Development Of Disease Research Articles

Roles of noncoding RNA in allergic rhinitis.

Allergic rhinitis (AR) is one of the most common respiratory noninfectious diseases and chronic inflammatory diseases, the incidence of which has been increasing in recent years. The main pathological characteristics of AR are repeated inflammation, airway hyperreactivity, mucus hypersecretion, and reversible airway obstruction due to inflammatory cell response. AR occurrence is associated with various factors, including those of genetic and environmental origins. Noncoding RNAs (ncRNAs) are a group of RNA molecules that cannot be converted into polypeptides. The three main categories of ncRNAs include microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs). NcRNAs play a crucial role in controlling gene expression and contribute to the development of numerous human diseases. Articles are selected based on Pubmed's literature review and the author's personal knowledge. The largest and highest quality studies were included. The search selection is not standardized. Several recent studies have indicated the relationship of ncRNAs with the development of respiratory allergic diseases. NcRNAs, including miRNAs, lncRNAs, and circRNAs, are important gene expression regulatory factors. We review the expression and function of ncRNAs in AR, their role as disease biomarkers, and their prospective applicability in future research and clinically. We also discuss interactions between ncRNAs and their influence on AR comprehensively, these interactions are essential for determining the underlying pathological mechanisms further and discovering new drug therapeutic targets. NcRNAs can be used as biomarkers for early AR diagnosis, disease surveillance and prognosis assessment. Various categories of ncRNAs play distinct yet interconnected roles and actively contribute to intricate gene regulatory networks. They are also therapeutic targets and biomarkers in other allergic diseases. This article demonstrates ncRNAs have a wide range of applications in AR treatment. The database covers three key areas: miRNAs, lncRNAs, and circRNAs. Additionally, potential avenues for future research to facilitate the practical application of ncRNAs as therapeutic targets and biomarkers will be explore. With further research and technological development, ncRNAs may provide additional innovative, effective solutions for AR treatment.

NBCR-ac4C: A Deep Learning Framework Based on Multivariate BERT for Human mRNA N4-Acetylcytidine Sites Prediction.

N4-acetylcytidine (ac4C) plays a crucial role in regulating cellular biological processes, particularly in gene expression regulation and disease development. However, experiments to identify ac4C in a wet lab are time-consuming and costly, and the learning-based methods struggle to capture the underlying semantic knowledge and relations within sequences. To address this, we propose a deep learning approach called NBCR-ac4C based on pretrained models. Specifically, we employ Nucleotide Transformer and DNABERT2 to construct contextual embedding of nucleotide sequences, which effectively mine and express context relations between different features in the sequence. Convolutional neural network (CNN) and ResNet18 are then applied to further extract shallow and deep knowledge from context embedding. Depending on extensive experiments for the prediction of ac4C sites in nucleotide sequences, we observe that NBCR-ac4C outperforms general learning-based models. It achieves the highest accuracy (ACC) of 83.51% and an Area Under the Receiver Operating Characteristic Curve (AUROC) of 89.58% on an independent test set. Moreover, the proposed model, compared to the current state-of-the-art (SOTA) model LSA-ac4C, demonstrates higher ACC and AUROC by 0.81-3.7% and 0.05-1.58%, respectively. The data set and code are available on https://github.com/2103374200/NBCR to facilitate further discussion on NBCR-ac4C.

8626 Associations Between Low Serum Bilirubin Levels and the Progression of Diabetic Kidney Disease in Individuals with Type 2 Diabetes, Including Those in a Normoalbuminuric State

Abstract Disclosure: E. Kim: None. Y. Cho: None. O. Hong: None. K. Jo: None. J. Han: None. S. Moon: None. Objective: This study aimed to investigate the potential correlation between serum bilirubin levels and the progression of diabetic nephropathy, assessing whether low serum bilirubin levels are associated with a decline in renal function, while considering the baseline albumin excretion status. Methods: The longitudinal observation, spanning 11 years, involved 1167 Korean subjects aged 20 years or older, diagnosed with type 2 diabetes mellitus (T2DM), and having a baseline estimated glomerular filtration rate (eGFR) greater than 60 ml/min per 1.73 m2. Albuminuria was assessed by the 24-hour urinary albumin to creatinine excretion rate (ACR) and categorized into normoalbuminuria (ACR <30 mg/g), micro- or macroalbuminuria (ACR >300/g). Cox regression analysis was employed to explore connections between serum bilirubin levels and eGFR decline ≥40%, with adjustments for potential confounding variables. Results: Over a median follow-up of 8.2 years, 128 individuals experienced a decline in eGFR >40%. The hazard ratio (HR) of incident GFR decline was 1.72 (95% CI: 1.04-2.85, P=0.036) in the lowest total bilirubin (TB) tertile compared to the highest TB tertile after multivariable adjustment. When stratified by baseline albuminuria status, low bilirubin levels were significantly associated with eGFR decline, even in the normoalbuminuria group (HR: 2.21, 95% CI: 1.26-3.90, P=0.006), with a gradually increasing risk according to the absence of low TB levels and albuminuria (HR: 2.92, 95% CI: 1.65-5.19, P<0.001), and low TB levels and albuminuria (HR: 3.01, 95% CI: 1.65-5.46, P<0.001). Conclusion: Low serum TB levels are associated with an increased risk of rapid GFR decline in Korean patients with T2DM. Serum bilirubin levels may serve as a prognostic marker for the development and progression of diabetic kidney disease. Presentation: 6/1/2024

7190 Serum uric acid and serum uric acid-to-creatinine ratio and its association with metabolic syndrome in Korean adolescents: the nation-wide population-based study

Abstract Disclosure: S. Jung: None. J. Kim: None. S. Kim: None. Backgrounds: As the prevalence of obesity and metabolic syndrome (MetS) among the pediatric population continues to rise, it is crucial to identify the factors associated with cardiometabolic risk factors (CMRFs) to prevent the future development of diabetes and cardiovascular disease. Elevated serum uric acid (SUA) and SUA-to-creatine ratio (SUA/Cr) levels are associated with MetS, CMRFs, and non-alcoholic fatty liver disease (NAFLD) in adults. However, studies on the usefulness of SUA or SUA/Cr to predict MetS in adolescents were sparse. The aim of this study is to investigate the association between SUA or SUA/Cr level and MetS and CMRFs among Korean adolescents. Material/Methods: Data collected from the Korea National Health and Nutrition Examination Survey between 2016 and 2021, which was nationally representative cross-sectional data, were used. A total of 2,218 subjects (1,185 males, 54.0%) aged 13-18 years were included in this study. They were classified into tertiles of SUA or SUA/Cr levels (T1, lower tertile; T2, mid-tertile; and T3, upper tertile) according to sex. The prevalence of MetS and CMRFs, including alanine aminotransferase (ALT), was compared by tertiles of SUA. Results: The mean SUA and SUA/Cr was higher in males than females (6.37 ± 0.04 mg/dL and 4.66 ± 0.06 mg/dL, P < 0.001 for SUA; 7.90 ± 0.07 mg/dL and 7.30 ± 0.06 mg/dL, P < 0.001 for SUA/Cr). Z-scores of body mass index, waist circumference, waist-height ratio, levels of total cholesterol, triglyceride, and ALT were significantly higher in T3 of SUA and SUA/Cr in both sexes, while high-density lipoprotein cholesterol (HDL-C) was lower. In T3 of SUA and SUA/Cr, the prevalence and odds ratio (95% confidence interval) increased significantly in abdominal obesity [34.5%, 5.5 (4.0, 7.7) vs. 31.3%, 5.3 (3.7, 7.6)], elevated blood pressure [19.5%, 2.1 (1.5, 2.9) vs. 16.3% 1.6 (1.1, 2.2)], elevated triglyceride [29.5%, 2.1 (1.5, 2.8) vs. 27.9%, 2.1 (1.6, 2.8)], low HDL-C [22.5%, 3.4 (2.4, 5.0) vs. 20.2%, 2.6 (1.8, 3.9)], elevated ALT [31.5%, 5.7 (3.8, 8.6) vs. 19.1% 4.9 (3.2, 7.6)], obesity [33.6%, 7.6 (5.2, 11.2) vs. 25.9%, 6.0 (3.9, 9.1)] and MetS [13.7%, 7.4 (4.3, 13.0) vs. 10.8%, 6.8 (3.9, 9.1)], compared with T1 of SUA and SUA/Cr, respectively. In the receiver operating characteristic curve analysis, the area under the curve of predicting MetS was 0.681 for males and 0.823 for females using SUA and 0.653 for males and 0.840 for females using SUA/Cr. The proportion of participants with ≥ 3 CMRFs was 2.1% in T1, 3.5% in T2, and 13.7% in T3 in SUA (P < 0.001) and 2.1% in T1, 5.8% in T2, and 10.8% in T3 in SUA/Cr (P < 0.001). Conclusions: In this nationwide cross-sectional study, SUA and SUA/Cr levels are associated with MetS, its components, and the marker of NAFLD in Korean adolescents. SUA and SUA/Cr seem to be more specific in diagnosing MetS in female adolescents. Both SUA and SUA/Cr could be used as important markers to predict MetS in adolescents. Presentation: 6/1/2024

Comparison between statistical and machine learning methods to detect the hematological indices with the greatest influence on elevated serum levels of low-density lipoprotein cholesterol

IntroductionElevated levels of low-density lipoprotein-cholesterol (LDL-C) is a significant risk factor for the development of cardiovascular diseases (CVD)s. Furthermore, studies have revealed an association between indices of the complete blood count (CBC) and dyslipidemia. We aimed to investigate the relationship between CBC parameters and serum levels of LDL. MethodIn a prospective study involving 9704 participants aged 35–65 years, comprehensive screening was conducted to estimate LDL-C levels and CBC indicators. The association between these biomarkers and high LDL-C (LDL-C≥130 mg/dL (3.25 mmol/L)) was investigated using various analytical methods, including Logistic Regression (LR), Decision Tree (DT), Random Forest (RF), