correspondence by aggregating pairwise region-word similarity. However, the local alignment is hard to achieve as some important image regions may be inaccurately detected or even missing. Meanwhile, some words with high-level semantics cannot be strictly corresponding to a single-image region. To tackle these problems, we address the importance of exploiting the global semantic consistence between image regions and sentence words as complementary for the local alignment. In this article, we propose a novel hybrid matching approach named Cross-modal Attention with Semantic Consistency (CASC) for image–text matching. The proposed CASC is a joint framework that performs cross-modal attention for local alignment and multilabel prediction for global semantic consistence. It directly extracts semantic labels from available sentence corpus without additional labor cost, which further provides a global similarity constraint for the aggregated region-word similarity obtained by the local alignment. Extensive experiments on Flickr30k and Microsoft COCO (MSCOCO) data sets demonstrate the effectiveness of the proposed CASC on preserving global semantic consistence along with the local alignment and further show its superior image–text matching performance compared with more than 15 state-of-the-art methods.