High Mass Research Articles

Cancer-associated foam cells hamper protective T cell immunity and favor tumor progression in human colon carcinogenesis

BackgroundColorectal cancer (CRC) remains a significant healthcare burden worldwide, characterized by a complex interplay between obesity and chronic inflammation. While the relationship between CRC, obesity and altered lipid metabolism is...

Association Between Body Mass Index and Risk of Aortic Stenosis in Women in the Swedish Medical Birth Registry.

Overweight and obesity are increasing globally with aging, as are life expectancy and aging-associated disorders, including calcific aortic stenosis (AS). Studies investigating the correlation between high body mass index (BMI) and AS are contradictory and inconclusive. This study examines a potential association between BMI and AS in women. By linking the Swedish Medical Birth Register and the Swedish National Patient Register, we included women aged 18 to 55 years with a first childbirth from 1981 to 2020. Diagnosis of AS and comorbidities were defined according to the International Classification of Diseases (ICD) codes. The women were divided into groups on the basis of BMI. Cox proportional hazards regression models were used to investigate the difference in the risk of being diagnosed with AS, with reference BMI 20 to <22.5 kg/m2. Among the 1 722 625 included women, the mean age was 28 years, and mean BMI was 24 kg/m2, with 21% being overweight (BMI 25 to <30 kg/m2) and 8.5% obese (BMI ≥30 kg/m2). During median follow-up of 19.5 years, 2488 women (0.14%) were diagnosed with AS. The age-adjusted risk of being diagnosed with AS increased with higher BMI to 2.82 (95% CI, 2.44-3.25) times higher in women with BMI 30 to <35 kg/m2, and to 3.72 (95% CI, 2.95-4.70) times higher in those with BMI ≥35 kg/m2. Similar results were found after excluding AS of rheumatic pathogenesis. An increase in BMI from its upper normal range was consistently and independently associated with the risk of developing AS in women.

ToF-SIMS Investigation of Environmental Effects on Analyte Migration in Matrix Coatings for Mass Spectrometry Imaging Using a Newly Developed Vapor Deposition System.

High resolution mass spectrometry images are of increasing importance in biological applications, such as the study of tissues and single cells. Two promising techniques for this are matrix-enhanced secondary ion mass spectrometry (ME-SIMS) and matrix-assisted laser desorption/ionization (MALDI). For both techniques, the sample of interest must be coated with a matrix prior to analysis, and analytes must migrate into the matrix. The mechanisms involved in this migration and the factors that influence the migration are poorly understood, which lead to difficulties with reproducibility. In this work, a sublimation matrix coater with an effusion cell and sample cooling was developed and built in-house for controlled physical vapor deposition. In this system, sample transfer between the coater and mass spectrometer is possible without breaking vacuum, which facilitates the study of environmental influences on analyte migration. The influence of exposure to ambient air on the migration of two analytes (a lipid and a peptide), which were coated with the matrix α-cyano-4-hydroxycinnamic acid (CHCA), was studied using 3D-SIMS imaging. Although the distribution of analyte in the matrix changed very little after 21 h of storage in vacuum, significant redistribution of the analyte was observed after exposure to ambient air. The magnitude of the effect was greater for the lipid than for the peptide. Further work is needed to determine the role of humidity in the redistribution process and the impact of analyte redistribution on MALDI measurements.

Metabolomic profiling of human semen in patients with oligospermia using high performance liquid chromatography-tandem mass spectrometry

Male infertility is one of the most common reproductive dysfunctions. Despite oligospermia being a cause of infertility, few studies have been conducted on it. This study aimed to investigate differences in semen metabolic patterns in patients with oligospermia and to identify potential biomarkers associated with oligospermia. Semen samples from oligospermia patients (20 cases) and healthy controls (20 cases) were detected by high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS), and 72 and 89 metabolites were identified as potential markers in positive and negative ion modes, respectively. In addition, the results identified multiple metabolic pathways in patients with oligospermia, such as glycine serine and threonine metabolism, Synthesis and degradation of ketone bodies, Valine, leucine, and isoleucine degradation. These results described unique metabolic characteristics of semen in patients with oligospermia and provided novel insights into the mechanism of the semen disorder.

