Miracle-dz/UniFAR-FTUs huggingface dataset:
High PD-L1/CD274 Expression of Monocytes and Blood Dendritic Cells Is a Risk Factor in Lung Cancer Patients Undergoing Treatment with PD1 Inhibitor Therapy

Simple Summary Tumor cells can evade destruction via immune cells by expressing coinhibitory membrane molecules, which suppress antitumoral immune responses. Immune checkpoint inhibitor therapy acts by blocking these inhibitory pathways. Although this type of immunotherapy has shown promising results for selected cancer patients during recent years, an important challenge remains to identify baseline characteristics of patients who will mostly benefit from such therapy. The aim of our study was to assess the expression of the coinhibitory molecule PD-L1/CD274 on different antigen-presenting cells (monocytes and dendritic cell subsets) in the peripheral blood of 35 patients with nonsmall cell lung cancer undergoing checkpoint inhibitor therapy. CD274 expression correlated with therapy response and the survival of patients. Tumor patients with high CD274 expression levels of antigen-presenting cells in blood rarely responded to checkpoint inhibitor therapy. Our results implicate that a high CD274 expression in monocytes and dendritic cell subsets is a risk factor for therapy response. Abstract The aim of this study was to investigate the expression of the coinhibitory molecule PD-L1/CD274 in monocytes and dendritic cells (DC) in the blood of lung cancer patients undergoing PD1 inhibitor therapy and to correlate data with patient’s outcome. PD-L1/CD274 expression of monocytes, CD1c+ myeloid DC (mDC) and CD303+ plasmacytoid DC (pDC) was determined by flow cytometry in peripheral blood at immunotherapy onset. The predictive value of the PD-L1/CD274-expression data was determined by patients’ survival analysis. Patients with a high PD-L1/CD274 expression of monocytes and blood DC subpopulations rarely responded to PD1 inhibitor therapy. Low PD-L1/CD274 expression of monocytes and DC correlated with prolonged progression-free survival (PFS) as well as overall survival (OS). The highest PD-L1/CD274 expression was found in CD14+HLA-DR++CD16+ intermediate monocytes. Whereas the PD-L1/CD274 expression of monocytes and DC showed a strong positive correlation, only the PD-L1/CD274 expression of DC inversely correlated with DC amounts and lymphocyte counts in peripheral blood. Our results implicate that a high PD-L1/CD274 expression of blood monocytes and DC subtypes is a risk factor for therapy response and for the survival of lung cancer patients undergoing PD1 inhibitor therapy.
Quantification of Receptor Occupancy by Ligand—An Understudied Class of Potential Biomarkers

Simple Summary Molecular complexes, such as those comprised of ligands such as hormones binding to their target receptors, are key determinants of health and disease. While research has focused on measuring receptors or ligands independently as biomarkers, very little attention has been given to measuring ligand-receptor complexes, in part, due to the limited availability of suitable technologies to do such measurements. This has led to underappreciation of ligand-receptor complexes as biomarkers in disease, including in cancer. In this commentary, the potential role of ligand-receptor complexes and their importance as biomarkers in cancer is discussed. We also describe a novel RNA aptamer-based technology, designated as ligand-receptor complex-binding aptamers (LIRECAP), that can provide precise measurement of the ligand occupancy of receptors and has potential use as a biomarker discovery platform. Abstract Molecular complexes, such as ligand–receptor complexes, are vital for both health and disease and can be shed into the circulation in soluble form. Relatively little is known about the biology of soluble ligand–receptor complexes. The functional importance of such complexes and their potential use as clinical biomarkers in diagnosis and therapy remains underappreciated. Most traditional technologies used to study ligand–receptor complexes measure the individual levels of soluble ligands or receptors rather than the complexes themselves. The fraction of receptors occupied by ligand, and the potential clinical relevance of such information, has been largely overlooked. Here, we review the biological significance of soluble ligand–receptor complexes with a specific focus on their potential as biomarkers of cancer and other inflammatory diseases. In addition, we discuss a novel RNA aptamer-based technology, designated ligand–receptor complex-binding aptamers (LIRECAP), that can provide precise measurement of the fraction of a soluble receptor occupied by its ligand. The potential applicability of the LIRECAP technology as a biomarker discovery platform is also described.
Characterization of the intestinal microbiota during Citrobacter rodentium infection in a mouse model of infection-triggered Parkinson’s disease

