Miracle-dz/UniFAR-FTUs huggingface dataset:
Targeting Pyruvate Kinase M2 and Lactate Dehydrogenase A Is an Effective Combination Strategy for the Treatment of Pancreatic Cancer

Reprogrammed glucose metabolism is one of the hallmarks of cancer, and increased expression of key glycolytic enzymes, such as pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA), has been associated with poor prognosis in various malignancies. Targeting these enzymes could attenuate aerobic glycolysis and inhibit tumor proliferation. We investigated whether the PKM2 activator, TEPP-46, and the LDHA inhibitor, FX-11, can be combined to inhibit in vitro and in vivo tumor growth in preclinical models of pancreatic cancer. We assessed PKM2 and LDHA expression, enzyme activity, and cell proliferation rate after treatment with TEPP-46, FX-11, or a combination of both. Efficacy was validated in vivo by evaluating tumor growth, PK and LDHA activity in plasma and tumors, and PKM2, LDHA, and Ki-67 expression in tumor tissues following treatment. Dual therapy synergistically inhibited pancreatic cancer cell proliferation and significantly delayed tumor growth in vivo without apparent toxicity. Treatment with TEPP-46 and FX-11 resulted in increased PK and reduced LDHA enzyme activity in plasma and tumor tissues and decreased PKM2 and LDHA expression in tumors, which was reflected by a decrease in tumor volume and proliferation. The targeting of glycolytic enzymes such as PKM2 and LDHA represents a promising therapeutic approach for the treatment of pancreatic cancer.
Perspectives of Quebec Primary Health Care Nurse Practitioners on Their Role and Challenges in Chronic Disease Management: A Qualitative Study

Background Primary health care nurse practitioners (PHCNPs) can play a key role in chronic disease management. However, little is known about the challenges they face. Purpose The study aimed to describe PHCNPs’ perspectives on their role for patients with chronic health conditions, the barriers they face, and facilitating factors. Methods A qualitative descriptive exploratory study was conducted with 24 PHCNPs in the Canadian province of Quebec. Results PHCNPs believe that they are in an optimal position to address the needs of patients with chronic health conditions, especially in providing self-management support. However, PHCNPs reported feeling pressured to practice according to a biomedical model and to constantly defend their role in chronic disease management. They feel that they are frequently being diverted from their role to compensate for the lack of family doctors. PHCNPs made concrete recommendations to optimize their autonomous practice and quality of care: promoting strong interprofessional communication skills, genuine mentoring relationships between PHCNPs and partner physicians, managers upholding the full scope of PHCNPs’ practice, and a more flexible legislative framework. Conclusions The original conception of PHCNPs as health professionals with unique characteristics is at stake. The factors that should be targeted to support the autonomy of PHCNPs were identified.
Isolation of Candida auris from invasive and non-invasive samples of a patient suffering from vascular disease, Italy, July 2019

We recently isolated Candida auris from a blood culture and cutaneous swabs of a patient in her mid-70s. Our routine phenotypic methods failed to identify the microorganism, but it was identified by molecular tests and MALDI-TOF MS analysis. Our report, the first from Italy, further underlines the geographically wide distribution of C. auris and the need to confirm species identification of any suspicious colony as soon as possible to stop its spread.
Neonatal Urine Metabolic Profiling and Development of Childhood Asthma

Urine metabolomics case-control studies of childhood asthma have demonstrated a discriminative ability. Here, we investigated whether urine metabolic profiles from healthy neonates were associated with the development of asthma in childhood. Untargeted metabolomics by liquid chromatography-mass spectrometry was applied to urine samples collected at age 4 weeks in 171 and 161 healthy neonates born from mothers with asthma from the COPSAC2000 and COPSAC2010 cohorts, respectively, where persistent wheeze/asthma was prospectively diagnosed using a symptom-based algorithm. Univariate and multivariate analyses were applied to investigate differences in metabolic profiles between children who developed asthma and healthy children. Univariate analysis showed 63 and 87 metabolites (q-value < 0.15) in COPSAC2000 and COPSAC2010, respectively, which is promising for discriminating between asthmatic and healthy children. Of those, 14 metabolites were common among the two cohorts. Multivariate random forest and projection to latent structures discriminant analyses confirmed the discriminatory capacity of the metabolic profiles in both cohorts with estimated errors in prediction equal to 35% and AUCpred > 0.60. Database search enabled annotation of three discriminative features: a glucoronidated compound (steroid), 3-hydroxytetradecanedioic acid (fatty acid), and taurochenodeoxycholate-3-sulfate (bile acid). The urine metabolomics profiles from healthy neonates were associated with the development of childhood asthma, but further research is needed to understand underlying metabolic pathways.
Instant messaging application for the care of people living with HIV/aids.

