Miracle-dz/UniFAR-FTUs huggingface dataset:
Fatty acid binding protein 5 promotes the proliferation, migration, and invasion of hepatocellular carcinoma cells by degradation of Krüppel-like factor 9 mediated by miR-889-5p via cAMP-response element binding protein

ABSTRACT Mounting evidence has demonstrated that fatty acid binding protein 5 (FABP5) is commonly upregulated in many human malignancies. However, the mechanisms explaining the involvement of FABP5 in hepatocellular carcinoma (HCC) remain unclear. In this study, we demonstrated the involvement of FABP5 and its downstream signaling molecules in HCC progression. We first confirmed that FABP5 expression was upregulated in HCC. Additionally, FABP5 promoted HCC cells proliferation, migration, and invasion. Mechanistic investigation showed that FABP5 could improve cAMP-response element binding protein (CREB) phosphorylation. Meanwhile, CREB, as a transcription factor, upregulated the miR-889-5p expression by binding to the miR-889-5p promoter region. Consequently, miR-889-5p led to downregulation of Krüppel-like factor 9 (KLF9) by binding to the 3ʹ-UTR of the KLF9 mRNA, potentiating the PI3K/AKT signaling pathway and promoting the proliferation, migration, and invasion of HCC cells. Our findings have identified a FABP5/CREB/miR-889-5p/KLF9 axis for HCC progression, and we postulate that blocking this key signaling pathway may represent a promising strategy for HCC treatment.
Conservative Media Use and Childhood COVID-19 Vaccine Information: A Test of the Contradictory Health Information Processing Model

The Contradictory Health Information Processing (CHIP) model explains individuals’ processing of conflicting health claims. Tests of the model, while highly supportive, have been experimental and have relied upon low-familiar topics. Accordingly, a survey of parents with a child aged <12 years (N = 510) was conducted to test the application of the CHIP model to the controversial issue of childhood COVID-19 vaccination; such a vaccine had not yet been approved for this age group at the time of the survey. As hypothesized, reliance upon conservative news was associated with the perception that media information contradicted official guidance to vaccinate children, which led to issue uncertainty. Issue uncertainty prompted negative appraisals and decision uncertainty. Specifically, decision uncertainty partially mediated the effect of issue uncertainty on negative appraisals of vaccination, which in turn aroused threat emotions. However, threat emotions did not predict information-seeking, as specified in the model. This result may have been due to respondents having already decided to vaccinate their child, or not – a reflection of the partisan nature of the topic and the extensive coverage it had received. Theoretical and practical implications are discussed.
Contexts and contradictions: a roadmap for computational drug repurposing with knowledge inference

Abstract The cost of drug development continues to rise and may be prohibitive in cases of unmet clinical need, particularly for rare diseases. Artificial intelligence-based methods are promising in their potential to discover new treatment options. The task of drug repurposing hypothesis generation is well-posed as a link prediction problem in a knowledge graph (KG) of interacting of drugs, proteins, genes and disease phenotypes. KGs derived from biomedical literature are semantically rich and up-to-date representations of scientific knowledge. Inference methods on scientific KGs can be confounded by unspecified contexts and contradictions. Extracting context enables incorporation of relevant pharmacokinetic and pharmacodynamic detail, such as tissue specificity of interactions. Contradictions in biomedical KGs may arise when contexts are omitted or due to contradicting research claims. In this review, we describe challenges to creating literature-scale representations of pharmacological knowledge and survey current approaches toward incorporating context and resolving contradictions.
Cold sensitivity and its association to functional disability following a major nerve trunk injury in the upper extremity—A national registry-based study

