Miracle-dz/UniFAR-FTUs huggingface dataset:
Emerging FLT3 inhibitors for the treatment of acute myeloid leukemia

ABSTRACT Introduction The FMS-like tyrosine kinase 3 (FLT3) gene is mutated in one-third of patients with Acute Myeloid Leukemia (AML). Midostaurin, quizartinib, and gilteritinib have been approved in the last years for the treatment of AML, and more Tyrosine Kinase Inhibitors (TKIs) targeting FLT3 are being developed such as crenolanib. Areas covered In this systematic review, we will analyze the available clinical data on FLT3 inhibitors in development and describe the potential role that these FLT3-TKIs may play in the future management of FLT3-mutated (FLT3mut) AML. Expert opinion Although several aspects may challenge the use of FLT3 inhibitors in AML (resistance mechanisms, on- and off-target toxicities or drug-drug interactions), these drugs are generally well tolerated, particularly if we compare their safety profile with classical chemotherapy agents or even with newer immunotherapies, thus enabling their use in fit and unfit AML patients, alone or combined. As AML is a polyclonal disease and FLT3 mutations are a late leukemogenic event, combinations of these FLT3 inhibitors with other antileukemic agents (like venetoclax or hypomethylating agents) seem a necessary research pathway.
212Pb-conjugated anti-rat HER2/neu antibody against a neu-N derived murine mammary carcinoma cell line: cell kill and RBE in vitro

Abstract Purpose In the current work, the RBE of a 212Pb-conjugated anti-HER2/neu antibody construct has been evaluated, in vitro, by colony formation assay. The RBE was estimated by comparing two absorbed dose-survival curves: the first obtained from the conjugated 212Pb experiments (test radiation), the second obtained by parallel experiments of single bolus irradiation of external beam (reference radiation). Materials and Methods Mammary carcinoma NT2.5 cells were treated with (0–2.47) kBq/ml of radiolabeled antibody. Nonspecific binding was assessed with addition of excess amount of unlabeled antibody. The colony formation curves were converted from activity concentration to cell nucleus absorbed dose by simulating the decay and transport of all daughter and secondary particles of 212Pb, using the Monte Carlo code GEANT 4. Results The radiolabeled antibody yielded an RBE of 11.5 at 37% survival and a survival independent RBE (i.e. RBE2) of 13.7. Unbound/untargeted 212Pb-labeled antibody, as obtained in blocking experiments yielded minimal alpha-particle radiation to cells. Conclusions: These results further highlight the importance of specific targeting toward achieving tumor cell kill and low toxicity to normal tissue.
Machine learning prediction of antibody aggregation and viscosity for high concentration formulation development of protein therapeutics

ABSTRACT Machine learning has been recently used to predict therapeutic antibody aggregation rates and viscosity at high concentrations (150 mg/ml). These works focused on commercially available antibodies, which may have been optimized for stability. In this study, we measured accelerated aggregation rates at 45°C and viscosity at 150 mg/ml for 20 preclinical and clinical-stage antibodies. Features obtained from molecular dynamics simulations of the full-length antibody and sequences were used for machine learning model construction. We found a k-nearest neighbors regression model with two features, spatial positive charge map on the CDRH2 and solvent-accessible surface area of hydrophobic residues on the variable fragment, gives the best performance for predicting antibody aggregation rates (r = 0.89). For the viscosity classification model, the model with the highest accuracy is a logistic regression model with two features, spatial negative charge map on the heavy chain variable region and spatial negative charge map on the light chain variable region. The accuracy and the area under precision recall curve of the classification model from validation tests are 0.86 and 0.70, respectively. In addition, we combined data from another 27 commercial mAbs to develop a viscosity predictive model. The best model is a logistic regression model with two features, number of hydrophobic residues on the light chain variable region and net charges on the light chain variable region. The accuracy and the area under precision recall curve of the classification model are 0.85 and 0.6, respectively. The aggregation rates and viscosity models can be used to predict antibody stability to facilitate pharmaceutical development.
QTc prolongation during levofloxacin and triazole combination chemoprophylaxis: Prevalence and predisposing risk factors in a cohort of hematopoietic cell transplantation recipients