ABSTRACT Parkinson’s disease (PD) is a neurodegenerative disorder that has been shown to be influenced by the intestinal milieu. The gut microbiota is altered in PD patients, and murine studies have begun suggesting a causative role for the gut microbiota in progression of PD. We have previously shown that repeated infection with the intestinal murine pathogen Citrobacter rodentium resulted in the development of PD-like pathology in Pink1 −/- mice compared to wild-type littermates. This addendum aims to expand this work by characterizing the gut microbiota during C. rodentium infection in our Pink1 −/- PD model. We observed little disturbance to the fecal microbiota diversity both between infection timepoints and between Pink1 −/- and wild-type control littermates. However, the level of short-chain fatty acids appeared to be altered over the course of infection with butyric acid significantly increasing in Pink1 −/- mice and isobutyric acid increasing in wild-type mice.
Biofilms in Diabetic Foot Ulcers: Significance and Clinical Relevance

Foot infections are the main disabling complication in patients with diabetes mellitus. These infections can lead to lower-limb amputation, increasing mortality and decreasing the quality of life. Biofilm formation is an important pathophysiology step in diabetic foot ulcers (DFU)—it plays a main role in the disease progression and chronicity of the lesion, the development of antibiotic resistance, and makes wound healing difficult to treat. The main problem is the difficulty in distinguishing between infection and colonization in DFU. The bacteria present in DFU are organized into functionally equivalent pathogroups that allow for close interactions between the bacteria within the biofilm. Consequently, some bacterial species that alone would be considered non-pathogenic, or incapable of maintaining a chronic infection, could co-aggregate symbiotically in a pathogenic biofilm and act synergistically to cause a chronic infection. In this review, we discuss current knowledge on biofilm formation, its presence in DFU, how the diabetic environment affects biofilm formation and its regulation, and the clinical implications.
Comparison of histologic and cytologic specimens of urothelial carcinoma with image analysis. Implications for grading.

OBJECTIVE: To compare DNA results obtained by each of three preparation types (cytologic smears or cytocentrifuge samples, tissue sections and nuclei extracted from paraffin-embedded tissue) on patients with primary urothelial cell carcinoma of the bladder. STUDY DESIGN: Cases were selected for study based on the histologic diagnosis and the availability of corresponding bladder washing cytologic specimens. Five-micrometer sections and nuclear extracts were prepared from biopsies. DNA analysis was accomplished by use of an image cytometer on the Feulgen-stained material. RESULTS: DNA content results correlated with both histologic and cytologic grade. Using a binary classification system, bladder washings and thin tissue section results concurred in 40/43 patients. Nuclear extracts were performed on 27 of the biopsies. The DNA content determined by nuclear extract agreed with the tissue section results for all 27 biopsies. CONCLUSION: All three specimen preparations yield comparable DNA content results using a binary DNA classification scheme (diploid or aneuploid). Histologic grading can be enhanced with DNA content results, particularly in the heterogeneous, grade 2 group of urothelial carcinomas.
Determinants of Initial Public Offer (IPO) Pricing In The Nigerian Stock Exchange: Does Adoption of IFRS Matter?

The study investigates the effect of adoption of IFRS on asymmetric information and the implication on IPO pricing in Nigeria. 38 IPOs are included in the study between 2001 and 2016. The study investigated the influence of the asymmetric information both before and after the adoption of the IFRS. An extension of regression analysis called CHOW test is used to test the influence of the IFRS on asymmetric information and its influence of the IPO pricing in the Nigeria Stock exchange NSE. The results indicate that asymmetric information has significant impact on IPO pricing before and after the adoption of IFRS. However, it is also revealed in the study that adoption on IFRS made a significance difference on the effect of asymmetric information on the IPOs in Nigeria. The study further emphasized the need to reduce the flow of asymmetric information that increases the mispricing of the IPOs.
Sur l'origine du sang et des vaisseaux chez Lebistes reticulatus (Téléostéen)