OBJECTIVE To assess a specific instant messaging application as a tool of care for people living with HIV/aids, based on analysis of the interactions between nurse and patients. METHOD Descriptive, quantitative study with 102 patients from two outpatient infectious disease clinics of Fortaleza, Ceará. During four months, participants received a message every 15 days, totaling eight messages, regarding: adherence to antiretroviral therapy; physical activity; social support; self-esteem; anxiety/depression; eating habits; alcohol and drugs; and sexuality. RESULTS There were 816 interactions, especially for dialogs about performing physical activity (27.87%), sharing of signs and symptoms (18.03%), report of engagement with treatment (9.84%) and requests of information on the intake of medicine (9.84%). Most participants showed satisfaction with the follow-up, with willingness to continue receiving messages (90.58%). CONCLUSION The use of this application is a viable strategy to improve care for people with HIV by promoting instant communication.
Prophylaxis of Mycobacterium tuberculosis H37Rv Infection in a Preclinical Mouse Model via Inhalation of Nebulized Bacteriophage D29

Globally, more people die annually from tuberculosis than from any other single infectious agent. Unfortunately, there is no commercially available vaccine that is sufficiently effective at preventing the acquisition of pulmonary tuberculosis in adults. In this study, preexposure prophylactic pulmonary delivery of active aerosolized antituberculosis bacteriophage D29 was evaluated as an option for protection against Mycobacterium tuberculosis infection. ABSTRACT Globally, more people die annually from tuberculosis than from any other single infectious agent. Unfortunately, there is no commercially available vaccine that is sufficiently effective at preventing the acquisition of pulmonary tuberculosis in adults. In this study, preexposure prophylactic pulmonary delivery of active aerosolized antituberculosis bacteriophage D29 was evaluated as an option for protection against Mycobacterium tuberculosis infection. An average bacteriophage concentration of approximately 1 PFU/alveolus was achieved in the lungs of mice using a nose-only inhalation device optimized with a dose simulation technique and adapted for use with a vibrating mesh nebulizer. Within 30 min of bacteriophage delivery, the mice received either a low dose (∼50 to 100 CFU) or an ultralow dose (∼5 to 10 CFU) of M. tuberculosis H37Rv aerosol to the lungs. A prophylactic effect was observed, with bacteriophage aerosol pretreatment significantly decreasing M. tuberculosis burden in mouse lungs at 24 h and 3 weeks postchallenge (P < 0.05). These novel results indicate that a sufficient dose of nebulized mycobacteriophage aerosol to the lungs may be a valuable intervention to provide extra protection to health care professionals and other individuals at risk of exposure to M. tuberculosis.
Immunomodulatory Mechanism of Acyclic Nucleoside Phosphates in Treatment of Hepatitis B Virus Infection

Current treatment with nucleos(t)ide analogs (NUCs) safely controls the replication of hepatitis B virus (HBV) and improves prognosis in patients with HBV. However, the inability to completely clear HBV is problematic, and novel therapies are desired. It has been believed that all NUCs have similar functions to inhibit HBV reverse transcriptase. However, our recent findings that only acyclic nucleoside phosphonates (ANPs; adefovir dipivoxil and tenofovir disoproxil fumarate) had an additional effect of inducing interferon (IFN)‐λ3 in the gastrointestinal tract suggests that ANPs are not only distinct from nucleoside analogs (lamivudine and entecavir) in their structures but also in their functions. Because enteric lipopolysaccharide (LPS) can cross the intestine and affect peripheral blood mononuclear cells (PBMCs), we hypothesized that orally administered ANPs could have further additional effects to modulate LPS‐mediated cytokine profile in PBMCs.
Parallel Computing for Quantitative Blood Flow Imaging in Photoacoustic Microscopy

