Miracle-dz/UniFAR-FTUs huggingface dataset:
JAK inhibition increases bone mass in steady-state conditions and ameliorates pathological bone loss by stimulating osteoblast function

JAK inhibition enhances the function of bone-forming osteoblasts, increases bone mass, and induces repair of arthritic bone erosions. Boosting osteoblasts to battle bone erosion Inhibitors of Janus kinase (JAK) reduce inflammation and are approved to treat rheumatoid arthritis; however, the direct effects of inhibitors on bone remain unclear. Adam et al. found that JAK inhibitors increased bone mass in mice under homeostatic conditions and mitigated bone loss in a mouse model of osteoporosis. Mice with inflammatory bone loss mimicking rheumatoid arthritis had reduced bone erosions after treatment with JAK inhibitors, and two patients with rheumatoid arthritis treated with tofacitinib showed similar results. The authors determined that JAK inhibitors induced bone repair by altering gene expression and increasing activity of osteoblasts, supporting use of inhibitors as potential osteoanabolics. Janus kinase (JAK)–mediated cytokine signaling has emerged as an important therapeutic target for the treatment of inflammatory diseases such as rheumatoid arthritis (RA). Accordingly, JAK inhibitors compose a new class of drugs, among which tofacitinib and baricitinib have been approved for the treatment of RA. Periarticular bone erosions contribute considerably to the pathogenesis of RA. However, although the immunomodulatory aspect of JAK inhibition (JAKi) is well defined, the current knowledge of how JAKi influences bone homeostasis is limited. Here, we assessed the effects of the JAK inhibitors tofacitinib and baricitinib on bone phenotype (i) in mice during steady-state conditions or in mice with bone loss induced by (ii) estrogen-deficiency (ovariectomy) or (iii) inflammation (arthritis) to evaluate whether effects of JAKi on bone metabolism require noninflammatory/inflammatory challenge. In all three models, JAKi increased bone mass, consistent with reducing the ratio of receptor activator of NF-κB ligand/osteoprotegerin in serum. In vitro, effects of tofacitinib and baricitinib on osteoclast and osteoblast differentiation were analyzed. JAKi significantly increased osteoblast function (P < 0.05) but showed no direct effects on osteoclasts. Additionally, mRNA sequencing and ingenuity pathway analyses were performed in osteoblasts exposed to JAKi and revealed robust up-regulation of markers for osteoblast function, such as osteocalcin and Wnt signaling. The anabolic effect of JAKi was illustrated by the stabilization of β-catenin. In humans with RA, JAKi induced bone-anabolic effects as evidenced by repair of arthritic bone erosions. Results support that JAKi is a potent therapeutic tool for increasing osteoblast function and bone formation.
Skeletal muscle mass predicts the outcome of nivolumab treatment for non-small cell lung cancer

Abstract Nivolumab, a monoclonal antibody targeting programmed cell death-1, significantly prolongs survival for patients with advanced non-small-cell lung cancer (NSCLC). However, little is known about the value of predictive biomarkers. Hence, we investigated the impact of skeletal muscle (SM) mass loss on clinical outcomes in NSCLC patients undergoing nivolumab treatment. Thirty patients with histologically confirmed NSCLC treated with nivolumab were included in this study. Computed tomography was used to determine SM loss based on the SM index (SMI). The SMI is the cross-sectional area of the bilateral psoas muscles at the third lumbar vertebra, divided by height squared. The cut-off values were defined as 6.36 cm2/m2 for men and 3.92 cm2/m2 for women. Among the 30 patients, 13 (43%) had SM loss. There was no significant association between SM loss and immune-related adverse events. The SM loss group had undergone significantly more prior chemotherapy cycles (P = .04). SM loss was significantly associated with fewer nivolumab cycles (P = .01). No patients in the SM loss group achieved a partial response. Patients with SM loss had a significantly shorter progression-free survival period (P = .008) and median overall survival than those with normal SM mass (10 vs 25 months, respectively, P = .03). SM loss was an independent prognostic factor of poor survival. In conclusion, SM loss may be a predictive factor of poor outcomes in NSCLS patients undergoing nivolumab therapy.
Endoscopic transpapillary gallbladder drainage for acute cholecystitis is feasible for patients receiving antithrombotic therapy

