Therapeutic potential of ramipril, losartan, and spironolactone against sepsis-associated liver tissue injury induced by cecal ligation and puncture in rats.

OBJECTIVE: Sepsis-associated liver injury is responsible for the high morbidity and mortality rates seen with septic shock. Activation of the renin-angiotensin-aldosterone system (RAAS) is an essential counteractive mechanism during the hypotensive phase of sepsis; however, excessive activation is associated with exaggerated pro-oxidant and inflammatory response, which aggravates organ damage. This study aimed to evaluate the effect of RAAS inhibition on sepsis-induced liver damage. MATERIALS AND METHODS: The cecal ligation and puncture (CLP) model was employed as a model of sepsis. Rats were divided into five groups: sham-operated, vehicle-treated septic rats, septic rats treated with ramipril in a dose of 10 mg/kg, septic rats treated with losartan in a dose of 20 mg/kg, and finally septic rats treated with spironolactone in a dose of 25 mg/kg. Rats received the treatment one hour after induction. Twenty-four hours later, rats were euthanized, and serum samples and liver tissue were collected to evaluate liver function and hepatic oxidative, anti-oxidative, inflammatory, and apoptotic markers. The microscopic integrity of the hepatic tissue was also assessed. RESULTS: The results of our study showed that all the treatments used ameliorated sepsis-induced liver injury. This was reflected by improved liver function parameters and histopathological appearance of liver tissue. Treatment with ramipril, losartan, or spironolactone reduced tissue malondialdehyde (MDA), nitric oxide, activated caspase-3, and TNF-α. Moreover, these drugs increased hepatic reduced-glutathione (GSH) levels, superoxide dismutase (SOD) activity, and proliferating cell nuclear antigen (PCNA) expression. CONCLUSIONS: Administration of ramipril, losartan, or spironolactone after CLP produced a hepatoprotective effect in rats, possibly by reducing oxidative stress, inflammation, and apoptosis.

Feasibility of abdominal fat quantification on MRI and impact on effectiveness of abdominal compression for radiotherapy motion management.

The impact of fat on abdominal compression effectiveness in abdominal cancers was determined using magnetic resonance imaging (MRI). Visceral and subcutaneous fat were delineated on T2W 3D MRI, and motion change with compression was measured on 2D cine MRI. Results from 16 participants showed no correlation between fat percentage, body mass index (BMI), and motion change. Median BMI was 28.7 (SD, 4.9). Mean motion reduction was 7.8 mm (IQR, 5.0; p = 0.001) with compression. While no direct link was found between fat, BMI, and compression effectiveness, abdominal compression remains crucial for motion management in radiotherapy planning, providing dosimetric benefits.

The development and acceptability of an educational and training intervention for recruiters to neonatal trials: the TRAIN project.

BACKGROUND: Suboptimal or slow recruitment affects 30-50% of trials. Education and training of trial recruiters has been identified as one strategy for potentially boosting recruitment to randomised controlled trials (hereafter referred to as trials). The Training tRial recruiters, An educational INtervention (TRAIN) project was established to develop and assess the acceptability of an education and training intervention for recruiters to neonatal trials. In this paper, we report the development and acceptability of TRAIN. METHODS: TRAIN involved three sequential phases, with each phase contributing information to the subsequent phase(s). These phases were 1) evidence synthesis (systematic review of the effectiveness of training interventions and a content analysis of the format, content, and delivery of identified interventions), 2) intervention development using a Partnership (co-design/co-creation) approach, and 3) intervention acceptability assessments with recruiters to neonatal trials. RESULTS: TRAIN, accompanied by a comprehensive intervention manual, has been designed for online or in-person delivery. TRAIN can be offered to recruiters before trial recruitment begins or as refresher sessions during a trial. The intervention consists of five core learning outcomes which are addressed across three core training units. These units are the trial protocol (Unit 1, 50 min, trial-specific), understanding randomisation (Unit 2, 5 min, trial-generic) and approaching and engaging with parents (Unit 3, 70 min, trial-generic). Eleven recruiters to neonatal trials registered to attend the acceptability assessment training workshops, although only four took part. All four positively valued the training Units and resources for increasing recruiter preparedness, knowledge, and confidence. More flexibility in how the training is facilitated, however, was noted (e.g., training divided across two workshops of shorter duration). Units 2 and 3 were considered beneficial to incorporate into Good Clinical Practice Training or as part of induction training for new staff joining neonatal units. CONCLUSION: TRAIN offers a comprehensive co-produced training and education intervention for recruiters to neonatal trials. TRAIN was deemed acceptable, with minor modification, to neonatal trial recruiters. The small number of recruiters taking part in the acceptability assessment is a limitation. Scale-up of TRAIN with formal piloting and testing for effectiveness in a large cluster randomised trial is required.