Background QTc interval prolongation has been reported when combining fluoroquinolones and triazoles for chemoprophylaxis in cancer patients. Herein, we aimed to identify the prevalence and contributing factors to QTc prolongation in hematopoietic cell transplantation (HCT) recipients who received these agents during the neutropenic phase. Methods This is a retrospective medical chart review conducted at a university hospital in Lebanon from 2017 to 2020. It included all adult HCT inpatients on antimicrobial prophylaxis with fluoroquinolones and triazoles and whose baseline ECG monitoring done prior to chemoprophylaxis administration, then on day-3 and day-6 of therapy, were available. Results Overall, 68 HCT recipients met our inclusion criteria, of which 22% developed QTc prolongation. Based on bivariate analysis, female gender contributed to QTc prolongation (P = 0.001). There was a trend to QTc prolongation in patients with predisposing thyroid disease (P = 0.12), grade 2 vomiting and diarrhea (P = 0.16, P = 0.46, respectively), baseline hypokalemia (P = 0.18) and hypocalcemia (P = 0.3), hypomagnesemia on day-3 (P = 0.21) and day-6 hyponatremia (P = 0.36). Patients receiving two or more drugs with a known or probable risk of QTc prolongation (other than the fluoroquinolone/ triazole combination) were more prone to experience a prolonged QTc interval (P = 0.09). None of the patients that had QTc prolongation died or developed serious arrhythmias. Conclusion The prevalence of QTc prolongation was 22% among HCT recipients on fluoroquinolone and triazole prophylaxis, yet we did not identify any independent risk factors for this issue. None of the patients that had QTc interval prolongation died or developed serious arrhythmias.
A randomized controlled trial (RCT) to explore the effect of audio-visual entrainment among psychological disorders

Background and aim: Although many mental disorders have relevant proud in neurobiological dysfunctions, most intervention approaches neglect neurophysiological features or use pharmacological intervention alone. Non-invasive Brain-Computer Interfaces (BCIs), providing natural ways of modulating mood states, can be promoted as an alternative intervention to cope with neurobiological dysfunction. Methods: A BCI prototype was proposed to feedback a person’s affective state such that a closed-loop interaction between the participant’s brain responses and the musical stimuli is established. It returns flickering lights in real-time matching with the individual’s brain rhythms subjected to auditory stimuli. A RCT was carried out on 15 individuals of both genders (mean age = 49.27 years) with anxiety and depressive spectrum disorders randomly assigned to 2 groups (experimental vs. active control). Results: Outcome measures revealed either a significant decrease in Hamilton Rating Scale for Depression (HAM-D) scores and gains in cognitive functions only for participants who undergone to the experimental treatment. Variability in HAM-D scores seems explained by the changes in Beta 1, Beta 2, and Delta bands. Conversely, the rise in cognitive function scores appear associated with Theta variations. Conclusions: Future work needs to validate the relationship proposed here between music and brain responses. Findings of the present study provided support to a range of research examining brain modulation with BCIs and contribute to the understanding of this technique as instruments to alternative therapies. We believe that Neuro-Upper can be used as an effective new tool for investigating affective responses, and emotion regulation (www.actabiomedica.it).
Genitourinary syndrome, local oestrogen therapy and endometrial pathology: a single-centre, randomised study