Mendelian randomization reveals that abnormal lipid metabolism mediates the causal relationship between body mass index and keratoconus

Previous studies suggest that a high body mass index (BMI) may be a risk factor for keratoconus (KC), but the causal relationship remains unclear. This study used Mendelian randomization (MR) to investigate this connection and explore the mediating role of circulating serum metabolites and inflammatory factors in this association. Two-sample MR analysis was conducted to assess the relationship between BMI and KC. The study employed a two-step MR approach to evaluate the mediating roles of 91 inflammatory markers and 249 serum metabolites in the BMI-KC relationship. Inverse variance weighting (IVW) was the primary method, and multiple sensitivity analyses were performed to ensure robustness. IVW analysis revealed a positive causal relationship between BMI and KC (OR IVW = 1.811, 95% CI 1.005–3.262, P = 0.048). Although IL-12β and IL-4 were causally associated with KC, they did not mediate the BMI-KC relationship. Five serum metabolites were identified as potential mediators, with HDL cholesterol and triglyceride ratios showing significance. This study clarified the causal relationship between high BMI and KC, suggesting that high BMI may induce KC through lipid metabolism abnormalities. These findings underscore the importance of managing BMI for KC prevention.

Highly reliable LC-MS lipidomics database for efficient human plasma profiling based on NIST SRM 1950

Liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS)-based methods have become the gold standard methodology for the comprehensive profiling of the human plasma lipidome. However, both the complexity of lipid chemistry and LC-HRMS-associated data pose challenges to the characterization of this biological matrix. In accordance with the current consensus of quality requirements for LC-HRMS lipidomics data, we aimed to characterize the NIST® Standard Reference Material for Human Plasma (SRM 1950) using an LC-ESI(+/–)-MS method compatible with high-throughput lipidome profiling. We generated a highly curated lipid database with increased coverage, quality, and consistency, including additional quality assurance procedures involving adduct formation, within-method m/z evaluation, retention behavior of species within lipid chain isomers, and expert-driven resolution of isomeric and isobaric interferences. As a proof-of-concept, we showed the utility of our in-house LC-MS lipidomic database –consisting of 592 lipid entries– for the fast, comprehensive, and reliable lipidomic profiling of the human plasma from healthy human volunteers. We are confident that the implementation of this robust resource and methodology will have a significant impact by reducing data redundancy and the current delays and bottlenecks in untargeted plasma lipidomic studies.

Impact of Laser Ablation Strategies on Electrochemical Performances of 3D Batteries Containing Aqueous Acid Processed Li(Ni0.6Mn0.2Co0.2)O2 Cathodes with High Mass Loading

Lithium-ion batteries are currently one of the most important energy storage devices for various applications. However, it remains a great challenge to achieve both high energy density and high-power density while reducing the production costs. Cells with three-dimensional electrodes realized by laser ablation are proven to have enhanced electrochemical performance compared to those with conventional two-dimensional electrodes, especially at fast charging/discharging. Nevertheless, laser structuring of electrodes is still limited in terms of achievable processing speed, and the upscaling of the laser structuring process is of great importance to gain a high technology readiness level. In the presented research, the impact of different laser structuring strategies on the electro-chemical performance was investigated on aqueous processed Li(Ni0.6Mn0.2Co0.2)O2 cathodes with acid addition during the slurry mixing process. Rate capability analyses of cells with laser structured aqueous processed electrodes exhibited enhanced performance with capacity increases of up to 60 mAh/g at high current density, while a 65% decrease in ionic resistance was observed for cells with laser structured electrodes. In addition, pouch cells with laser structured acid-added electrodes maintained 29–38% higher cell capacity after 500 cycles and their end-of-life was extended by a factor of about 4 in contrast to the reference cells with two-dimensional electrodes containing common organic solvent processed polyvinylidene fluoride binder.

Abnormal Relaxation Behavior of Excited Electrons in the Flat Band of Kagome Compound Nb3Cl8.