Patients with acute cholecystitis receiving antithrombotic therapy (ATT) have an increased risk of bleeding complications during surgery and percutaneous drainage. Endoscopic transpapillary gallbladder drainage (ETGBD) is recommended for such cases; however, evidence is limited. To investigate this issue further, we performed a retrospective multicenter study.
Neoadjuvant therapy for triple-negative breast cancer: potential predictive biomarkers of activity and efficacy of platinum chemotherapy, PARP- and immune-checkpoint-inhibitors

ABSTRACT Introduction Despite recent advances in the molecular characterization of triple-negative breast cancer (TNBC), the standard treatment for early-stage TNBC is represented by the historically used anthracycline and taxane-based chemotherapy. In this modern era of precision medicine, several new therapeutic strategies and novel agents have been investigated in the neoadjuvant setting of TNBC, in order to individualize treatment. Areas covered This review provides a comprehensive overview of the currently available evidence regarding the activity and efficacy of platinum agents, PARP- and immune-checkpoint-inhibitors for the neoadjuvant treatment of TNBC, highlighting the available data on potential predictive biomarkers of response or resistance to such treatments. Expert opinion The genomic and immune landscape of TNBC has encouraged the exploration of drugs that interfere with the DNA repair mechanism and that modulate immune response. Overall, these drugs seem to improve the pCR rate in TNBC, despite preliminary and heterogeneous results. Taking into account the economic issues and the side effects of these drugs, it is crucial to further explore the potential predictive role of BRCA mutational status and homologous recombination deficiency score, for platinum agents and PARP-inhibitors, and tumor infiltrating lymphocytes and other immune biomarkers for checkpoint inhibitors, respectively.
Improved QuEChERS for analysis of polybrominated diphenyl ethers and novel brominated flame retardants in Capsicum cultivars using gas chromatography.

One of the main challenges for analytical laboratories and food safety authorities is the control of food contaminants hazardous to human health. For the first time, a simple, fast and cost-effective sample preparation method is proposed as an extraction technique to determine 12 brominated flame retardants (BFRs) (7 congeners polybrominated diphenyl ether (PBDE) and 5 novel BFRs) in Capsicum cultivars. Different QuEChERS and dispersive solid-phase extract (d-SPE) sorbent compositions were evaluated in terms of recovery and matrix effects. The best results were obtained with citrate buffered version QuEChERS and a cleanup step, with 150 mg MgSO4, 50 mg PSA, 50 mg C18, and 5 mg of carbon. The limit of detection (LOD) was between 1.4-9.3 µg/kg and R2>0.99. Recoveries and matrix effects were between 66-104% and 0.58-2.18, respectively. The relative standard deviations from repeatability and reproducibility studies and estimation of measurement uncertainty were lower than 20%. Gas chromatography coupled with a mass spectrometer was used to confirm the presence of the BFRs in the samples. Novel BFRs were detected lower than the LOD.
Health Properties and Composition of Honeysuckle Berry Lonicera caerulea L. An Update on Recent Studies

Lonicera caerulea L. , also known as haskap or honeysuckle berry, is a fruit commonly planted in eastern Europe, Canada and Asia. The fruit was registered as a traditional food from a third country under European Union regulations only on December 2018. It is resistant to cold, pests, various soil acidities and diseases. However, its attractiveness is associated mostly with its health properties. The fruit shows anticancer, anti-inflammatory, and antioxidant activity—important factors in improving health. These features result from the diverse content of phytochemicals in honeysuckle berries with high concentrations of phytocompounds, mainly hydroxycinnamic acids, hydroxybenzoic acids, flavanols, flavones, isoflavones, flavonols, flavanones and anthocyanins but also iridoids, present in the fruit in exceptional amounts. The content and health properties of the fruit were identified to be dependent on cultivar, genotype and the place of harvesting. Great potential benefits of this nutritious food are its ability to minimize the negative effects of UV radiation, diabetes mellitus and neurodegenerative diseases, and to exert hepato- and cardioprotective activity.
Perylene Diimide-Based Fluorescent and Colorimetric Sensors for Environmental Detection