Dans l9ensemble des Vertebres, l9ebauche du sang et des vaisseaux est constitutee par une portion du mesoblaste situee en contact avec l9entoblaste et a distance des grands organes axiaux. Qu9il s9agisse de l9ilot sanguin medio-ventral des formes holoblastiques si typique chez les Amphibiens, ou des ilots de Pander—Wolff extra-embryonnaires des formes teloblastiques, le lieu d9origine du sang et des vaisseaux se localise toujours aussi loin que possible des receptacles medio-dorsaux de substances morphogenetiquement actives, entre l9entoblaste et la splanchnopleure, Il est classiquement admis depuis les travaux de Swaen & Brachet (1899, 1901) que les Teleosteens forment une exception a cette regle generale. Dans leurs germes pourtant teloblastiques l9ebauche sanguine est en effet intra-embryonnaire et representee par la ‘masse intermediaire’, amas mesoblastique situe entre les somites et le bord median des lames laterales. Les observations que nous relatons ici montreront que cette regle n9est du moins pas aussi generale qu9on ne l9enonce habituellement.
Cortical dynamics of movement‐evoked pain in chronic low back pain

Cortical activity underlying movement‐evoked pain is not well understood, despite being a key symptom of chronic musculoskeletal pain. We combined high‐density electroencephalography with a full‐body reaching protocol in a virtual reality environment to assess cortical activity during movement‐evoked pain in chronic low back pain. Movement‐evoked pain in individuals with chronic low back pain was associated with longer reaction times, delayed peak velocity and greater movement variability. Movement‐evoked pain was associated with attenuated disinhibition in prefrontal motor areas, as evidenced by an attenuated reduction in beta power in the premotor cortex and supplementary motor area.
Gut–Brain Axis: Role of Gut Microbiota on Neurological Disorders and How Probiotics/Prebiotics Beneficially Modulate Microbial and Immune Pathways to Improve Brain Functions

The gut microbiome acts as an integral part of the gastrointestinal tract (GIT) that has the largest and vulnerable surface with desirable features to observe foods, nutrients, and environmental factors, as well as to differentiate commensals, invading pathogens, and others. It is well-known that the gut has a strong connection with the central nervous system (CNS) in the context of health and disease. A healthy gut with diverse microbes is vital for normal brain functions and emotional behaviors. In addition, the CNS controls most aspects of the GI physiology. The molecular interaction between the gut/microbiome and CNS is complex and bidirectional, ensuring the maintenance of gut homeostasis and proper digestion. Besides this, several mechanisms have been proposed, including endocrine, neuronal, toll-like receptor, and metabolites-dependent pathways. Changes in the bidirectional relationship between the GIT and CNS are linked with the pathogenesis of gastrointestinal and neurological disorders; therefore, the microbiota/gut-and-brain axis is an emerging and widely accepted concept. In this review, we summarize the recent findings supporting the role of the gut microbiota and immune system on the maintenance of brain functions and the development of neurological disorders. In addition, we highlight the recent advances in improving of neurological diseases by probiotics/prebiotics/synbiotics and fecal microbiota transplantation via the concept of the gut–brain axis.
Randomized Trial of 2 Delayed-Release Formulations of Linaclotide in Patients With Irritable Bowel Syndrome With Constipation

INTRODUCTION: Immediate-release (IR) formulation of linaclotide 290 μg improves abdominal pain and constipation (APC) in patients with irritable bowel syndrome (IBS) with constipation. Delayed-release (DR) formulations were developed on the premise that targeting the ileum (delayed-release formulation 1 [DR1]) or ileocecal junction and cecum (MD-7246, formerly DR2) would modulate linaclotide's secretory effects while preserving pain relief effects. METHODS: This phase 2b study randomized patients with IBS with constipation to placebo or 1 of 7 once-daily linaclotide doses (DR1 30, 100, or 300 μg; MD-7246 30, 100, or 300 μg; or IR 290 μg) for 12 weeks. Key efficacy endpoints were change from baseline in abdominal pain and complete spontaneous bowel movement frequency, and 6/12-week combined APC+1 responder rate. RESULTS: Overall, 532 patients were randomized; mean age was 45.1 years, and most were women (83.3%) and White (64.7%). All linaclotide DR1 and MD-7246 groups experienced greater improvements in abdominal pain from baseline and vs placebo throughout treatment. Linaclotide DR1 and IR led to numerically greater improvements from baseline in complete spontaneous bowel movement frequency and higher APC+1 responder rates compared with placebo; MD-7246 results were similar to placebo. Diarrhea was the most common adverse event with DR1 and IR; rates were similar between MD-7246 and placebo. DISCUSSION: Altering the site of drug delivery in the intestine might uncouple linaclotide's pain relief from secretory effects. Persistent, modest abdominal pain improvement with limited impact on bowel symptom parameters, as seen across MD-7246 doses, warrants further study of MD-7246 as a novel treatment for abdominal pain, regardless of IBS subtype.
Molecular Epidemiology of Carbapenemases in Enterobacteriales from Humans, Animals, Food and the Environment

The Enterobacteriales order consists of seven families including Enterobacteriaceae, Erwiniaceae, Pectobacteriaceae, Yersiniaceae, Hafniaceae, Morganellaceae, and Budviciaceae and 60 genera encompassing over 250 species. The Enterobacteriaceae is currently considered as the most taxonomically diverse among all seven recognized families. The emergence of carbapenem resistance (CR) in Enterobacteriaceae caused by hydrolytic enzymes called carbapenemases has become a major concern worldwide. Carbapenem-resistant Enterobacteriaceae (CRE) isolates have been reported not only in nosocomial and community-acquired pathogens but also in food-producing animals, companion animals, and the environment. The reported carbapenemases in Enterobacteriaceae from different sources belong to the Ambler class A (blaKPC), class B (blaIMP, blaVIM, blaNDM), and class D (blaOXA-48) β-lactamases. The carbapenem encoding genes are often located on plasmids or associated with various mobile genetic elements (MGEs) like transposons and integrons, which contribute significantly to their spread. These genes are most of the time associated with other antimicrobial resistance genes such as other β-lactamases, as well as aminoglycosides and fluoroquinolones resistance genes leading to multidrug resistance phenotypes. Control strategies to prevent infections due to CRE and their dissemination in human, animal and food have become necessary. Several factors involved in the emergence of CRE have been described. This review mainly focuses on the molecular epidemiology of carbapenemases in members of Enterobacteriaceae family from humans, animals, food and the environment.
Prevalence of ICU Delirium in Postoperative Pediatric Cardiac Surgery Patients.

OBJECTIVES The objective of this study was to determine the prevalence of ICU delirium in children less than 18 years old that underwent cardiac surgery within the last 30 days. The secondary aim of the study was to identify risk factors associated with ICU delirium in postoperative pediatric cardiac surgical patients. DESIGN A 1-day, multicenter point-prevalence study of delirium in pediatric postoperative cardiac surgery patients. SETTING Twenty-seven pediatric cardiac and general critical care units caring for postoperative pediatric cardiac surgery patients in North America. PATIENTS All children less than 18 years old hospitalized in the cardiac critical care units at 06:00 on a randomly selected, study day. INTERVENTIONS Eligible children were screened for delirium using the Cornell Assessment of Pediatric Delirium by the study team in collaboration with the bedside nurse. MEASUREMENT AND MAIN RESULTS Overall, 181 patients were enrolled and 40% (n = 73) screened positive for delirium. There were no statistically significant differences in patient demographic information, severity of defect or surgical procedure, past medical history, or postoperative day between patients screening positive or negative for delirium. Our bivariate analysis found those patients screening positive had a longer duration of mechanical ventilation (12.8 vs 5.1 d; p = 0.02); required more vasoactive support (55% vs 26%; p = 0.0009); and had a higher number of invasive catheters (4 vs 3 catheters; p = 0.001). Delirium-positive patients received more total opioid exposure (1.80 vs 0.36 mg/kg/d of morphine equivalents; p < 0.001), did not have an ambulation or physical therapy schedule (p = 0.02), had not been out of bed in the previous 24 hours (p < 0.0002), and parents were not at the bedside at time of data collection (p = 0.008). In the mixed-effects logistic regression analysis of modifiable risk factors, the following variables were associated with a positive delirium screen: 1) pain score, per point increase (odds ratio, 1.3; 1.06-1.60); 2) total opioid exposure, per mg/kg/d increase (odds ratio, 1.35; 1.06-1.73); 3) SBS less than 0 (odds ratio, 4.01; 1.21-13.27); 4) pain medication or sedative administered in the previous 4 hours (odds ratio, 3.49; 1.32-9.28); 5) no progressive physical therapy or ambulation schedule in their medical record (odds ratio, 4.40; 1.41-13.68); and 6) parents not at bedside at time of data collection (odds ratio, 2.31; 1.01-5.31). CONCLUSIONS We found delirium to be a common problem after cardiac surgery with several important modifiable risk factors.
Aberrant DNA Methylation of ABC Transporters in Cancer

ATP-binding cassette (ABC) transporters play a crucial role in multidrug resistance (MDR) of cancers. They function as efflux pumps, resulting in limited effectiveness or even failure of therapy. Increasing evidence suggests that ABC transporters are also involved in tumor initiation, progression, and metastasis. Tumors frequently show multiple genetic and epigenetic abnormalities, including changes in histone modification and DNA methylation. Alterations in the DNA methylation status of ABC transporters have been reported for a variety of cancer types. In this review, we outline the current knowledge of DNA methylation of ABC transporters in cancer. We give a brief introduction to structure, function, and gene regulation of ABC transporters that have already been investigated for their DNA methylation status in cancer. After giving an overview of the applied methodologies and the CpGs analyzed, we summarize and discuss the findings on aberrant DNA methylation of ABC transporters by cancer types. We conclude our review with the discussion of the potential to target aberrant DNA methylation of ABC transporters for cancer therapy.
Nanopharmaceuticals for Eye Administration: Sterilization, Depyrogenation and Clinical Applications

Simple Summary Nanopharmaceuticals have revolutionized the way ophthalmic drugs are administered to overcome ocular delivery barriers and improve drug bioavailability. The design and production of an efficient ocular drug delivery system still remain a challenge. In this review, we discuss the sterilization and depyrogenation methods, commonly used for ophthalmic nanopharmaceuticals, and their clinical applications. Abstract As an immune-privileged target organ, the eyes have important superficial and internal barriers, protecting them from physical and chemical damage from exogenous and/or endogenous origins that would cause injury to visual acuity or even vision loss. These anatomic, physiological and histologic barriers are thus a challenge for drug access and entry into the eye. Novel therapeutic concepts are highly desirable for eye treatment. The design of an efficient ocular drug delivery system still remains a challenge. Although nanotechnology may offer the ability to detect and treat eye diseases, successful treatment approaches are still in demand. The growing interest in nanopharmaceuticals offers the opportunity to improve ophthalmic treatments. Besides their size, which needs to be critically monitored, nanopharmaceuticals for ophthalmic applications have to be produced under sterilized conditions. In this work, we have revised the different sterilization and depyrogenation methods for ophthalmic nanopharmaceuticals with their merits and drawbacks. The paper also describes clinical sterilization of drugs and the outcomes of inappropriate practices, while recent applications of nanopharmaceuticals for ocular drug delivery are also addressed.
The effect of antiplatelet therapy on survival and cardiac allograft vasculopathy following heart transplantation: A systematic review and meta‐analysis

Cardiac allograft vasculopathy (CAV) is mediated by endothelial inflammation, platelet activation and thrombosis. Antiplatelet therapy may prevent the development of CAV. This systematic review and meta‐analysis summarizes and appraises the evidence on the effect of antiplatelet therapy after heart transplantation (HT). CENTRAL(Ovid), MEDLINE(Ovid), Embase(Ovid) were searched from inception until April 30, 2020. Outcomes included CAV, all‐cause mortality, and CAV‐related mortality. Data were pooled using random‐effects models. Seven observational studies including 2023 patients, mean age 52 years, 22% female, 47% with ischemic cardiomyopathy followed over a mean 7.1 years proved eligible. All studies compared acetylsalicylic acid (ASA) to no treatment and were at serious risk of bias. Data from 1911 patients in 6 studies were pooled in the meta‐analyses. The evidence is very uncertain about the effect of ASA on all‐cause or CAV‐related mortality. ASA may reduce the development of CAV (RR 0.75, 95% CI: 0.44–1.29) based on very low certainty evidence. Two studies that conducted propensity‐weighted analyses showed further reduction in CAV with ASA (HR 0.31, 95% CI: 0.13–0.74). In conclusion, there is limited evidence that ASA may reduce the development of CAV. Definitive resolution of the impact of antiplatelet therapy on CAV and mortality will require randomized clinical trials.