Carrier dynamics is crucial in semiconductors, and it determines their conductivity, response time, and overall functionality. In flat bands (FBs), carriers with high effective masses are predicted to host unconventional transport properties. The FBs usually overlap with other trivial energy bands, however, making it difficult to accurately distinguish their carrier dynamics. In this paper, we have investigated the flat-band carrier dynamics of excited electrons in Nb3Cl8, which hosts ideal nonoverlapping FBs near the Fermi level. The optical transition between Hubbard bands is abnormally weakened, exhibiting weak interband absorption and its related slow photoresponse with a time constant of ∼120 s, which are associated with flat-band Mottness-induced large electron effective mass and parity-forbidden transitions. Besides, the localized states created by chlorine vacancies also act as trapping centers for carriers with a time constant of ∼600 s, which are similar to those of the compact localized states of the FB, making the relaxation behavior even more extraordinary. The presence and impacts of atomic defects are confirmed experimentally and theoretically. This work has revealed the abnormal flat-band carrier dynamics of Nb3Cl8, which is essential for understanding the optical, electrical, and thermal transport properties of flat-band materials.

Hypopressive abdominal gymnastics protocol in postpartum women after cesarean section in the remote period: Preliminary case series

Background: The postpartum period is pronounced by important changes to return to the pre-pregnancy situation. During pregnancy, the recumbent muscles of the abdomen suffer withdrawal, characterizing diastasis of the rectus abdominis muscles (DRAM), and this condition may remain pathological postpartum. Hypopressive abdominal gymnastics (HAG) has a beneficial role in activating the abdominal muscles, presenting positive results in reducing DRAM. Objective: To describe the effect of a HAG protocol in postpartum women undergoing cesarean section in the remote period, comparing the inter-rectum distance (IRD) and abdominal circumference before and after applying the protocol. Methods: Case series quasi-experimental character involving participants had their IRD assessed using a portable ultrasound machine with a linear transducer and abdominal circumference measured using a flexible measuring tape. They received a HAG protocol, with nine postures, for three weeks, twice a week, totaling six sessions lasting 45 to 60 minutes each. After intervention, all participants were reevaluated using the same methods. Results: Four postpartum women participated. The largest point before intervention was the umbilical at rest. Both supraumbilical points analyzed obtained greater results in reducing IRD. Participant 001 achieved the greatest reduction in IRD after the protocol, as she had higher IRD values ​​during evaluation, in addition to a high body mass index (BMI) and a largest measurement of abdominal circumference. The measurement of abdominal circumference showed a change after HAG, reaching a reduction of 10 cm in one of the participants. Conclusion: This case series demonstrated positive results from the practice of HAG in reducing RAD, mainly supra-umbilical, and also in reducing abdominal circumference. Participants with higher BMI and waist circumference showed greater reductions in IRD.

Global burden of atrial fibrillation attributable to high body mass index from 1990 to 2021: findings from the Global Burden of Disease Study 2021.

To assess the global burden of atrial fibrillation (AF) attributable to high body mass index (BMI) from 1990 to 2021 and analyze its spatiotemporal distribution characteristics. An observational study based on GBD 2021 data. Data on AF burden due to high BMI were obtained from the Global Burden of Disease Study (GBD) 2021. Estimated annual percentage change (EAPC) was calculated to evaluate temporal trends in age-standardized rates of deaths and disability-adjusted life years (DALYs) over 30 years. In 2021, high BMI-related AF caused 27,000 deaths and 725,000 DALYs globally, a 376% increase since 1990. Females and the elderly (aged 70+) bore a higher burden. Upper-middle-income regions surpassed high-income regions in AF burden. Australasia had the highest age-standardized rates, while High-income Asia Pacific and South Asia had the lowest. South Asia showed rapid growth in age-standardized death rates. The global burden of high BMI-related AF varies across regions and time, threatening global health, especially for females and the elderly. Targeted strategies are needed to reduce AF and obesity.

Diabetes Risk Factors in People With HIV Receiving Pitavastatin Versus Placebo for Cardiovascular Disease Prevention : A Randomized Trial.

REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) led to new guidelines for statin use among people with HIV (PWH) with low to moderate risk for atherosclerotic cardiovascular disease (ASCVD). Little is known about the natural history of diabetes mellitus (DM) or mechanisms contributing to statin effects on DM among this population. To determine the contribution of known DM risk factors to excess risk for DM with pitavastatin in REPRIEVE. Phase 3, primary ASCVD prevention trial over a median of 5.6 years of follow-up. (ClinicalTrials.gov: NCT02344290). Global, multicenter trial. 7731 PWH aged 40 to 75 years with low to moderate ASCVD risk (by the pooled cohort equations from the American College of Cardiology and American Heart Association) without DM at study entry. Random 1:1 assignment to pitavastatin, 4 mg daily, or placebo. New-onset DM was determined at each visit by clinical diagnosis requiring initiation of medication treatment for DM. The incidence of new-onset DM was assessed in relation to predefined demographic and metabolic risk factors, stratified by treatment group. Treatment effects of pitavastatin on progression to new DM in key subgroups were determined. Participants with at least 3 DM risk factors (vs. no risk factors) had increased risk for DM in each treatment group (incidence rate, 3.24 per 100 person-years [PY] vs. 0.34 per 100 PY [pitavastatin] and 2.66 per 100 PY vs. 0.27 per 100 PY [placebo]). The incidence of DM was highest in South Asia. In adjusted analyses, high body mass index, prediabetes, and metabolic syndrome components were strongly associated with new-onset DM (all P < 0.005). Pitavastatin was the only statin assessed; DM was assessed clinically. Metabolic risk factors, including prediabetes and obesity, contributed to new-onset DM in statin- and placebo-treated participants. A clinically significant effect of pitavastatin on DM was seen primarily among those with multiple risk factors for DM at entry. Strategies targeting key metabolic risk factors, like obesity and prediabetes, may help protect against DM among PWH. National Heart, Lung, and Blood Institute of the National Institutes of Health.

The structure of massive star-forming galaxies from JWST and ALMA: Dusty, high-redshift disc galaxies

We present an analysis of the NIRCam and MIRI morphological and structural properties of 80 massive ($ (M_ M_ odot )$\,=\,11.2\,pm \,0.1) dusty star-forming galaxies at $, identified as sub-millimetre galaxies (SMGs) by ALMA, which have been observed as part of the PRIMER project. To compare the structure of these massive, active galaxies to more typical, less actively star-forming galaxies, we defined two comparison samples. The first of 850 field galaxies matched in specific star formation rate and redshift and the second of 80 field galaxies matched in stellar mass . From the visual classification of the SMGs, we have identified 20\,pm \,5&lt;!PCT!&gt; as candidate late-stage major mergers, a further 40\,pm \,10&lt;!PCT!&gt; as potential minor mergers, and 40\,pm \,10&lt;!PCT!&gt; that have comparatively undisturbed disc-like morphologies, with no obvious massive neighbours on lesssim \,20\,--\,30\,kpc (projected) scales. These rates are comparable to those for the field samples and indicate that the majority of the sub-millimetre-detected galaxies are not late-stage major mergers, but have interaction rates similar to the general field population at $z$\,sim \,2--3. Through a multi-wavelength morphological analysis, using parametric and non-parametric techniques, we establish that SMGs have comparable near-infrared, mass-normalised sizes to the less active population, $ F444W $\,=\,2.7\,pm \,0.2\,kpc versus $ F444W $\,=\,3.1\,pm \,0.1\,kpc, but exhibit lower S\'ersic indices, consistent with bulge-less discs: F444W $\,=\,1.1\,pm \,0.1, compared to F444W $\,=\,1.9\,pm \,0.1 for the less active field galaxies and $n_ F444W $\,=\,2.8\,pm \,0.2 for the most massive field galaxies . The SMGs exhibit greater single-S\'ersic fit residuals and their morphologies are more structured at 2 relative to 4 when compared to the field galaxies. This appears to be caused by significant structured dust content in the SMGs and we find evidence for dust reddening as the origin of the morphological differences by identifying a strong correlation between the F200W$-$F444W pixel colour and the 870 surface brightness using high-resolution ALMA observations. We conclude that SMGs and both massive and less massive star-forming galaxies at the same epochs share a common disc-like structure, but the weaker bulge components (and potentially lower black hole masses) of the SMGs result in their gas discs being less stable. Consequently, the combination of high gas masses and instabilities triggered either secularly or by minor external perturbations results in higher levels of activity (and dust content) in SMGs compared to typical star-forming galaxies.