Perylene tetracarboxylic diimide (PDI) and its derivatives exhibit excellent thermal, chemical and optical stability, strong electron affinity, strong visible-light absorption and unique fluorescence on/off features. The combination of these features makes PDIs ideal molecular frameworks for development in a broad range of sensors for detecting environmental pollutants such as heavy metal ions (e.g., Cu2+, Cd2+, Hg2+, Pd2+, etc.), inorganic anions (e.g., F−, ClO4−, PO4−, etc.), as well as poisonous organic compounds such as nitriles, amines, nitroaromatics, benzene homologues, etc. In this review, we provide a comprehensive overview of the recent advance in research and development of PDI-based fluorescent sensors, as well as related colorimetric and multi-mode sensor systems, for environmental detection in aqueous, organic or mixed solutions. The molecular design of PDIs and structural optimization of the sensor system (regarding both sensitivity and selectivity) in response to varying analytes are discussed in detail. At the end, a perspective summary is provided covering both the key challenges and potential solutions for the future development of PDI-based optical sensors.
Oral health status of children with phenylketonuria

Abstract Background Diet plays an integral role in the maintenance of oral health, but dietary modifications due to medical problems such as phenylketonuria (PKU) can have adverse effects on oral health. This descriptive study was performed to evaluate the oral health status of children with PKU. Methods One hundred and ninety-seven patients with PKU aged between 1 and 22 years were evaluated. Clinical evaluations were performed by one experienced dentist regarding dental caries, gingival health and dental erosion. Categorical variables were assessed with descriptive statistics. Differences in feeding frequencies and sociodemographic characteristics were compared regarding dental caries using chi-square (χ2) tests. Results One hundred and thirty-two patients (67%) had dental caries. The mean plaque index (PI) and gingival index (GI) values were 1.37 ± 0.58 and 1.40 ± 0.64, respectively, which shows moderate plaque accumulation and moderate gingival inflammation. Of the patients, 85.3% did not brush their teeth regularly and 90.4% had never visited a dentist before. No statistically significant differences were found in dental caries according to feeding frequencies (p = 0.448). Conclusions Despite the high prevalence of caries in patients with PKU, most had never seen a dentist. Physicians must encourage patients with PKU and their parents to have regular dental visits to maintain an optimal general and oral health.
Looking or talking: Visual attention and verbal engagement during shared book reading of preschool children on the autism spectrum

Visual attention and active engagement during shared book reading are important for facilitating emergent literacy learning during the preschool years. Children on the autism spectrum often show difficulties in language and literacy development, yet research investigating potential indicators of shared book reading engagement, including visual attention and verbal engagement, for this group of preschoolers is currently limited. To better understand the relationship between children’s visual attention and verbal engagement during shared book reading, parent shared book reading behaviors, and children’s emergent literacy skills (e.g. receptive vocabulary and letter-name knowledge), we observed 40 preschoolers on the spectrum and their parents sharing an unfamiliar storybook. Videos of the shared book reading interactions were transcribed and coded for child and parent behaviors using observational coding schemes. Strong significant associations were found between children’s visual attention, verbal engagement, and parents’ use of questions and/or prompts during the shared book reading interaction. Contrary to expectations, children’s visual attention was not related to their emergent literacy skills. Overall, our findings emphasize the interplay between parent behaviors and how preschoolers on the spectrum engage in this important literacy-related context and provide directions for future research. Lay abstract Children who have an autism diagnosis often have trouble learning to talk and read. These difficulties become noticeable before children start school and may be linked to lower attention and engagement in literacy-related activities such as sharing storybooks with their parents. To date, few researchers have looked at possible ways to measure how children on the autism spectrum engage during shared storybook reading, for example, where children look or how much they talk, and how this may be related to their letter-name knowledge and their vocabulary knowledge. In this study, we analyzed videos of 40 preschoolers on the spectrum and their parents sharing an unfamiliar storybook. We wanted to see whether where children looked (i.e. toward the storybook, their parent, or elsewhere) and how much they talked were related to what their parents did (e.g. ask questions or provide prompts) and/or children’s letter-name knowledge and vocabulary. The videos were coded for different child and parent behaviors. We found that where children looked and how much they talked were strongly related to each other and what parents did during the shared book reading interaction, particularly asking questions and using prompts. In contrast to what we expected, where children looked was not related to children’s letter or vocabulary knowledge. Overall, results of the study draw attention to the connection between what parents do and what preschoolers on the spectrum do when sharing storybooks and provide directions for future research.
Applying Tobacco, Environmental, and Dietary-Related Biomarkers to Understand Cancer Etiology and Evaluate Prevention Strategies