Photoacoustic microscopy (PAM) is an emerging biomedical imaging technology capable of quantitative measurement of the microvascular blood flow by correlation analysis. However, the computational cost is high, limiting its applications. Here, we report a parallel computation design based on graphics processing unit (GPU) for high-speed quantification of blood flow in PAM. Two strategies were utilized to improve the computational efficiency. First, the correlation method in the algorithm was optimized to avoid redundant computation and a parallel computing structure was designed. Second, the parallel design was realized on GPU and optimized by maximizing the utilization of computing resource in GPU. The detailed timings and speedup for each calculation step were given and the MATLAB and C/C++ code versions based on CPU were presented as a comparison. Full performance test shows that a stable speedup of ~80-fold could be achieved with the same calculation accuracy and the computation time could be reduced from minutes to just several seconds with the imaging size ranging from 1 × 1 mm2 to 2 × 2 mm2. Our design accelerates PAM-based blood flow measurement and paves the way for real-time PAM imaging and processing by significantly improving the computational efficiency.
RNAi-mediated depletion of the NSL complex subunits leads to abnormal chromosome segregation and defective centrosome duplication in Drosophila mitosis

The Drosophila Nonspecific Lethal (NSL) complex is a major transcriptional regulator of housekeeping genes. It contains at least seven subunits that are conserved in the human KANSL complex: Nsl1/Wah (KANSL1), Dgt1/Nsl2 (KANSL2), Rcd1/Nsl3 (KANSL3), Rcd5 (MCRS1), MBD-R2 (PHF20), Wds (WDR5) and Mof (MOF/KAT8). Previous studies have shown that Dgt1, Rcd1 and Rcd5 are implicated in centrosome maintenance. Here, we analyzed the mitotic phenotypes caused by RNAi-mediated depletion of Rcd1, Rcd5, MBD-R2 or Wds in greater detail. Depletion of any of these proteins in Drosophila S2 cells led to defects in chromosome segregation. Consistent with these findings, Rcd1, Rcd5 and MBD-R2 RNAi cells showed reduced levels of both Cid/CENP-A and the kinetochore component Ndc80. In addition, RNAi against any of the four genes negatively affected centriole duplication. In Wds-depleted cells, the mitotic phenotypes were similar but milder than those observed in Rcd1-, Rcd5- or MBD-R2-deficient cells. RT-qPCR experiments and interrogation of published datasets revealed that transcription of many genes encoding centromere/kinetochore proteins (e.g., cid, Mis12 and Nnf1b), or involved in centriole duplication (e.g., Sas-6, Sas-4 and asl) is substantially reduced in Rcd1, Rcd5 and MBD-R2 RNAi cells, and to a lesser extent in wds RNAi cells. During mitosis, both Rcd1-GFP and Rcd5-GFP accumulate at the centrosomes and the telophase midbody, MBD-R2-GFP is enriched only at the chromosomes, while Wds-GFP accumulates at the centrosomes, the kinetochores, the midbody, and on a specific chromosome region. Collectively, our results suggest that the mitotic phenotypes caused by Rcd1, Rcd5, MBD-R2 or Wds depletion are primarily due to reduced transcription of genes involved in kinetochore assembly and centriole duplication. The differences in the subcellular localizations of the NSL components may reflect direct mitotic functions that are difficult to detect at the phenotypic level, because they are masked by the transcription-dependent deficiency of kinetochore and centriolar proteins.
Substantial Influence of ERAP2 on the HLA-B*40:02 Peptidome: Implications for HLA-B*27-Negative Ankylosing Spondylitis*