Pregnenolone protects the liver against doxorubicin-induced cellular injury by anti-inflammatory, antioxidant, and antiapoptotic mechanisms: role of Keap1/Nrf2/HO-1 and P-glycoprotein.

OBJECTIVE: Doxorubicin (DOX) is a widely used cytotoxic anthracycline antibiotic characterized by increased adverse effects that limit its clinical usefulness. Pregnenolone is a pregnane X receptor (PXR) agonist that increases the expression of xenobiotic transporters with anti-inflammatory and antioxidant potential. Thus, we hypothesized that pregnenolone would protect against DOX-induced hepatotoxicity. MATERIALS AND METHODS: Male Wistar rats (180-200 g) were randomized into four groups (n = 7): Control, Control + Pregnenolone (35 mg/kg/day, orally), DOX (15 mg/kg, i.p.) single dose on day five, and Pregnenolone + DOX. All treatments continued for seven consecutive days. Twenty-four hours after the last treatment, serum and liver tissues were collected for biochemical and histopathological assessment. The possible interaction between pregnenolone and DOX on cell viability was tested in HepG2 cells in vitro by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RESULTS: DOX treatment resulted in hepatic damage and fibrosis with increased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST). Liver samples of the DOX-treated group showed increased oxidative stress [malondialdehyde (MDA) and total nitrite/nitrate and decreased reduced glutathione (GSH) and superoxide dismutase (SOD)], increased hepatic tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), transforming growth factor-beta1 (TGF-ß1), and mRNA of interleukin-1beta (IL-1ß) and interleukin-6 (IL-6). Pretreating the rats with pregnenolone antagonized these DOX-induced effects. Moreover, pregnenolone upregulated the hepatic expression of Nrf2, heme oxygenase-1 (HO-1), and P-glycoprotein and decreased Keap1, opposing the effects of DOX. Moreover, pregnenolone prevented the DOX-induced activation and nuclear translocation of NFκB and increased cleaved caspase-3. Pregnenolone potentiated DOX-mediated cytotoxicity in HepG2 cells. CONCLUSIONS: These results illustrate the protective effects of pregnenolone against DOX-induced hepatotoxicity without limiting its anticancer activity.

Venoms classification and therapeutic uses: a narrative review.

The mere glimpse of venomous animals has always terrified humans because of the devastating effects of their venoms. However, researchers across the globe have isolated therapeutically active ingredients from these venoms and continue to explore them for drug leads. These efforts lead to the discovery of therapeutic molecules that the US-FDA has approved to treat different diseases, such as hypertension (Captopril), chronic pain (Ziconotide), and diabetes (Exenatide). The main active constituents of most venoms are proteins and peptides, which gained more attention because of advancements in biotechnology and drug delivery. The utilization of newer screening approaches improved our understanding of the pharmacological complexity of venom constituents and facilitated the development of novel therapeutics. Currently, with many venom-derived peptides undergoing different phases of clinical trials, more are in pre-clinical drug development phases. This review highlights the various sources of venoms, their pharmacological actions, and the current developments in venom-based therapeutics.

Distinct and shared genetic architectures of Gestational diabetes mellitus and Type 2 Diabetes Mellitus.

Gestational diabetes mellitus (GDM) affects more than 16 million pregnancies annually worldwide and is related to an increased lifetime risk of Type 2 diabetes (T2D). The diseases are hypothesized to share a genetic predisposition, but there are few GWAS studies of GDM and none of them is sufficiently powered to assess whether any variants or biological pathways are specific to GDM. We conducted the largest genome-wide association study of GDM to date in 12,332 cases and 131,109 parous female controls in the FinnGen Study and identified 13 GDM-associated loci including 8 novel loci. Genetic features distinct from T2D were identified both at the locus and genomic scale. Our results suggest that the genetics of GDM risk falls into two distinct categories - one part conventional T2D polygenic risk and one part predominantly influencing mechanisms disrupted in pregnancy. Loci with GDM-predominant effects map to genes related to islet cells, central glucose homeostasis, steroidogenesis, and placental expression. These results pave the way for an improved biological understanding of GDM pathophysiology and its role in the development and course of T2D.

Mono- and biallelic variant effects on disease at biobank scale.

Identifying causal factors for Mendelian and common diseases is an ongoing challenge in medical genetics1. Population bottleneck events, such as those that occurred in the history of the Finnish population, enrich some homozygous variants to higher frequencies, which facilitates the identification of variants that cause diseases with recessive inheritance2,3. Here we examine the homozygous and heterozygous effects of 44,370 coding variants on 2,444 disease phenotypes using data from the nationwide electronic health records of 176,899 Finnish individuals. We find associations for homozygous genotypes across a broad spectrum of phenotypes, including known associations with retinal dystrophy and novel associations with adult-onset cataract and female infertility. Of the recessive disease associations that we identify, 13 out of 20 would have been missed by the additive model that is typically used in genome-wide association studies. We use these results to find many known Mendelian variants whose inheritance cannot be adequately described by a conventional definition of dominant or recessive. In particular, we find variants that are known to cause diseases with recessive inheritance with significant heterozygous phenotypic effects. Similarly, we find presumed benign variants with disease effects. Our results show how biobanks, particularly in founder populations, can broaden our understanding of complex dosage effects of Mendelian variants on disease.

Spacecraft sample collection and subsurface excavation of asteroid (101955) Bennu.

Carbonaceous asteroids, such as (101955) Bennu, preserve material from the early Solar System, including volatile compounds and organic molecules. We report spacecraft imaging and spectral data collected during and after retrieval of a sample from Bennu's surface. The sampling event mobilized rocks and dust into a debris plume, excavating a 9-meter-long elliptical crater. This exposed material is darker, spectrally redder, and more abundant in fine particulates than the original surface. The bulk density of the displaced subsurface material was 500 to 700 kilograms per cubic meter, which is about half that of the whole asteroid. Particulates that landed on instrument optics spectrally resemble aqueously altered carbonaceous meteorites. The spacecraft stored 250 ± 101 grams of material, which will be delivered to Earth in 2023.

Dysfunction of complement receptors CR3 (CD11b/18) and CR4 (CD11c/18) in pre-eclampsia: a genetic and functional study.

OBJECTIVE: To study genetic variants and their function within genes coding for complement receptors in pre-eclampsia. DESIGN: A case-control study. SETTING: Pre-eclampsia is a common vascular disease of pregnancy. The clearance of placenta-derived material is one of the functions of the complement system in pregnancy. POPULATION: We genotyped 500 women with pre-eclamptic pregnancies and 190 pregnant women without pre-eclampsia, as controls, from the FINNPEC cohort, and 122 women with pre-eclamptic pregnancies and 1905 controls from the national FINRISK cohort. METHODS: The functional consequences of genotypes discovered by targeted exomic sequencing were explored by analysing the binding of the main ligand iC3b to mutated CR3 or CR4, which were transiently expressed on the surface of COS-1 cells. MAIN OUTCOME MEASURES: Allele frequencies were compared between pre-eclamptic pregnancies and controls in genetic studies. The functional consequences of selected variants were measured by binding assays. RESULTS: The most significantly pre-eclampsia-linked CR3 variant M441K (P = 4.27E-4, OR = 1.401, 95% CI = 1.167-1.682) displayed a trend of increased adhesion to iC3b (P = 0.051). The CR4 variant A251T was found to enhance the adhesion of CR4 to iC3b, whereas W48R resulted in a decrease of the binding of CR4 to iC3b. CONCLUSIONS: Results suggest that changes in complement-facilitated phagocytosis are associated with pre-eclampsia. Further studies are needed to ascertain whether aberrant CR3 and CR4 activity leads to altered pro- and anti-inflammatory cytokine responses in individuals carrying the associated variants, and the role of these receptors in pre-eclampsia pathogenesis. TWEETABLE ABSTRACT: Genetic variants of complement receptors CR3 and CR4 have functional consequences that are associated with pre-eclampsia.

Bennu's near-Earth lifetime of 1.75 million years inferred from craters on its boulders.

An asteroid's history is determined in large part by its strength against collisions with other objects1,2 (impact strength). Laboratory experiments on centimetre-scale meteorites3 have been extrapolated and buttressed with numerical simulations to derive the impact strength at the asteroid scale4,5. In situ evidence of impacts on boulders on airless planetary bodies has come from Apollo lunar samples6 and images of the asteroid (25143) Itokawa7. It has not yet been possible, however, to assess directly the impact strength, and thus the absolute surface age, of the boulders that constitute the building blocks of a rubble-pile asteroid. Here we report an analysis of the size and depth of craters observed on boulders on the asteroid (101955) Bennu. We show that the impact strength of metre-sized boulders is 0.44 to 1.7 megapascals, which is low compared to that of solid terrestrial materials. We infer that Bennu's metre-sized boulders record its history of impact by millimetre- to centimetre-scale objects in near-Earth space. We conclude that this population of near-Earth impactors has a size frequency distribution similar to that of metre-scale bolides and originates from the asteroidal population. Our results indicate that Bennu has been dynamically decoupled from the main asteroid belt for 1.75 ± 0.75 million years.

Protective mechanisms of piperine against acetaminophen-induced hepatotoxicity may be mediated through TGFBRAP1.

OBJECTIVE: To investigate the possible protective mechanisms of piperine against acetaminophen (APAP)-induced hepatotoxicity in mice. MATERIALS AND METHODS: Mice were given APAP (650 mg/kg i.p. once) with or without pretreatment with piperine (50 mg/kg/day orally for 3 days). RESULTS: APAP caused liver toxicity as indicated by increased serum alanine aminotransferase and liver microscopic pathology, decreased hepatic superoxide dismutase and glutathione reductase activities, without affecting nuclear factor erythroid 2-related factor 2 (Nrf2) expression. APAP administration induced inflammation and apoptosis manifested as increased NF-κB p65 and dysregulation of caspase 3/Bcl2 expression, respectively. In addition, APAP increased the expression of transforming growth factor-ß receptor-associated binding protein 1 (TGFBRAP1). On the other hand, pretreatment with piperine improved liver function and structure, reserved hepatic antioxidative defense, and attenuated inflammatory and apoptotic markers. Interestingly, piperine administration enhanced hepatic TGFBRAP1 expression compared to APAP alone. CONCLUSIONS: The hepatoprotective effects of piperine against APAP are mediated via its antioxidant, anti-inflammatory, and anti-apoptotic effects, in addition to regulation of TGFBRAP1.

Asteroid (101955) Bennu's weak boulders and thermally anomalous equator.

Thermal inertia and surface roughness are proxies for the physical characteristics of planetary surfaces. Global maps of these two properties distinguish the boulder population on near-Earth asteroid (NEA) (101955) Bennu into two types that differ in strength, and both have lower thermal inertia than expected for boulders and meteorites. Neither has strongly temperature-dependent thermal properties. The weaker boulder type probably would not survive atmospheric entry and thus may not be represented in the meteorite collection. The maps also show a high-thermal inertia band at Bennu's equator, which might be explained by processes such as compaction or strength sorting during mass movement, but these explanations are not wholly consistent with other data. Our findings imply that other C-complex NEAs likely have boulders similar to those on Bennu rather than finer-particulate regoliths. A tentative correlation between albedo and thermal inertia of C-complex NEAs may be due to relative abundances of boulder types.

Heterogeneous mass distribution of the rubble-pile asteroid (101955) Bennu.

The gravity field of a small body provides insight into its internal mass distribution. We used two approaches to measure the gravity field of the rubble-pile asteroid (101955) Bennu: (i) tracking and modeling the spacecraft in orbit about the asteroid and (ii) tracking and modeling pebble-sized particles naturally ejected from Bennu's surface into sustained orbits. These approaches yield statistically consistent results up to degree and order 3, with the particle-based field being statistically significant up to degree and order 9. Comparisons with a constant-density shape model show that Bennu has a heterogeneous mass distribution. These deviations can be modeled with lower densities at Bennu's equatorial bulge and center. The lower-density equator is consistent with recent migration and redistribution of material. The lower-density center is consistent with a past period of rapid rotation, either from a previous Yarkovsky-O'Keefe-Radzievskii-Paddack cycle or arising during Bennu's accretion following the disruption of its parent body.

Hemispherical differences in the shape and topography of asteroid (101955) Bennu.

We investigate the shape of near-Earth asteroid (101955) Bennu by constructing a high-resolution (20 cm) global digital terrain model from laser altimeter data. By modeling the northern and southern hemispheres separately, we find that longitudinal ridges previously identified in the north extend into the south but are obscured there by surface material. In the south, more numerous large boulders effectively retain surface materials and imply a higher average strength at depth to support them. The north has fewer large boulders and more evidence of boulder dynamics (toppling and downslope movement) and surface flow. These factors result in Bennu's southern hemisphere being rounder and smoother, whereas its northern hemisphere has higher slopes and a less regular shape. We infer an originally asymmetric distribution of large boulders followed by a partial disruption, leading to wedge formation in Bennu's history.

Bright carbonate veins on asteroid (101955) Bennu: Implications for aqueous alteration history.

The composition of asteroids and their connection to meteorites provide insight into geologic processes that occurred in the early Solar System. We present spectra of the Nightingale crater region on near-Earth asteroid Bennu with a distinct infrared absorption around 3.4 micrometers. Corresponding images of boulders show centimeters-thick, roughly meter-long bright veins. We interpret the veins as being composed of carbonates, similar to those found in aqueously altered carbonaceous chondrite meteorites. If the veins on Bennu are carbonates, fluid flow and hydrothermal deposition on Bennu's parent body would have occurred on kilometer scales for thousands to millions of years. This suggests large-scale, open-system hydrothermal alteration of carbonaceous asteroids in the early Solar System.

Variations in color and reflectance on the surface of asteroid (101955) Bennu.

Visible-wavelength color and reflectance provide information about the geologic history of planetary surfaces. Here we present multispectral images (0.44 to 0.89 micrometers) of near-Earth asteroid (101955) Bennu. The surface has variable colors overlain on a moderately blue global terrain. Two primary boulder types are distinguishable by their reflectance and texture. Space weathering of Bennu surface materials does not simply progress from red to blue (or vice versa). Instead, freshly exposed, redder surfaces initially brighten in the near-ultraviolet region (i.e., become bluer at shorter wavelengths), then brighten in the visible to near-infrared region, leading to Bennu's moderately blue average color. Craters indicate that the time scale of these color changes is ~105 years. We attribute the reflectance and color variation to a combination of primordial heterogeneity and varying exposure ages.

Standardization in Quantitative Imaging: A Multicenter Comparison of Radiomic Features from Different Software Packages on Digital Reference Objects and Patient Data Sets.

Radiomic features are being increasingly studied for clinical applications. We aimed to assess the agreement among radiomic features when computed by several groups by using different software packages under very tightly controlled conditions, which included standardized feature definitions and common image data sets. Ten sites (9 from the NCI's Quantitative Imaging Network] positron emission tomography-computed tomography working group plus one site from outside that group) participated in this project. Nine common quantitative imaging features were selected for comparison including features that describe morphology, intensity, shape, and texture. The common image data sets were: three 3D digital reference objects (DROs) and 10 patient image scans from the Lung Image Database Consortium data set using a specific lesion in each scan. Each object (DRO or lesion) was accompanied by an already-defined volume of interest, from which the features were calculated. Feature values for each object (DRO or lesion) were reported. The coefficient of variation (CV), expressed as a percentage, was calculated across software packages for each feature on each object. Thirteen sets of results were obtained for the DROs and patient data sets. Five of the 9 features showed excellent agreement with CV < 1%; 1 feature had moderate agreement (CV < 10%), and 3 features had larger variations (CV ≥ 10%) even after attempts at harmonization of feature calculations. This work highlights the value of feature definition standardization as well as the need to further clarify definitions for some features.

Episodes of particle ejection from the surface of the active asteroid (101955) Bennu.

Active asteroids are those that show evidence of ongoing mass loss. We report repeated instances of particle ejection from the surface of (101955) Bennu, demonstrating that it is an active asteroid. The ejection events were imaged by the OSIRIS-REx (Origins, Spectral Interpretation, Resource Identification, and Security-Regolith Explorer) spacecraft. For the three largest observed events, we estimated the ejected particle velocities and sizes, event times, source regions, and energies. We also determined the trajectories and photometric properties of several gravitationally bound particles that orbited temporarily in the Bennu environment. We consider multiple hypotheses for the mechanisms that lead to particle ejection for the largest events, including rotational disruption, electrostatic lofting, ice sublimation, phyllosilicate dehydration, meteoroid impacts, thermal stress fracturing, and secondary impacts.

Intraoperative cone-beam CT spatial priors for diffuse optical fluorescence tomography.

A hybrid system for intraoperative cone-beam CT (CBCT) imaging and continuous-wave fluorescence tomography (FT) has been developed using an image-guidance framework. Intraoperative CBCT images with sub-millimeter spatial resolution are acquired with a flat-panel C-Arm. Tetrahedral meshes are generated from CBCT for finite element method implementation of diffuse optical tomography (NIRFAST). Structural data from CBCT is incorporated directly into the optical reconstruction process using Laplacian-type regularization ('soft spatial priors'). Experiments were performed using an in-house optical system designed for indocyanine green (ICG) fluorescence. A dynamic non-contact geometry was achieved using a stereoscopic optical tracker for real-time localization of a laser diode and CCD camera. Source and detector positions were projected onto the boundary elements of the tissue mesh using algorithms for ray-triangle intersection and camera lens calibration. Simulation studies showed the capabilities of a soft-prior approach, even in the presence of segmentation uncertainties. Experiments with ICG targets embedded in liquid phantoms determined the improvements in the quantification of the fluorophore yield, with errors of 85% and <20% for no priors and spatial priors, respectively. Similar results were observed with the ICG target embedded in ex vivo porcine loin, with errors of 52% and 12%, respectively. A proof-of-principal animal study was performed in a VX2-tumor in vivo rabbit model using liposomal nanoparticles co-encapsulating contrast for CT (iohexol) and fluorescence (ICG) imaging. Fusion of CBCT and FT reconstructions demonstrated concurrent anatomical and functional delineations of contrast enhancement around the periphery of the buccal tumor. These developments motivate future clinical translation of the FT system into an ongoing CBCT-guided head and neck surgery trial.