Abstract The objective of this study was to assess the endometrial pathology developed (EP) in postmenopausal women with genitourinary syndrome during and after vaginal oestrogen therapy. The 67 patients included were randomly grouped into group I underwent local oestrogen (oestriol) therapy and group II, underwent no therapy. Each patient’s medical history was taken and clinical and gynecological examination, with transvaginal ultrasound at the time of inclusion and during the control visits, was done. The study results show no statistically higher risk of EP for vaginal oestrogen therapy of genitourinary syndrome users compared to the non-users in menopause. No one atypical endometrial hyperplasia and endometrial intraepithelial neoplasia case during the study period was found. Impact statement What is already known on this subject? Treatment of genitourinary syndrome with oestrogens in menopausal women is the most commonly used and affordable method. Topical vaginal oestrogens do not have the same stimulating effect on the endometrium as oral ones, and therefore the association between them and endometrial hyperplasia or cancer has not been established categorically. What do the results of this study add? This single-center, randomised study found no statistically higher risk of endometrial pathology for vaginal oestrogen (oestriol) therapy of genitourinary syndrome users compared to the non-users in menopause. No one atypical endometrial hyperplasia and endometrial intraepithelial neoplasia case during the study period was found. What the implications are of these findings for clinical practice and/or further research? This study confirms the safety of local oestrogen (oestriol) therapy of genitourinary syndrome in menopausal women with regards to the development of endometrial pathology and especially atypical endometrial hyperplasia and endometrial intraepithelial neoplasia or well-differentiated carcinoma
Impact of miRNA-binding site polymorphisms in STAT3 gene on occurrence and clinical characteristics of systemic lupus erythematosus

Background Signal transducer and activator of transcription 3 (STAT3) is a major regulator of immune response and chronic inflammatory conditions acting through regulation of B cells, T-helper 17 (Th17) cells, and IL-17 production. Previous studies have demonstrated that dysregulation of STAT3 is crucial for SLE pathogenesis and disease severity. It is believed that single nucleotide polymorphisms (SNPs) located at the 3′-UTR sequence of the target genes could dysregulate their expression by disrupting the binding site of miRNAs. In the present study, we assessed the possible association between rs1053005 and rs1053023 SNPs at miRNA binding sites in the STAT3 gene and the risk of SLE in the Iranian population for the first time. Methods 112 SLE cases and 120 healthy controls were genotyped for rs1053005 (A>G) and rs1053023 (A>G) polymorphisms in STAT3 using real-time PCR high resolution melting method (HRM). Results Our results revealed substantial associations between GG genotype and G allele of rs1053023 with enhanced risk of SLE (OR for GG genotype= 3.13; 95%CI [1.61–6.1], OR for G allele = 2.22; 95%CI [1.51–3.25]). However, no important correlations have been found between rs1053005 polymorphism and SLE susceptibility in this population (p>0.05). Moreover, stratification analysis showed that these polymorphisms are correlated with parameters indicating disease activity and more severe course of the disease. These factors include some laboratory test results and clinical manifestations such as renal involvements. Conclusion The current study suggests a significant association between STAT3 polymorphisms and augmented risk of SLE, clinical symptoms, disease activity, and severity.
Necrotic enteritis in chickens: a review of pathogenesis, immune responses and prevention, focusing on probiotics and vaccination

Abstract Necrotic enteritis (NE), caused by Clostridium perfringens (CP), is one of the most common of poultry diseases, causing huge economic losses to the poultry industry. This review provides an overview of the pathogenesis of NE in chickens and of the interaction of CP with the host immune system. The roles of management, nutrition, probiotics, and vaccination in reducing the incidence and severity of NE in poultry flocks are also discussed.
Strongyloides Stercoralis Infection in Hispanic Veterans Living in Puerto Rico: A Tropical Issue or a Global One?

OBJECTIVE Strongyloidiasis is a parasitic infection classified by the World Health Organization as a neglected tropical disease. Although predominantly asymptomatic, it can become a life-threatening disease in an immunocompromised host. Epidemiologic studies in the Western Hemisphere are scarce, but even more scarce are descriptions of the natural course of this disease. Our objectives were to identify the different manifestations and outcomes of Strongyloides stercoralis infection in the Hispanic veteran population in Puerto Rico. We also discuss the importance of pursuing a timely diagnosis in high-risk patients migrating from or traveling to endemic areas, regardless of their symptomatic status. METHODS This was a single-center, retrospective record review study involving patients diagnosed with S. stercoralis via serology, stool samples, or organ biopsies, from 2008 through 2014. RESULTS A total of 270 patients tested positive; 210 (77.8%) were asymptomatic. The mean age at diagnosis was 75.4 years old. Symptomatic patients had pulmonary (n = 25), gastrointestinal (n = 21), and dermatologic (n = 5) symptoms; 9 had multiple symptoms. Five had hyperinfection, mostly after treatment with systemic steroids or preexisting immunosuppression. The most common laboratory abnormality was eosinophilia. Reasons for testing were eosinophilia, asthma, diarrhea, screening for parasites, and unexplained skin rash. CONCLUSION Our study highlights the importance of being aware of this potentially fatal infection, especially when treating patients traveling from endemic countries. It also highlights the importance of timely screening, diagnosis, and treatment of S. stercoralis infection in order to prevent potentially fatal outcomes, especially when considering immunosuppressive drugs.
F Plasmid Lineages in Escherichia coli ST95: Implications for Host Range, Antibiotic Resistance, and Zoonoses

E. coli ST95 is one of five dominant ExPEC lineages globally and noted for causing urinary tract and bloodstream infections and neonatal meningitis in humans and colibacillosis in poultry. Using high-resolution phylogenomics, we show that F replicon sequence type is linked to ST95 clade structure and zoonotic potential. ABSTRACT Escherichia coli sequence type 95 (ST95) is an extraintestinal pathogenic E. coli (ExPEC) renowned for its ability to cause significant morbidity and mortality in humans and poultry. A core genome analysis of 668 ST95 isolates generated 10 clades (A to J), 5 of which are reported here for the first time. F plasmid replicon sequence typing showed that almost a third (178/668 [27%]) of the collection carry pUTI89 (F29:B10) and were restricted to clade A and a sublineage of clade B. In contrast, almost half (328/668 [49%]) of the collection across multiple clades harbor ColV plasmids (multiple F types). Strikingly, ST95 lineages with pUTI89 were almost exclusively from humans, while ColV+ ST95 lineages were sourced from poultry and humans. Clade I was notable because it comprises temporally and geographically matched ColV+ isolates sourced from human and retail poultry meat, suggesting interspecies transmission via food. Clade F contained ST95 isolates of bovine origin, none of which carried ColV or pUTI89 plasmids. Remarkably, an analysis of a cohort of 34,176 E. coli isolates comprising 2,570 sequence types mirrored what was observed in ST95: (i) pUTI89 was overwhelmingly linked to E. coli sourced from humans but almost entirely absent from 13,027 E. coli isolates recovered from poultry, pigs, and cattle, and (ii) E. coli isolates harboring ColV plasmids were from multiple sources, including humans, poultry, and swine. Overall, our data suggest that F plasmids influence E. coli host range, clade structure, and zoonotic potential in ST95 and ExPEC more broadly. IMPORTANCE E. coli ST95 is one of five dominant ExPEC lineages globally and noted for causing urinary tract and bloodstream infections and neonatal meningitis in humans and colibacillosis in poultry. Using high-resolution phylogenomics, we show that F replicon sequence type is linked to ST95 clade structure and zoonotic potential. Specifically, human centric ST95 clades overwhelmingly harbor F29:B10 (pUTI89) plasmids, while clades carrying both human- and poultry-sourced isolates are typically ColV+ with multiple replicon types. Importantly, several clades identified clonal ColV+ ST95 isolates from human and poultry sources, but clade I, which housed temporally and spatially matched isolates, provided the most robust evidence. Notably, patterns of association of F replicon types with E. coli host were mirrored within a diverse collection of 34,176 E. coli genomes. Our studies indicate that the role of food animals as a source of human ExPEC disease is complex and warrants further investigation.
Treatment of ankylosed deciduous molars with or without permanent successors in children and adolescents: a systematic review.