ERAP2 and HLA-B*40:02 are associated with ankylosing spondylitis independently of HLA-B*27. ERAP2 process MHC-I ligands, preferentially trimming N-terminal basic residues. The B*40:02 peptidomes from wild-type and ERAP2-KO cells were compared, which demonstrated a substantial role of ERAP2 on the generation/destruction balance of HLA-B*40:02 ligands. The major effect was on N-terminal residues, although other peptide positions were also affected. We propose that the non-epistatic association of ERAP2 with spondyloarthropathy might be related to processing of peptides with N-terminal basic residues. Graphical Abstract Highlights HLA-B*40:02 and ERAP2 are risk factors for ankylosing spondylitis. The effects of ERAP2 on the B*40:02 peptidome are defined. ERAP2 has a major influence mainly due to alterations of N-terminal residues. These effects provide a basis for the association of ERAP2 with disease. HLA-B*40:02 is one of a few major histocompatibility complex class I (MHC-I) molecules associated with ankylosing spondylitis (AS) independently of HLA-B*27. The endoplasmic reticulum aminopeptidase 2 (ERAP2), an enzyme that process MHC-I ligands and preferentially trims N-terminal basic residues, is also a risk factor for this disease. Like HLA-B*27 and other AS-associated MHC-I molecules, HLA-B*40:02 binds a relatively high percentage of peptides with ERAP2-susceptible residues. In this study, the effects of ERAP2 depletion on the HLA-B*40:02 peptidome were analyzed. ERAP2 protein expression was knocked out by CRISPR in the transfectant cell line C1R-B*40:02, and the differences between the peptidomes from the wild-type and ERAP2-KO cells were determined by label-free quantitative comparisons. The qualitative changes dependent on ERAP2 affected about 5% of the peptidome, but quantitative changes in peptide amounts were much more substantial, reflecting a significant influence of this enzyme on the generation/destruction balance of HLA-B*40:02 ligands. As in HLA-B*27, a major effect was on the frequencies of N-terminal residues. In this position, basic and small residues were increased, and aliphatic/aromatic ones decreased in the ERAP2 knockout. Other peptide positions were also affected. Because most of the non-B*27 MHC-I molecules associated with AS risk bind a relatively high percentage of peptides with N-terminal basic residues, we hypothesize that the non-epistatic association of ERAP2 with AS might be related to the processing of peptides with these residues, thus affecting the peptidomes of AS-associated MHC-I molecules.
Development of decision trees to discriminate HDAC8 inhibitors and non-inhibitors using recursive partitioning

Abstract Histone deacetylase 8 (HDAC8) is involved in malignancy. Overexpression of HDAC8 is correlated with various cancers. Design of selective HDAC8 inhibitors is always a challenging task to the chemistry audiences. In this communication, a diverse set comprising large number of compounds are subjected to recursive partitioning (RP) analysis to develop decision trees to discriminate compounds into HDAC8 inhibitors (active) and non-inhibitors (inactive). Acquiring knowledge about the essential structural and physicochemical parameters can be useful in designing potential and selective HDAC8 inhibitors. Moreover, this work validates our previous results observed in Bayesian modelling study of this dataset. This comparative learning will surely enrich drug discovery aspects related to HDAC8 inhibitors. Communicated by Ramaswamy H. Sarma
Retinoic Acid Promotes Retinoic Acid Signaling by Suppression of Pitx1 In Tendon Cells: A Possible Mechanism of a Clubfoot-Like Phenotype Induced by Retinoic Acid