Many human cancers are caused by environmental and lifestyle factors. Biomarkers of exposure and risk developed by our team have provided critical data on internal exposure to toxic and genotoxic chemicals and their connection to cancer in humans. This review highlights our research using biomarkers to identify key factors influencing cancer risk as well as their application to assess the effectiveness of exposure intervention and chemoprevention protocols. The use of these biomarkers to understand individual susceptibility to the harmful effects of tobacco products is a powerful example of the value of this type of research and has provided key data confirming the link between tobacco smoke exposure and cancer risk. Furthermore, this information has led to policy changes that have reduced tobacco use and consequently, the tobacco-related cancer burden. Recent technological advances in mass spectrometry led to the ability to detect DNA damage in human tissues as well as the development of adductomic approaches. These new methods allowed for the detection of DNA adducts in tissues from patients with cancer, providing key evidence that exposure to carcinogens leads to DNA damage in the target tissue. These advances will provide valuable insights into the etiologic causes of cancer that are not tobacco-related. See all articles in this CEBP Focus section, “Environmental Carcinogenesis: Pathways to Prevention. ”
High-Cholesterol Diet Decreases the Level of Phosphatidylinositol 4,5-Bisphosphate by Enhancing the Expression of Phospholipase C (PLCβ1) in Rat Brain

Cholesterol is a critical component of eukaryotic membranes, where it contributes to regulating transmembrane signaling, cell–cell interaction, and ion transport. Dysregulation of cholesterol levels in the brain may induce neurodegenerative diseases, such as Alzheimer’s disease, Parkinson disease, and Huntington disease. We previously reported that augmenting membrane cholesterol level regulates ion channels by decreasing the level of phosphatidylinositol 4,5-bisphosphate (PIP2), which is closely related to β-amyloid (Aβ) production. In addition, cholesterol enrichment decreased PIP2 levels by increasing the expression of the β1 isoform of phospholipase C (PLC) in cultured cells. In this study, we examined the effect of a high-cholesterol diet on phospholipase C (PLCβ1) expression and PIP2 levels in rat brain. PIP2 levels were decreased in the cerebral cortex in rats on a high-cholesterol diet. Levels of PLCβ1 expression correlated with PIP2 levels. However, cholesterol and PIP2 levels were not correlated, suggesting that PIP2 level is regulated by cholesterol via PLCβ1 expression in the brain. Thus, there exists cross talk between cholesterol and PIP2 that could contribute to the pathogenesis of neurodegenerative diseases.
Auxiliary domains of the HrpB bacterial DExH-box helicase shape its RNA preferences

ABSTRACT RNA helicases are fundamental players in RNA metabolism: they remodel RNA secondary structures and arrange ribonucleoprotein complexes. While DExH-box RNA helicases function in ribosome biogenesis and splicing in eukaryotes, information is scarce about bacterial homologs. HrpB is the only bacterial DExH-box protein whose structure is solved. Besides the catalytic core, HrpB possesses three accessory domains, conserved in all DExH-box helicases, plus a unique C-terminal extension (CTE). The function of these auxiliary domains remains unknown. Here, we characterize genetically and biochemically Pseudomonas aeruginosa HrpB homolog. We reveal that the auxiliary domains shape HrpB RNA preferences, affecting RNA species recognition and catalytic activity. We show that, among several types of RNAs, the single-stranded poly(A) and the highly structured MS2 RNA strongly stimulate HrpB ATPase activity. In addition, deleting the CTE affects only stimulation by structured RNAs like MS2 and rRNAs, while deletion of accessory domains results in gain of poly(U)-dependent activity. Finally, using hydrogen-deuterium exchange, we dissect the molecular details of HrpB interaction with poly(A) and MS2 RNAs. The catalytic core interacts with both RNAs, triggering a conformational change that reorients HrpB. Regions within the accessory domains and CTE are, instead, specifically responsive to MS2. Altogether, we demonstrate that in bacteria, like in eukaryotes, DExH-box helicase auxiliary domains are indispensable for RNA handling. Graphical abstract
Interactions between cytoplasmic and nuclear genomes confer sex-specific effects on lifespan in Drosophila melanogaster

A large body of studies has demonstrated that genetic variation that resides outside of the cell nucleus can affect the organismal phenotype. The cytoplasm is home to the mitochondrial genome and, at least in arthropods, often hosts intracellular endosymbiotic bacteria such as Wolbachia. While numerous studies have implicated epistatic interactions between cytoplasmic and nuclear genetic variation as key to mediating patterns of phenotypic expression, two outstanding questions remain. Firstly, the relative contribution of mitochondrial genetic variation to other cytoplasmic sources of variation in shaping the phenotypic outcomes of cyto-nuclear interactions remains unknown. Secondly, it remains unclear whether the outcomes of cyto-nuclear interactions will manifest differently across the two sexes, as might be predicted given that cytoplasmic genomes are screened by natural selection only through females as a consequence of their maternal inheritance. Here, we address these questions, creating a fully-crossed set of replicated cyto-nuclear populations derived from three geographically distinct populations of Drosophila melanogaster, and measuring the lifespan of males and females from each population. We report cyto-nuclear interactions for lifespan, with the outcomes of these interactions differing across the sexes, and reconcile these findings with information on the full mitochondrial sequences and Wolbachia infection status of each of the populations.
Age‐related prevalence and clinical significance of neutropenia ‐ isolated or combined with other cytopenias: Real world data from 373 820 primary care individuals

Neutropenia (NP), that is, an absolute blood neutrophil count (ANC) <1.5 g/L, accompanies various diseases. However, the clinical significance of NP, detected in routine complete blood cell counts (CBC) in primary care, is poorly characterized. Here, from a primary care resource with ANCs from >370 000 individuals, we identified and followed neutropenic subjects for the next 4 years for novel ICD‐10 based diagnoses of viral infections and hematological malignancies (ie, previously identified major outcomes in NP individuals) in Danish nationwide health registers. Risk estimates were assessed for children/adolescents (1‐18 years) and adults (19‐90 years) in relation to NP severity, and for isolated NP, bi‐ or pancytopenias. We found that NP was observed in 4.9% of children and in 1.9% of adults. The lower the ANC, the likelier was a diagnosis of viral infections or hematological malignancies established during the ensuing 4 years. Among neutropenic children, unspecified viral infections predominated, followed by mononucleosis (with other cytopenias in only 7% and 25% of the cases, respectively). All NP children with acute leukemia presented with bi‐ or pancytopenia from start of follow‐up. In NP adults, hepatitis, followed by HIV, were the most common infections, and acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDSs) the predominating hematological malignancies. Adult NP patients, subsequently diagnosed with hepatitis, HIV or AML, MDS, were bi‐ or pancytopenic in 42%, 47%, 90% and 91% of cases, respectively. Thus, presence of NP in even one CBC may be the first sign of a latent viral or hematological disorder requiring careful follow‐up.