Miracle-dz/UniFAR-FTUs huggingface dataset:
Impact of a Faulty Germinal Center Reaction on the Pathogenesis of Primary Diffuse Large B Cell Lymphoma of the Central Nervous System

Simple Summary The pathogenetic mechanisms and peculiar tropism of primary CNS lymphoma (PCNSL) of the central nervous system (CNS) have been the subject of debate for decades. Hypothesis-driven targeted molecular studies have revealed that PCNSLs derived from self-/polyreactive B cells that have escaped developmental control mechanisms. The early acquisition of activating mutations targeting the B cell receptor pathway provides a survival advantage. The failure of the germinal center (GC) reaction and its checkpoints increases tumor B cell affinity for the CNS. During this faulty GC reaction, PCNSL tumor cells acquire further oncogenic alterations converging on the Toll-like receptor, B cell receptor, and NF-κB pathway. These activated pathways sustain proliferation. Concomitantly, cells become unable to complete terminal B cell differentiation, becoming trapped within the vicious cycle of the GC reaction as low-affinity IgM+ B cells related to memory cells. Abstract Primary lymphoma of the central nervous system (PCNSL, CNS) is a specific diffuse large B cell lymphoma (DLBCL) entity confined to the CNS. Key to its pathogenesis is a failure of B cell differentiation and a lack of appropriate control at differentiation stages before entrance and within the germinal center (GC). Self-/polyreactive B cells rescued from apoptosis by MYD88 and/or CD79B mutations accumulate a high load of somatic mutations in their rearranged immunoglobulin (IG) genes, with ongoing somatic hypermutation (SHM). Furthermore, the targeting of oncogenes by aberrant SHM (e.g., PIM1, PAX5, RHOH, MYC, BTG2, KLHL14, SUSD2), translocations of the IG and BCL6 genes, and genomic instability (e.g., gains of 18q21; losses of 9p21, 8q12, 6q21) occur in these cells in the course of their malignant transformation. Activated Toll-like receptor, B cell receptor (BCR), and NF-κB signaling pathways foster lymphoma cell proliferation. Hence, tumor cells are arrested in a late B cell differentiation stage, corresponding to late GC exit B cells, which are genetically related to IgM+ memory cells. Paradoxically, the GC reaction increases self-/polyreactivity, yielding increased tumor BCR reactivity for multiple CNS proteins, which likely contributes to CNS tropism of the lymphoma. The loss of MHC class I antigen expression supports tumor cell immune escape. Thus, specific and unique interactions of the tumor cells with resident CNS cells determine the hallmarks of PCNSL.
Maternal Phthalates Exposure and Blood Pressure during and after Pregnancy in the PROGRESS Study

Background: Phthalate exposure is ubiquitous and may affect biological pathways related to regulators of blood pressure. Given the profound changes in vasculature during pregnancy, pregnant women may be particularly susceptible to the potential effects of phthalates on blood pressure. Objectives: We examined associations of phthalate exposure during pregnancy with maternal blood pressure trajectories from mid-pregnancy through 72 months postpartum. Methods: Women with singleton pregnancies delivering a live birth in Mexico City were enrolled during the second trimester (n=892). Spot urine samples from the second and third trimesters were analyzed for 15 phthalate metabolites. Blood pressure and covariate data were collected over nine visits through 72 months postpartum. We used linear, logistic, and linear mixed models; latent class growth models (LCGMs); and Bayesian kernel machine regression to estimate the relationship of urinary phthalate biomarkers with maternal blood pressure. Results: As a joint mixture, phthalate biomarker concentrations during pregnancy were associated with higher blood pressure rise during mid-to-late gestation. With respect to individual biomarkers, second trimester concentrations of monobenzyl phthalate (MBzP) and di(2-ethylhexyl) phthalate biomarkers (ΣDEHP) were associated with higher third trimester blood pressure. Two trajectory classes were identified by LCGM, characterized by increasing blood pressure through 72 months postpartum (“increase–increase”) or decreased blood pressure through 18 months postpartum with a gradual increase thereafter (“decrease–increase”). Increasing exposure to phthalate mixtures during pregnancy was associated with higher odds of being in the increase–increase class. Similar associations were observed for mono-2-ethyl-5-carboxypentyl terephthalate (MECPTP) and dibutyl phthalate (ΣDBP) biomarkers. When specific time periods were examined, we observed specific temporal relationships were observed for ΣDEHP, MECPTP, MBzP, and ΣDBP. Discussion: In our cohort of pregnant women from Mexico City, exposure to phthalates and phthalate biomarkers was associated with higher blood pressure during late pregnancy, as well as with long-term changes in blood pressure trajectories. https://doi.org/10.1289/EHP8562
Inhaled ciprofloxacin-loaded poly(2-ethyl-2-oxazoline) nanoparticles from dry powder inhaler formulation for the potential treatment of lower respiratory tract infections