3D Tunnel Copper Tetrathiovanadate Nanocube Cathode Achieving Ultrafast Magnesium Storage Reactions through a Charge Delocalization and Displacement Mechanism.

Rechargeable magnesium batteries are attractive candidates for large-scale energy storage applications because of the low cost and high safety, but the scarcity and inferior performance of the cathode materials are hindering the development. In the present study, a kind of copper tetrathiovanadate (Cu3VS4) cathode is designed and developed with a comprehensive consideration of the chemical and electronic structures. The vanadium and sulfur atoms form chemical bonds with high covalent proportion, facilitating electron delocalization via the vanadium-sulfur bonds. This reduces the interaction with the bivalent magnesium cation and induces the coredox of vanadium and sulfur. The crystal structure of Cu3VS4 has interlaced 3D tunnels for solid-state magnesium cation transport. The Cu3VS4 cathode shows a high capacity of 350 mA h g-1 at 100 mA g-1, an outstanding rate performance of 67 mA h g-1 at 10 A g-1, and stable cycling for 1000 cycles at 5 A g-1 without obvious capacity fading. Prominently, a high areal mass load of 3.5 mg cm-2 could be achieved without obvious rate capability decay, which is quite favorable to pair with the high-capacity magnesium metal anode in practical application. The mechanism investigation and theoretical computation demonstrate that Cu3VS4 undergoes first a magnesium intercalation and then a displacement reaction, during which the crystal structure is maintained, assisting the reaction reversibility and cycling stability. All the copper, vanadium, and sulfur elements experience redox and contribute to the high capacity. Moreover, the weakened interaction with magnesium cations, well-kept 3D cation transport tunnels, and high electronic conductivity result in the superior rate performance and high areal active material loading. The present study develops a high-performance cathode for rechargeable magnesium batteries and reveal the design principle based on both of chemical and electronic structures.

A-SLOTH reveals the nature of the first stars

Abstract The first generation of stars (Pop III) are too dim to be observed directly and probably too short-lived to have survived for local observations. Hence, we rely on simulations and indirect observations to constrain the nature of the first stars. In this study, we calibrate the semi-analytical model a-sloth (Ancient Stars and Local Observables by Tracing Halos), designed for simulating star formation in the early Universe, using a likelihood function based on nine independent observables. These observables span Milky Way-specific and cosmologically representative variables, ensuring a comprehensive calibration process. This calibration methodology ensures that a-sloth provides a robust representation of the early Universe’s star formation processes, aligning simulated values with observed benchmarks across a diverse set of parameters. The outcome of this calibration process is best-fit values and their uncertainties for 11 important parameters that describe star formation in the early Universe, such as the shape of the initial mass function (IMF) of Pop III stars or escape fractions of ionizing photons. Our best-fitting model has a Pop III IMF with a steeper slope, dN/dM∝M−1.77, than the log-flat models often proposed in the literature, and also relatively high minimum and maximum masses, Mmin = 13.6 M⊙ and Mmax = 197 M⊙. However, we emphasize that the IMF-generating parameters are poorly constrained and, e.g., the IMF slope could vary from log-flat to Salpeter. We also provide data products, such as delay time distribution, bubble size distributions for ionizing and metal-enriched bubbles at high redshift, and correlation plots between all 11 input parameters. Our study contributes to understanding the formation of early stars through a-sloth, providing valuable insights into the nature of Pop III stars and the intricate processes involved in the early Universe’s star formation.

Hunting for Bileptons at Hadron Colliders

I review possible signals at hadron colliders of bileptons, namely doubly charged vectors or scalars with lepton number L=±2, as predicted by a 331 model, based on a SU(3)c×SU(3)L×U(1)X symmetry. In particular, I account for a version of the 331 model wherein the embedding of the hypercharge is obtained with the addition of three exotic quarks and vector bileptons. Furthermore, a sextet of SU(3)L, necessary to provide masses to leptons, yields an extra scalar sector, including a doubly charged Higgs, i.e., scalar bileptons. As bileptons are mostly produced in pairs at hadron colliders, their main signal is provided by two same-sign lepton pairs at high invariant mass. Nevertheless, they can also decay according to non-leptonic modes, such as a TeV-scale heavy quark, charged 4/3 or 5/3, plus a Standard Model quark. I explore both leptonic and non-leptonic decays and the sensitivity to the processes of the present and future hadron colliders.

z ∼ 2 dual AGN host galaxies are disky: stellar kinematics in the ASTRID Simulation

We study dual AGN host galaxy morphologies at z=2 using the ASTRID simulation, selecting black hole (BH) pairs with small separation (), high mass ( MBH,12&gt;107M⊙), and luminosity (). We kinematically decompose (using MORDOR) ∼1000 dual AGN hosts into standard components - a ‘disk’ (thin and thick disk, pseudo-bulge) and ‘bulge’ (bulge and halo) and define disk-dominated galaxies by the disk-to-total D/T≥0.5. In ASTRID, 60.9±2.1% of dual AGN hosts (independent of separation) are disk-dominated, with the D/T distribution peaking at ∼0.7. In dual-AGN hosts, the D/T increases from $17% $ at to $ 64% $ for , and the pseudo-bulge is the dominant component of the disk fraction at the high mass end. Moreover, dual AGN hosts exhibit a higher fraction of disk/large pseudo-bulge than single-AGN hosts. The Disk-to-Total ratio is approximately constant with BH mass or AGN luminosity. We also create mock images of dual AGN host galaxies, employing morphological fitting software Statmorph to calculate morphological parameters and compare them with our kinematic decomposition results. Around 83.3±2.4% of galaxies display disk-like profiles, of which ∼60.7±2.2% are kinematically confirmed as disks. Se'rsic indices and half-mass radii of dual AGN host galaxies align with observational measurements from HST at z∼2. Around 34% are identified as mergers from the Gini−M20 relation. We find two dual AGN hosted by galaxies that exhibit disk-like se'rsic index n12&lt;1 and (D/T)12&gt;0.5, which are in remarkable agreement with properties of recently discovered dual quasars in disk galaxies at z∼2.

A randomized phase I study of BI 1820237, a novel neuropeptide Y receptor type 2 agonist, alone or in combination with low-dose liraglutide in otherwise healthy men with overweight or obesity.

Pharmacotherapeutic options for obesity treatment include glucagon-like peptide-1 receptor (GLP-1R) agonists, for example, liraglutide. However, an unmet need remains, particularly in patients with a high body mass index (BMI), as GLP-1R agonists are associated with gastrointestinal adverse events (AEs) and some patients do not respond to treatment. Neuropeptide Y (NPY) and peptide YY bind G-protein-coupled Y receptors and represent attractive targets for modulating bodyweight. This first-in-human, three-part, partially blinded phase I study (NCT04903509) investigated the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of the peptidic NPY2R agonist BI 1820237, with/without low-dose liraglutide: part 1 (participants randomized to receive BI 1820237: 0.075-2.4 mg or placebo), part 2 (BI 1820237: 1.2 mg or placebo) and part 3 (BI 1820237: 0.025-1.2 mg + liraglutide 0.6 mg or placebo + liraglutide 0.6 mg). Primary endpoint is the proportion of participants with drug-related AEs. Secondary endpoints are tolerability, PK and PD. In total, 95 otherwise healthy men with increased BMI (25.0-34.9 kg/m2) were randomized. Drug-related AEs, mainly gastrointestinal events, were reported by 39.0% of participants (n = 23) in parts 1 + 2 and 30.6% of participants (n = 11) in part 3; one drug-related AE (11.1%, part 3) was reported in a participant receiving placebo with liraglutide. Post-dose paracetamol PK suggested that BI 1820237 and low-dose liraglutide exhibited additive effects on gastric emptying. BI 1820237 treatment was associated with transient nausea and vomiting at higher doses. No differences in tolerability were observed when combined with liraglutide; effects on gastric emptying appeared additive.

8528 An Unusual Case Of Adrenal Hemorrhage As An Initial Manifestation Of Castleman Disease In A 29 yo Male With Unsuspected Late-Onset Congenital Adrenal Hyperplasia

Abstract Disclosure: L.M. Martel: None. F. Mercier: None. S. Parisien-La Salle: None. A. Lacroix: None. A. Liberman: None. N. Bettache: None. H. Olney: None. I. Bourdeau: None. Background: Castleman disease is a lymphoproliferative disorder with no clear etiology. We report the case of a 29 yo man presenting with an adrenal hemorrhage as initial manifestation of Castleman disease and unsuspected late-onset congenital adrenal hyperplasia. Clinical case: A 29-year-old male with no significant past medical history except for unilateral orchiectomy at 1 year-old for a possible testicular mass was referred to our adrenal clinic for a 6,2x7,5 cm left adrenal mass showing at CT scan necrosis and an hemorrhagic component (HU52). The patient presented initially with acute left abdominal pain. The adrenal mass showed at peripheral high uptake at PET-FDG (SUVmax 5,3) with no central uptake. His physical exam was unremarkable except for obesity. The hormonal work-up for the adrenal mass revealed normal metanephrines, and normal 1mg-dexamethasone suppression test with morning cortisol of 18 nmol/L (N&amp;lt;50). Further hormonal investigations based on the high adrenal mass uptake and possible adrenocortical carcinoma included: 17-OH Progesterone: 7.7 nmol/L (N:1.1-7.0), Androstenedione: 14.1 nmol/L (N: 1.5-9.0), Testosterone: 11.3 nmol/L (N: 9.0-28.3) and DHEAS: 3.6 umol/L (2.3-18.7). The ACTH levels were increased at 21.2 pmol/L (N:2-11) with morning cortisol of 220 nmol/L. During the consultation, the patient reported a pleuritic chest pain and underwent an urgent CT pulmonary angiography showing a pulmonary embolism with lung infarction in addition to mediastinal lymphadenopathy (biopsy negative) and a mass in his thymus. He underwent thymectomy and the pathology report described Castleman disease (hyaline vascular type). Taking into account the increased level of 17-OH progesterone, we performed an ACTH stimulation test (250 mcg) that showed an increase of cortisol levels from 333nmol/L to 874nmol/L at 60 minutes and of 17OH Progesterone levels from 5.2nmol/L to 44.2nmo/L excluding adrenal insufficiency, but confirming the diagnosis of late-onset congenital adrenal hyperplasia. Genetic analyses: After written consent, the patient underwent genetic analysis of the CYP21A2 gene by direct sequencing and MLPA. The analyses revealed a heterozygous pathogenic variant in the CYP21A2 gene (c.293-13A/C&amp;gt;G). No other genetic variant was identified in the gene. Follow-up: Subsequent adrenal MRIs showed decreasing size of the left adrenal mass; 3 cm at 3 months, 2 cm at 6 months and no residual mass was seen at 9 months supporting the diagnosis of adrenal hemorrhage. Conclusion: To our knowledge, we report a first case of Castleman disease presenting with adrenal hemorrhage as initial symptom with the association of late-onset congenital adrenal hyperplasia. The possible link between these diseases remains to be explored. Presentation: 6/3/2024

12538 Blocking Oxidized Phospholipids Improves Bone Mass In Mice By Transcriptional Reprogramming Of Osteoblastic Cells: Analysis At The Single Cell Level

Abstract Disclosure: M. Palmieri: None. I. Nookaew: None. M. Almeida: None. T.E. Joseph: None. C. O'Brien: None. E. Ambrogini: None. Oxidized phospholipids containing phosphatidylcholine (PC-OxPLs), present on oxidized low-density lipoproteins (OxLDL) and apoptotic cells, are pathogenic in many diseases, including osteoporosis. The E06 IgM antibody binds PC-OxPLs and blocks their adverse effects. In our studies, six-month-old female and male mice overexpressing a single chain (scFv) form of the antigen-binding domain of E06 IgM (E06-scFv) have high cancellous and cortical bone mass. In addition, E06-scFv transgenic mice are protected against high fat diet- and age-induced bone loss. E06-scFv increases osteoblast number, bone formation rate and reduces osteoblast apoptosis. To investigate the effect of E06-scFv on osteoblastic cells transcriptional reprogramming, we performed single cell RNA-sequencing (scRNA-seq) of mesenchymal cells from long bones of 6-months old WT and E06-scFv transgenic female and male mice. Based on the total of over 7,500 osteoblastic cells, we focused the analysis on 3 cell clusters, pre-osteoblasts, identified by high levels of osteopontin (Spp1), osteoblasts, identified by high expression of osteocalcin (Bglap) and adipo-CAR expressing the adipogenic marker Adipoq in addition to high expression of the stromal marker Cxcl12. In both males and female transgenic mice, the relative number osteoblasts increased [12.0 % in females and 23.7 % in males; conversely, the relative number of adipo-CAR cells decreased [18.2 % in females and 15.1 % in males] compared to WT. We performed the analysis of functional enrichment-based gene ontology by piano software package and found that, in the three clusters of both male and female transgenic mice, there was an upregulation of gene expression, with a range of 37-125 genes per cluster, related to extracellular matrix organization [p range 0.0003-3.95E-09], bone mineralization [p range 0.04-0.0022] and cell adhesion [p range 0.019-0.00008]. Consistent with these results, bulk RNA sequencing indicated that these ontology terms were downregulated in calvaria-derived osteoblasts treated with OxLDL [extracellular matrix organization p= 1.19E-13; bone mineralization p= 0.0018655; cell adhesion p= 2.73E-12]. Based on these results, we conclude that PC-OxPLs not only affect osteoblast number but also decrease osteoblast activity on a single cell basis. Presentation: 6/1/2024

Proteomic analysis and experimental validation reveal the blood–brain barrier protective of Huanshaodan in the treatment of SAMP8 mouse model of Alzheimer’s disease

BackgroundHuanshaodan (HSD) is a Chinese Herbal Compound which has a definite clinical effect on Alzheimer’s disease (AD), however, the underlying mechanism remains unclear. The aim of this study is to preliminarily reveal the mechanism of HSD in the treatment of AD model of SAMP8 mice.MethodsChemical composition of HSD and its drug-containing serum were identified by Q-Orbitrap high resolution liquid mass spectrometry. Six-month-old SAMP8 mice were treated with HSD and Donepezil hydrochloride by gavage for 2 months, and Wogonin for 28 days. Behavioral test was performed to test the learning and memory ability of mice. Immunofluorescence (IF) or Western-blot methods were used to detect the levels of pSer404-tau and β-amyloid (Aβ) in the brain of mice. Hematoxylin–eosin (H&E) staining and Transmission electron microscopy (TEM) assay was applied to observe the pathological changes of neurons. Proteomic technology was carried out to analyze and identify the protein network of HSD interventions in AD. Then the pathological process of the revealed AD-related differential proteins was investigated by IF, Q-PCR, Western-blot, Fluorescence in situ hybridization (FISH) and 16S rRNA sequencing methods.ResultsThe results showed that HSD and Wogonin, one of the components in its drug-containing serum, can effectively improve the cognitive impairments of SAMP8 mice, protect hippocampal neurons and synapses, and reduce the expression of pSer404-tau and Aβ. HSD and Wogonin reduced the levels of fibrinogen β chain (FGB) and γ chain (FGG), the potential therapeutic targets revealed by proteomics analysis, reduced the colocalization of FGB and FGG with Aβ, ionized calcium binding adaptor molecule 1 (Iba-1), glial fibrillary acidic protein (GFAP), increased level of and myelin basic protein (MBP). Meanwhile, HSD and Wogonin increased ZO-1 and Occludin levels, improved brain microvascular injury, and reduced levels of bacteria/bacterial DNA and lipopolysaccharide (LPS) in the brain of mice. In addition, 16S rRNA sequencing indicated that HSD regulated the structure of intestinal microbiota of mice.ConclusionThe effects of HSD on AD may be achieved by inhibiting the levels of fibrinogen and the interactions on glia cells in the brain, and by modulating the structure of intestinal microbiota and improving the blood–brain barrier function.