Aims To investigate self-reported cold sensitivity and functional disability after a repaired major nerve trunk injury in the upper extremity. Methods We identified 735 individuals with a major nerve trunk injury in the upper extremity, surgically treated with direct nerve repair or reconstructed with nerve autografts, in the Swedish national quality registry for hand surgery (HAKIR). Patient-reported symptoms, including cold sensitivity, and perceived disability were collected using two questionnaires (HQ-8 and QuickDASH) preoperatively, and at three and 12 months postoperatively. Results We included 281 individuals, who had responded the questionnaires, where 197 (70%) were men (median age 34 [interquartile range 25–52] years) and 84 (30%) were women (median age 41 [25–55]). Cold sensitivity (scored 0–100) was the most prominent symptom 12 months postoperatively after an injured and repaired/reconstructed median (p<0.001) or ulnar (p<0.001) nerve, while individuals with a radial nerve injury showed milder symptoms. Concomitant injuries did not affect cold sensitivity scores. Individuals with ulnar nerve injuries scored higher in stiffness (p = 0.019), weakness (p<0.001) and ability to perform daily activities (p = 0.003) at 12 months postoperatively than median nerve injuries. Individuals with a median, ulnar or radial nerve injury with severe (>70) cold sensitivity had 25, 37 and 30 points higher QuickDASH scores, respectively (p<0.001), at 12 months postoperatively than individuals with mild (<30) cold sensitivity. There were no differences in QuickDASH score or cold sensitivity score at 12 months postoperatively between direct nerve repair or nerve reconstruction with nerve autografts. Neither age, nor sex, affected QuickDASH score at 12 months postoperatively. Conclusion Cold sensitivity after surgery for a major nerve trunk injury in the upper extremity can be substantial with impaired ability to perform daily activities, where an ulnar nerve injury may have a worse outcome.
Impact of Hepatitis C Treatment Uptake on Cirrhosis and Mortality in Persons Who Inject Drugs

BACKGROUND Hepatitis C virus (HCV) infection can be cured, and the United States has joined the World Health Organization in calling for HCV elimination by 2030. However, historically low uptake of HCV treatment among people who inject drugs (PWID) threatens HCV elimination and exacerbates social and racial health disparities. OBJECTIVE To assess whether all-oral HCV treatments were accessed by PWID and reduced liver disease burden and mortality. DESIGN Community-based, longitudinal cohort study of persons with a history of injection drug use. SETTING Baltimore, Maryland. PARTICIPANTS 1323 participants enrolled in the ALIVE (AIDS Linked to the IntraVenous Experience) study from 2006 to 2019 and chronically infected with HCV. MEASUREMENTS Liver stiffness measures (LSMs) by transient elastography, HCV RNA, and mortality from the National Death Index. RESULTS Among 1323 persons with evidence of chronic HCV infection at baseline, the median age was 49 years. Most were Black (82%), male (71%), and HIV-negative (66%). The proportion in whom HCV RNA was detected decreased from 100% (by definition) in 2006 to 48% in 2019. Across 10 350 valid LSMs, cirrhosis was detected in 15% of participants in 2006, 19% in 2015, and 8% in 2019. Undetectable HCV RNA was significantly associated with reduced odds of cirrhosis (adjusted odds ratio, 0.28 [95% CI, 0.17 to 0.45]) and reduced all-cause mortality risk (adjusted hazard ratio, 0.54 [CI, 0.38 to 0.77]). LIMITATION Noninvasive markers of liver fibrosis have not been validated in persons with sustained virologic response. CONCLUSION Many community-based PWID in Baltimore are receiving HCV treatment, which is associated with sharp decreases in liver disease and mortality. Additional efforts will be needed to reduce residual barriers to treatment and to eliminate HCV as a public health threat for PWID. PRIMARY FUNDING SOURCE National Institutes of Health.
Comparative Efficacy and Safety of Monoclonal Antibodies and Janus Kinase Inhibitors in Moderate-to-severe Atopic Dermatitis: A Systematic Review and Meta-analysis

The aim of this study was to compare the efficacies of systemic treatments with dupilumab, tralokinumab and Janus kinase inhibitors for moderate-to-severe atopic dermatitis. A systematic review following Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines was performed using Medline, EMBASE and Cochrane library. All randomized controlled trials investigating the efficacy of systemic treatments for moderate-to-severe atopic dermatitis in adults were included. Primary outcomes were the proportion of patients with atopic dermatitis achieving 50%, 75%, and 90% improvement in Eczema Area and Severity Index (EASI) score after dupilumab, tralokinumab or Janus kinase inhibitors. Nineteen studies totalling 6,444 patients were included. In monotherapy studies, upadacitinib 30 mg once daily had the numerically highest efficacy regarding EASI-50, EASI-75 and EASI-90. In combination therapy studies with topical corticosteroids, dupilumab 300 mg once every other week had highest efficacy regarding EASI-50, and abrocitinib 200 mg once daily had the highest score regarding EASI-75 and EASI-90. Analysis provided evidence that dupilumab, tralokinumab and Janus kinase inhibitors all had an acceptable efficacy profile and resulted in clinically relevant improvements in EASI score. Furthermore, upadacitinib and abrocitinib seem to have great potential to treat patients with atopic dermatitis. However, further studies are needed to determine the long-term efficacy of Janus kinase inhibitors in adults with moderate-to-severe atopic dermatitis.
What Do White Parents Teach Youth About Race? Qualitative Examination of White Racial Socialization

Research has examined racial socialization practices within families of color, but less is known regarding what White parents teach their children about race and/or racism. To explore White racial socialization processes, we interviewed 30 White parents of White children ages 7–17 years living in the Midwest. Using thematic analysis, we identified 22 themes organized into four domains: Content of conversations, factors to consider in socialization, developmental differences, and White identity/privilege. A majority of parents reported conversations about current or historic racial events, while relatively few also reported speaking specifically about systemic racism and microaggressions. Parents viewed adolescents as better able to handle difficult topics than children. Findings contribute to theoretical frameworks and may inform the development of educational resources.
The Neonatal Palliative Care Attitude Scale: Psychometric properties for Portuguese neonatal nurses.

BACKGROUND This study is aimed to perform the translation and cultural adaptation of the Neonatal Palliative Care Attitude Scale (NiPCAS) and evaluation of its psychometric properties with Portuguese neonatal nurses. METHODS The research started with a scoping review that allowed the identification of the NiPCAS. It was a methodological study with a quantitative approach. The semantic equivalence of the items was adjusted with the participation of 20 neonatal nurse experts. They performed facial and quantitative content validation. Psychometric validation of the NiPCAS was performed on a nonprobability nurses sample (n = 283) in 13 level 3 neonatal units between July 2021 and February 2022. Confirmatory factor analysis using the polychoric correlation matrix was performed to estimate factor validity using the "lavaan" package for R statistical software. Internal consistency was estimated using Cronbach's alpha coefficient, and item sensitivity was assessed using the asymmetry and kurtosis coefficients. Empirical indices were considered: chi-square over degrees of freedom; comparative fit index; normed fit index; Tucker-Lewis index, and root mean square error of approximation; average extracted variance and composite reliability were used to assess convergent validity. RESULTS Asymmetry and kurtosis were <|3| and <|7|, respectively, suggesting psychometric sensitivity. The convergent validity of the factors was: F1, FCF1 = 0.90 and for F2, FCF2 = 0.80, and a lower value for F3, FCF3 = 0.40. According to the squared correlation criterion average variance extracted (AVE) between the factors, there was no discriminant validity for F1 and F2, but there was discriminant validity for F1, F3, F2, and F3. SIGNIFICANCE OF RESULTS This instrument has implications for providing end-of-life care to newborns and their families. The use of this instrument reveals several barriers and facilitating elements inherent in the organization and culture of the facility and nursing education.
The association of human leucocyte antigen (HLA) alleles with COVID‐19 severity: A systematic review and meta‐analysis

Due to their pivotal role in orchestrating the immune response, HLA loci were recognized as candidates for genetic association studies related to the severity of COVID‐19. Since the findings on the effects of HLA alleles on the outcome of SARS‐CoV‐2 infection remain inconclusive, we aimed to elucidate the potential involvement of genetic variability within HLA loci in the molecular genetics of COVID‐19 by classifying the articles according to different disease severity/outcomes and by conducting a systematic review with meta‐analysis. Potentially eligible studies were identified by searching PubMed, Scopus and Web of Science literature databases. A total of 28 studies with 13,073 participants were included in qualitative synthesis, while the results of 19 studies with 10,551 SARS‐CoV‐2‐positive participants were pooled in the meta‐analysis. According to the results of quantitative data synthesis, association with COVID‐19 severity or with the lethal outcome was determined for the following alleles and allele families: HLA‐A*01, HLA‐A*03, HLA‐A*11, HLA‐A*23, HLA‐A*31, HLA‐A*68, HLA‐A*68:02, HLA‐B*07:02, HLA‐B*14, HLA‐B*15, HLA‐B*40:02, HLA‐B*51:01, HLA‐B*53, HLA‐B*54, HLA‐B*54:01, HLA‐C*04, HLA‐C*04:01, HLA‐C*06, HLA‐C*07:02, HLA‐DRB1*11, HLA‐DRB1*15, HLA‐DQB1*03 and HLA‐DQB1*06 (assuming either allelic or dominant genetic model). We conclude that alleles of HLA‐A, ‐B, ‐C, ‐DRB1 and ‐DQB1 loci may represent potential biomarkers of COVID‐19 severity and/or mortality, which needs to be confirmed in a larger set of studies.
Protective role of tissue-resident Tregs in a murine model of beryllium-induced disease