INTRODUCTION The aim of this systematic review was to provide guidelines for decision-making during orthodontic treatment planning of infra-occluded deciduous molars with or without their successors in children and adolescents. EVIDENCE ACQUISITION Computerized search was conducted on Medline via PubMed, and Cochrane Library. Articles published until 2020 in English language were analyzed following the Preferred Reporting Items for Systematic Reviews (PRISMA) Checklist. Observational and interventional longitudinal studies reporting the treatment of ankylosed deciduous molars with or without successor tooth in 3 to 15-year-old patients were included. EVIDENCE SYNTHESIS In case of ankylosis with presence of successor, exfoliation took place in 77% of teeth, while extraction involved 23%. Infra-occlusion happened in 53% of teeth (worsening in 52%), alveolar bone loss in 37%, mesial tipping of first permanent molar in 5%, and over-eruption of antagonist in no cases (after exfoliation and eruption of successor). In case of ankylosis without successor, exfoliation took place in 1% of teeth, progression of infra-occlusion in 42%, progression of root resorption in 58%, development of mesial tipping of first permanent molars in 25%, while no case of antagonist over-eruption was reported. CONCLUSIONS When the permanent tooth is present and the ankylosed tooth is slightly or moderately infra-occluded, observation is appropriate. In case of severe infra-occlusion or absence of successor, tooth extraction may be considered together with orthodontic space closure, transplantation, or prosthetic replacement. Alternatively, nonextraction and a prosthetic build-up may be considered.
Conversion of ileo‐pouch anal anastomosis to continent ileostomy: strategic surgical considerations and outcome

The aim was to evaluate surgical strategies for conversion of failed ileo‐pouch anal anastomosis (IPAA) to continent ileostomy (CI), taking morbidity and overall outcome into account. The hypothesis was that complex conversions are equivalent to the primary construction of a CI at the time of proctocolectomy.
Langerhans cells and cDC1s play redundant roles in mRNA-LNP induced protective anti-influenza and anti-SARS-CoV-2 immune responses

Nucleoside modified mRNA combined with Acuitas Therapeutics’ lipid nanoparticles (LNPs) has been shown to support robust humoral immune responses in many preclinical animal vaccine studies and later in humans with the SARS-CoV-2 vaccination. We recently showed that this platform is highly inflammatory due to the LNPs’ ionizable lipid component. The inflammatory property is key to support the development of potent humoral immune responses. However, the mechanism by which this platform drives T follicular helper (Tfh) cells and humoral immune responses remains unknown. Here we show that lack of Langerhans cells or cDC1s neither significantly affected the induction of PR8 HA and SARS-CoV-2 RBD-specific Tfh cells and humoral immune responses, nor susceptibility towards the lethal challenge of influenza and SARS-CoV-2. However, the combined deletion of these two DC subsets led to a significant decrease in the induction of PR8 HA and SARS-CoV-2 RBD-specific Tfh cell and humoral immune responses. Despite these observed defects, these mice remained protected from lethal influenza and SARS-CoV-2 challenges. We further found that IL-6, unlike neutrophils, was required to generate normal Tfh cells and antibody responses, but not for protection from influenza challenge. In summary, here we bring evidence that the mRNA-LNP platform can support the induction of protective immune responses in the absence of certain innate immune cells and cytokines.
Correlation between vaccine coverage and the COVID‐19 pandemic throughout the world: Based on real‐world data

The aim of the study was to examine the correlation between COVID‐19 vaccine coverage rates and outcomes of the COVID‐19 epidemic in the case of COVID‐19 variants based on real‐world data. The data came from Our World in Data, which is building the international COVID‐19 vaccination data set and is an open‐source data set for everyone to use. The vaccination data set uses the most recent official numbers from governments and health ministries worldwide. We assessed the correlation between COVID‐19 vaccine coverage rates and outcomes of the COVID‐19 epidemic with existing variants by performing temporal analysis and spatial analysis. Overall, new cases per million population, the reproduction rate of COVID‐19, new deaths from all causes per million population, excess mortality attributed to COVID‐19 pandemic, and hospital patients or intensive care unit (ICU) patients per million population were not decreased with the time course. However, at the same time point, new cases per million population, the reproduction rate of COVID‐19, new deaths per million population, and hospital patients or ICU patients per million population gradually decreased as the rate of vaccination coverage increased. High coverage percentages of COVID‐19 vaccination were negatively correlated with the reproduction rate of COVID‐19 (correlation coefficient −0.116) and ICU patients per million of the local population (correlation coefficient −0.055). Currently, there is no effective treatment for the COVID‐19 pandemic, and prevention of the COVID‐19 pandemic mainly depends on vaccines, especially when the rate of COVID‐19 vaccine coverage is over 60%. The benefits of preventing severe disease and preventing transmission of infection are likely to be obvious.