Background The pathogenesis of idiopathic congenital clubfoot (CCF) is unknown. Although some familial patients have Pitx1 mutations, and the Pitx1+/− genotype causes a clubfoot-like phenotype in mice, the mechanism of Pitx1-induced CCF is unknown. Material/Methods We used tibialis anterior tendon samples to detect the expression of Pitx1 in idiopathic and neurogenic clubfoot patients. After obtaining Sprague-Dawley (SD) rat Achilles tendon cells, the expression of Pitx1 was knocked down by SiRNA. After 48 h of culture, mass spectrometry was used to quantitatively analyze proteins. Then, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were used to assess the downstream pathway of PITX1. The relationship between Pitx1 and the promoter region of deacetylase 1 (Sirtuin-1 and Sirt1) was examined by luciferase and ChIP assays. Results We found that Pitx1 expression in the tendon samples of idiopathic CCF patients was downregulated. Mass spectrometry analysis revealed that the inhibition of Pitx1 induced the downregulation of Sirt1 expression in tendon cells. Luciferase and ChIP assays confirmed that Pitx1 binds to the promoter region of SIRT1 and promotes Sirt1 gene transcription. Further results showed that, after the inhibition of Pitx1 in tendon cells, CRABP2 acetylation increased, the nuclear import of CRABP2 was enhanced, and the expression of RARβ2 increased. After the inhibition of Pitx1, RARβ2 expression was further increased by RA treatment in tendon cells. In the presence of retinoic acid, the expression of Pitx1 was inhibited in tendon cells. Conclusions Pitx1 binds to the promoter region of SIRT1 and promotes the transcription of SIRT1. Positive feedback occurs between RA signaling and Pitx1.
Hemocyte Changes During Immune Melanization in Bombyx Mori Infected with Escherichia coli

Hemolymph melanization is a conserved immune response in insects and other arthropods. However, the physiological process of the hemolymph system in the melanization response is hardly studied. Here, alterations of hemocytes in immune melanization were observed by Escherichia coli infection in Bombyx mori. Results first showed that there were cells aggregating into clusters. However, it vanished, and only part of clustered hemocytes were melanized during the period of intense immunity. The hemocyte numbers immediately decreased following an immune challenge, slowly increased to a peak, then reduced and finally returned to normalization. Granulocytes participated in cells aggregation at the early and later immune stage, while plasmatocytes were responsible for hemocytes agglomerate and melanization for the longest time, and more oenocytoids appeared at the peak stage of melanization. Moreover, hemocytes played a crucial role in resisting invasion of pathogens by agglomerate and melanization, and the circulatory system maintained higher hemocyte numbers and stronger antibacterial activity in fifth than fourth instar larvae after infection. In vitro immune melanization was most likely preferentially implemented in an independent process. These were the main characteristics reflecting the physiological process of hemolymph immune melanization, which provided an important foundation for further study of the complete mechanisms in the immunity of silkworm.
Use of antimicrobial dressings in England and the association with published clinical guidance: interrupted time series analysis

Objectives In healthcare systems, practices and products of unproven value and cost-effectiveness can decrease value and increase waste. Using the management of complex wounds, this study investigates temporal trends in the use of antimicrobials dressings, places this in the context of available evidence and discusses the potential impacts on the UK National Health Service (NHS). Design Secondary descriptive and interrupted time series (ITS) analysis of NHS prescription data. Setting Prescribing Cost Analysis (PCA) details all NHS prescriptions dispensed in the community in England. Interventions An ITS design was used to compare annual changes in the expenditure and use of antimicrobial and non-antimicrobial dressings before and after the publication of the ‘intervention’ of key evidence-based Scottish Intercollegiate Guidelines Network (SIGN) guidance in 2010. Primary and secondary outcome measures Trends in use and expenditure of antimicrobial dressings in relation to published clinical guidance. Results There was a large increase in the prescribing of, and expenditure on, antimicrobial wound dressings between 1997 and 2016. In 1997, the total number of dressings prescribed was 5 792 700; increasing to 11 447 102 in 2009 with expenditure increasing from £1 960 386 to £32 841 263. During the year of the SIGN intervention (2010), there was a significant drop in the use of silver but there was no consistent ongoing reduction from 2011 to 2015. Conclusions Prescribing data can be used to identify products of unproven benefit, which also impose a significant financial burden. This study quantifies the huge increase in the use of antimicrobial wound dressings over a 20-year period despite the lack of compelling evidence to support their routine use. There is some suggestion, however that the use and expenditure decreased after the publication of key guidance. Routine data can be used to as part of more systematic efforts to increase value and reduce waste in health systems.