CD4+ T cells drive the immunopathogenesis of chronic beryllium disease (CBD), and their recruitment to the lung heralds the onset of granulomatous inflammation. We have shown that CD4+ Tregs control granuloma formation in an HLA-DP2 Tg model of CBD. In these mice, beryllium oxide (BeO) exposure resulted in the accumulation of 3 distinct CD4+ T cell subsets in the lung, with the majority of tissue-resident memory cells expressing FoxP3. The amount of Be regulated the number of total and antigen-specific CD4+ T cells and Tregs in the lungs of HLA-DP2 Tg mice. Depletion of Tregs increased the number of IFN-γ–producing CD4+ T cells and enhanced lung injury, while mice treated with IL-2/αIL-2 complexes had increased Tregs and reduced inflammation and Be-responsive T cells in the lung. BeO-experienced resident Tregs suppressed anti-CD3–induced proliferation of CD4+ T cells in a contact-dependent manner. CTLA-4 and ICOS blockade, as well as the addition of LPS to BeO-exposed mice, increased the effector T cell (Teff)/Treg ratio and enhanced lung injury. Collectively, these data show that the protective role of tissue-resident Tregs is dependent on quantity of Be exposure and is overcome by blocking immune regulatory molecules or additional environmental insults.
Pathogenic neuropsychiatric effect of stress-induced microglial interleukin 12/23 axis in systemic lupus erythematosus

Objectives The central nervous system disorder in systemic lupus erythematosus (SLE), called neuropsychiatric lupus (NPSLE), is one of the most severe phenotypes with various clinical symptoms, including mood disorder, psychosis and delirium as diffuse neuropsychological manifestations (dNPSLE). Although stress is one of the aggravating factors for neuropsychiatric symptoms, its role in the pathogenesis of dNPSLE remains to be elucidated. We aimed to investigate stress effects on the neuropsychiatric pathophysiology in SLE using lupus-prone mice and patients’ data. Methods Sleep disturbance stress (SDS) for 2 weeks was placed on 6–8-week-old female MRL/lpr and control mice. Behavioural phenotyping, histopathological analyses and gene and protein expression analyses were performed to assess SDS-induced neuroimmunological alterations. We also evaluated cytokines of the cerebrospinal fluid and brain regional volumes in patients with dNPSLE and patients with non-dNPSLE. Results SDS-subjected MRL/lpr mice exhibited less anxiety-like behaviour, whereas stressed control mice showed increased anxiety. Furthermore, stress strongly activated the medial prefrontal cortex (mPFC) in SDS-subjected MRL/lpr. A transcriptome analysis of the PFC revealed the upregulation of microglial activation-related genes, including Il12b. We confirmed that stress-induced microglial activation and the upregulation of interleukin (IL) 12/23p40 proteins and increased dendritic spines in the mPFC of stressed MRL/lpr mice. IL-12/23p40 neutralisation and tyrosine kinase 2 inhibition mitigated the stress-induced neuropsychiatric phenotypes of MRL/lpr mice. We also found a higher level of cerebrospinal fluid IL-12/23p40 and more atrophy in the mPFC of patients with dNPSLE than those with non-dNPSLE. Conclusions The microglial IL-12/23 axis in the mPFC might be associated with the pathogenesis and a promising therapeutic target for dNPSLE.
Inhibition of Cytochrome P450 2J2-Mediated Metabolism of Rivaroxaban and Arachidonic Acid by Ibrutinib and Osimertinib

Covalent tyrosine kinase inhibitors (TKIs) ibrutinib and osimertinib are associated with cardiac arrhythmia. The interactions between these TKIs with CYP2J2 that is highly expressed in the human heart are unknown. In vitro metabolism experiments were performed to characterize CYP2J2-mediated metabolism of ibrutinib and osimertinib. Unbound distribution coefficient (Kpuu) for both TKIs was determined in AC16 cardiomyocytes. In vitro reversible and time-dependent CYP2J2 inhibition experiments were conducted with exogenous and endogenous substrates, namely rivaroxaban and arachidonic acid (AA), respectively, where kinetic parameters were estimated via one-site and multisite kinetic modeling. Ibrutinib was efficiently metabolized by CYP2J2 to a hydroxylated metabolite, M35, following substrate inhibition kinetics. Osimertinib is not a substrate of CYP2J2. Both TKIs depicted Kpuu values above 1 and equipotently inhibited CYP2J2-mediated hydroxylation of rivaroxaban in a concentration-dependent manner without time-dependency. The mode of reversible inhibition of CYP2J2-mediated metabolism of rivaroxaban and AA by osimertinib was described by Michaelis-Menten kinetics, whereas a two-site kinetic model recapitulated the atypical inhibitory kinetics of ibrutinib, assuming multiple substrate-binding domains within the CYP2J2 active site. The inhibition of ibrutinib and osimertinib on cardiac AA metabolism could be clinically significant considering the preferable distribution of both TKIs to cardiomyocytes with R cut-off values of 1.160 and 1.026, respectively. The dysregulation of CYP2J2-mediated metabolism of AA to cardioprotective epoxyeicosatrienoic acids by ibrutinib and osimertinib serves as a novel mechanism for TKI-induced cardiac arrhythmia. Mechanistic characterization of CYP2J2-mediated typical and atypical enzyme kinetics further illuminates the unique catalytic properties of CYP2J2. SIGNIFICANCE STATEMENT We reported for the first time that ibrutinib is efficiently metabolized by CYP2J2. By using rivaroxaban and arachidonic acid (AA) as substrates, we characterized the typical and atypical inhibition kinetics of CYP2J2 by ibrutinib and osimertinib. The inhibition of both drugs on cardiac AA metabolism could be clinically significant considering their preferable distribution to cardiomyocytes. Our findings serve as a novel mechanism for drug-induced cardiac arrhythmia and shed insights into the multisite interactions between CYP2J2 and ligands.
Junctional adhesion molecule-A deletion increases phagocytosis and improves survival in a murine model of sepsis

Expression of the tight junction–associated protein junctional adhesion molecule-A (JAM-A) is increased in sepsis, although the significance of this is unknown. Here, we show that septic JAM-A –/– mice have increased gut permeability, yet paradoxically have decreased bacteremia and systemic TNF and IL-1β expression. Survival is improved in JAM-A–/– mice. However, intestine-specific JAM-A–/– deletion does not alter mortality, suggesting that the mortality benefit conferred in mice lacking JAM-A is independent of the intestine. Septic JAM-A–/– mice have increased numbers of splenic CD44hiCD4+ T cells, decreased frequency of TNF+CD4+ cells, and elevated frequency of IL-2+CD4+ cells. Septic JAM-A–/– mice have increased numbers of B cells in mesenteric lymph nodes with elevated serum IgA and intraepithelial lymphocyte IgA production. JAM-A–/– × RAG–/– mice have improved survival compared with RAG–/– mice and identical mortality as WT mice. Gut neutrophil infiltration and neutrophil phagocytosis are increased in JAM-A–/– mice, while septic JAM-A–/– mice depleted of neutrophils lose their survival advantage. Therefore, increased bacterial clearance via neutrophils and an altered systemic inflammatory response with increased opsonizing IgA produced through the adaptive immune system results in improved survival in septic JAM-A–/– mice. JAM-A may be a therapeutic target in sepsis via immune mechanisms not related to its role in permeability.
Division of labor within the DNA damage tolerance system reveals non-epistatic and clinically actionable targets for precision cancer medicine

Abstract Crosslink repair depends on the Fanconi anemia pathway and translesion synthesis polymerases that replicate over unhooked crosslinks. Translesion synthesis is regulated via ubiquitination of PCNA, and independently via translesion synthesis polymerase REV1. The division of labor between PCNA-ubiquitination and REV1 in interstrand crosslink repair is unclear. Inhibition of either of these pathways has been proposed as a strategy to increase cytotoxicity of platinating agents in cancer treatment. Here, we defined the importance of PCNA-ubiquitination and REV1 for DNA in mammalian ICL repair. In mice, loss of PCNA-ubiquitination, but not REV1, resulted in germ cell defects and hypersensitivity to cisplatin. Loss of PCNA-ubiquitination, but not REV1 sensitized mammalian cancer cell lines to cisplatin. We identify polymerase Kappa as essential in tolerating DNA damage-induced lesions, in particular cisplatin lesions. Polk-deficient tumors were controlled by cisplatin treatment and it significantly delayed tumor outgrowth and increased overall survival of tumor bearing mice. Our results indicate that PCNA-ubiquitination and REV1 play distinct roles in DNA damage tolerance. Moreover, our results highlight POLK as a critical TLS polymerase in tolerating multiple genotoxic lesions, including cisplatin lesions. The relative frequent loss of Polk in cancers indicates an exploitable vulnerability for precision cancer medicine.