Lower respiratory tract infections (LRTIs) are one of the fatal diseases of the lungs that have severe impacts on public health and the global economy. The currently available antibiotics administered orally for the treatment of LRTIs need high doses with frequent administration and cause dose-related adverse effects. To overcome this problem, we investigated the development of ciprofloxacin (CIP) loaded poly(2-ethyl-2-oxazoline) (PEtOx) nanoparticles (NPs) for potential pulmonary delivery from dry powder inhaler (DPI) formulations against LRTIs. NPs were prepared using a straightforward co-assembly reaction carried out by the intermolecular hydrogen bonding among PEtOx, tannic acid (TA), and CIP. The prepared NPs were characterized by scanning electron microscopy (SEM), dynamic light scattering (DLS), Fourier transform infrared spectroscopy (FTIR), powder X-ray diffraction analysis (PXRD), differential scanning calorimetry (DSC), and thermogravimetric analysis (TGA). The CIP was determined by validated HPLC and UV spectrophotometry methods. The CIP loading into the PEtOx was between 21–67% and increased loading was observed with the increasing concentration of CIP. The NP sizes of PEtOx with or without drug loading were between 196–350 nm and increased with increasing drug loading. The in vitro CIP release showed the maximum cumulative release of about 78% in 168 h with a burst release of 50% in the first 12 h. The kinetics of CIP release from NPs followed non-Fickian or anomalous transport thus suggesting the drug release was regulated by both diffusion and polymer degradation. The in vitro aerosolization study carried out using a Twin Stage Impinger (TSI) at 60 L/min air flow showed the fine particle fraction (FPF) between 34.4% and 40.8%. The FPF was increased with increased drug loading. The outcome of this study revealed the potential of the polymer PEtOx as a carrier for developing CIP-loaded PEtOx NPs as DPI formulation for pulmonary delivery against LRTIs.
Effects of Self-Esteem on Self-Viewing: An Eye-Tracking Investigation on Mirror Gazing

While some people enjoy looking at their faces in the mirror, others experience emotional distress. Despite these individual differences concerning self-viewing in the mirror, systematic investigations on this topic have not been conducted so far. The present eye-tracking study examined whether personality traits (self-esteem, narcissism propensity, self-disgust) are associated with gaze behavior (gaze duration, fixation count) during free mirror viewing of one’s face. Sixty-eight adults (mean age = 23.5 years; 39 females, 29 males) viewed their faces in the mirror and watched a video of an unknown person matched for gender and age (control condition) for 90 s each. The computed regression analysis showed that higher self-esteem was associated with a shorter gaze duration for both self-face and other-face. This effect may reflect a less critical evaluation of the faces.
Role of Intestinal Alkaline Phosphatase in Innate Immunity

Intestinal alkaline phosphatase (IAP) is a multi-functional protein that has been demonstrated to primarily protect the gut. The role of IAP in maintaining intestinal homeostasis is underscored by the observation that IAP expression is defective in many gastrointestinal-related disorders such as inflammatory bowel disease IBD, necrotizing enterocolitis, and metabolic syndrome and that exogenous IAP supplementation improves the outcomes associated with these disorders. Additionally, studies using transgenic IAP-knock out (IAP-KO) mouse models further support the importance of the defensive role of IAP in the intestine. Supplementation of exogenous IAP and cellular overexpression of IAP have also been used in vitro to dissect out the downstream mechanisms of this protein in mammalian cell lines. Some of the innate immune functions of IAP include lipopolysaccharide (LPS) detoxification, protection of gut barrier integrity, regulation of gut microbial communities and its anti-inflammatory roles. A novel function of IAP recently identified is the induction of autophagy. Due to its critical role in the gut physiology and its excellent safety profile, IAP has been used in phase 2a clinical trials for treating conditions such as sepsis-associated acute kidney injury. Many excellent reviews discuss the role of IAP in physiology and pathophysiology and here we extend these to include recent updates on this important host defense protein and discuss its role in innate immunity via its effects on bacteria as well as on host cells. We will also discuss the relationship between IAP and autophagy and how these two pathways may act in concert to protect the gut.
Long-Term Treatment with Atypical Antipsychotic Iloperidone Modulates Cytochrome P450 2D (CYP2D) Expression and Activity in the Liver and Brain via Different Mechanisms

CYP2D enzymes engage in the synthesis of endogenous neuroactive substances (dopamine, serotonin) and in the metabolism of neurosteroids. The present work investigates the effect of iloperidone on CYP2D enzyme expression and activity in rat brains and livers. Iloperidone exerted a weak direct inhibitory effect on CYP2D activity in vitro in the liver and brain microsomes (Ki = 11.5 μM and Ki = 462 μM, respectively). However, a two-week treatment with iloperidone (1 mg/kg ip.) produced a significant decrease in the activity of liver CYP2D, which correlated positively with the reduced CYP2D1, CYP2D2 and CYP2D4 protein and mRNA levels. Like in the liver, iloperidone reduced CYP2D activity and protein levels in the frontal cortex and cerebellum but enhanced these levels in the nucleus accumbens, striatum and substantia nigra. Chronic iloperidone did not change the brain CYP2D4 mRNA levels, except in the striatum, where they were significantly increased. In conclusion, by affecting CYP2D activity in the brain, iloperidone may modify its pharmacological effect, via influencing the rate of dopamine and serotonin synthesis or the metabolism of neurosteroids. By elevating the CYP2D expression/activity in the substantia nigra and striatum (i.e., in the dopaminergic nigrostriatal pathway), iloperidone may attenuate extrapyramidal symptoms, while by decreasing the CYP2D activity and metabolism of neurosteroiods in the frontal cortex and cerebellum, iloperidone can have beneficial effects in the treatment of schizophrenia. In the liver, pharmacokinetic interactions involving chronic iloperidone and CYP2D substrates are likely to occur.
Determining Immunoglobulin Content of Bovine Colostrum and Factors Affecting the Outcome: A Review

Simple Summary Colostrum management plays an essential role in calf husbandry and strongly influences the calf. The immunoglobulin concentration denominates the quality of the colostrum, which is influenced by numerous factors. Therefore, the measurement of the immunoglobulin concentration is important. This review provides an overview of measurement methods for estimating the immunoglobulin concentration in bovine colostrum. In addition, influencing factors are identified and their impact on the immunoglobulin concentration is discussed. Radial immunodiffusion and the Enzyme-linked immunosorbent assay are the most commonly used direct measurement methods. A refractometer and a colostrometer are practical indirect on-farm instruments that can be used to estimate the immunoglobulin concentration. External characteristics such as viscosity or color allow for an initial assessment but are too inaccurate. Animal-related factors such as colostrum yield, parity, and breed influence the immunoglobulin concentration. In addition, environmental factors are also important. The duration between birth and first feeding postpartum is important for the supply of colostrum with a sufficient immunoglobulin concentration. The influence of treatment methods such as freezing and thawing, on the other hand, depends strongly on the procedure and does not necessarily lead to a reduction in the immunoglobulin concentration. The influencing factors are complex and newer ones, such as genetics, have not yet been sufficiently investigated. Abstract The immunoglobulin concentration in bovine colostrum should be measured to ensure feeding with sufficient immunoglobulins (≥50 mg immunoglobulin G mL−1). Adequate feeding prevents diseases, promotes development, and has a positive influence on the adult animal. Indirect and direct measurement methods are available for this purpose. Direct measurement methods cannot be easily used in practice; therefore, farmers use indirect methods such as a colostrometer and a refractometer. Many factors influence the immunoglobulin concentration of colostrum; some of them have already been intensively researched. In particular, lactation and temporal aspects play an essential role. Newer aspects such as dry period, seasonal influences, and genetics are gaining importance, but their impact on immunoglobulin content has not been sufficiently investigated. Developments are still needed, especially in data management. This review analyzes the outcome of different studies on the indirect and direct measurement methods and discusses different factors influencing the immunoglobulin concentration of bovine colostrum.
Chimeric Antigen Receptors Expand the Repertoire of Antigenic Macromolecules for Cellular Immunity

T-cell therapies have made significant improvements in cancer treatment over the last decade. One cellular therapy utilizing T-cells involves the use of a chimeric MHC-independent antigen-recognition receptor, typically referred to as a chimeric antigen receptor (CAR). CAR molecules, while mostly limited to the recognition of antigens on the surface of tumor cells, can also be utilized to exploit the diverse repertoire of macromolecules targetable by antibodies, which are incorporated into the CAR design. Leaning into this expansion of target macromolecules will enhance the diversity of antigens T-cells can target and may improve the tumor-specificity of CAR T-cell therapy. This review explores the types of macromolecules targetable by T-cells through endogenous and synthetic antigen-specific receptors.
Is There a Causal Link between the Left Lateralization of Language and Other Brain Asymmetries? A Review of Data Gathered in Patients with Focal Brain Lesions

This review evaluated if the hypothesis of a causal link between the left lateralization of language and other brain asymmetries could be supported by a careful review of data gathered in patients with unilateral brain lesions. In a short introduction a distinction was made between brain activities that could: (a) benefit from the shaping influences of language (such as the capacity to solve non-verbal cognitive tasks and the increased levels of consciousness and of intentionality); (b) be incompatible with the properties and the shaping activities of language (e.g., the relations between language and the automatic orienting of visual-spatial attention or between cognition and emotion) and (c) be more represented on the right hemisphere due to competition for cortical space. The correspondence between predictions based on the theoretical impact of language on other brain functions and data obtained in patients with lesions of the right and left hemisphere was then assessed. The reviewed data suggest that different kinds of hemispheric asymmetries observed in patients with unilateral brain lesions could be subsumed by common mechanisms, more or less directly linked to the left lateralization of language.
Epigenome-Wide Histone Acetylation Changes in Peripheral Blood Mononuclear Cells in Patients with Type 2 Diabetes and Atherosclerotic Disease

There is emerging evidence of an association between epigenetic modifications, glycemic control and atherosclerosis risk. In this study, we mapped genome-wide epigenetic changes in patients with type 2 diabetes (T2D) and advanced atherosclerotic disease. We performed chromatin immunoprecipitation sequencing (ChIP-seq) using a histone 3 lysine 9 acetylation (H3K9ac) mark in peripheral blood mononuclear cells from patients with atherosclerosis with T2D (n = 8) or without T2D (ND, n = 10). We mapped epigenome changes and identified 23,394 and 13,133 peaks in ND and T2D individuals, respectively. Out of all the peaks, 753 domains near the transcription start site (TSS) were unique to T2D. We found that T2D in atherosclerosis leads to an H3K9ac increase in 118, and loss in 63 genomic regions. Furthermore, we discovered an association between the genomic locations of significant H3K9ac changes with genetic variants identified in previous T2D GWAS. The transcription factor 7-like 2 (TCF7L2) rs7903146, together with several human leukocyte antigen (HLA) variants, were among the domains with the most dramatic changes of H3K9ac enrichments. Pathway analysis revealed multiple activated pathways involved in immunity, including type 1 diabetes. Our results present novel evidence on the interaction between genetics and epigenetics, as well as epigenetic changes related to immunity in patients with T2D and advanced atherosclerotic disease.
Experimental Applications and Factors Involved in Validating Thermal Windows Using Infrared Thermography to Assess the Health and Thermostability of Laboratory Animals

Simple Summary Laboratory animals are fundamental in biomedical science and monitoring their health and metabolic processes is essential to ensure their welfare and the quality of the research conducted. Infrared thermography (IRT) is a tool that can assess pathological or stressful states by measuring changes in the amount of heat that bodies dissipate. To date, some thermal windows have been utilized to evaluate animals’ thermoregulatory capacity, such as the orbital region, the auricle or ear pavilion region, the tail, and the interscapular zone where brown adipose tissue (BAT) is stored. However, the sensitivity and specificity of these windows are still subject to controversy because the scientific evidence that is available differs regarding the thermal information reported. Therefore, this paper aims to discuss the neurophysiological mechanisms of the vasomotor and thermogenesis responses (using BAT) in laboratory animals, the scientific usefulness of IRT, and the various thermal windows that are currently being used with laboratory animals. Abstract Evaluating laboratory animals’ health and thermostability are fundamental components of all experimental designs. Alterations in either one of these parameters have been shown to trigger physiological changes that can compromise the welfare of the species and the replicability and robustness of the results obtained. Due to the nature and complexity of evaluating and managing the species involved in research protocols, non-invasive tools such as infrared thermography (IRT) have been adopted to quantify these parameters without altering them or inducing stress responses in the animals. IRT technology makes it possible to quantify changes in surface temperatures that are derived from alterations in blood flow that can result from inflammatory, stressful, or pathological processes; changes can be measured in diverse regions, called thermal windows, according to their specific characteristics. The principal body regions that were employed for this purpose in laboratory animals were the orbital zone (regio orbitalis), auricular pavilion (regio auricularis), tail (cauda), and the interscapular area (regio scapularis). However, depending on the species and certain external factors, the sensitivity and specificity of these windows are still subject to controversy due to contradictory results published in the available literature. For these reasons, the objectives of the present review are to discuss the neurophysiological mechanisms involved in vasomotor responses and thermogenesis via BAT in laboratory animals and to evaluate the scientific usefulness of IRT and the thermal windows that are currently used in research involving laboratory animals.
Identification of Potential Prognostic and Predictive Immunological Biomarkers in Patients with Stage I and Stage III Non-Small Cell Lung Cancer (NSCLC): A Prospective Exploratory Study

Simple Summary Over the last 5 years, immune checkpoint inhibitors (ICIs) are increasingly used in the treatment of non-small cell lung cancer (NSCLC) as either monotherapy or in combination with chemo- and/or radiotherapy. However, despite these advances, outcome still remains poor for most patients and there is still a lot of room to improve prognosis in these patients. To date, we have no tools that allow us to identify the patients that will benefit from chemo- and/or radiotherapy combined with immunotherapy, what treatment-induced immune changes can be expected, and what are the most optimal treatment combinations. Therefore, prognostic and predictive immunological biomarkers are urgently needed. This prospective exploratory study aimed to identify potential prognostic and predictive immune-related proteins that are associated with progression-free survival in patients with stage I/III NSCLC. The results of this trial provide a good starting point to implement blood-based immune profiling analyses in future clinical trials. Abstract Radiotherapy (RT) and chemotherapy can induce immune responses, but not much is known regarding treatment-induced immune changes in patients. This exploratory study aimed to identify potential prognostic and predictive immune-related proteins associated with progression-free survival (PFS) in patients with non-small cell lung cancer (NSCLC). In this prospective study, patients with stage I NSCLC treated with stereotactic body radiation therapy (n = 26) and patients with stage III NSCLC treated with concurrent chemoradiotherapy (n = 18) were included. Blood samples were collected before (v1), during (v2), and after RT (v3). In patients with stage I NSCLC, CD244 (HR: 10.2, 95% CI: 1.8–57.4) was identified as a negative prognostic biomarker. In patients with stage III NSCLC, CR2 and IFNGR2 were identified as positive prognostic biomarkers (CR2, HR: 0.00, 95% CI: 0.00–0.12; IFNGR2, HR: 0.04, 95% CI: 0.00–0.46). In addition, analysis of the treatment-induced changes of circulating protein levels over time (Δv2/v3−v1) also identified CXCL10 and IL-10 as negative predictive biomarkers (CXCL10, HR: 3.86, 95% CI: 1.0–14.7; IL-10, HR: 16.92 (2.74–104.36)), although serum-induced interferon (IFN) response was a positive prognostic. In conclusion, we identified several circulating immunogenic proteins that are correlated with PFS in patients with stage I and stage III NSCLC before and during treatment.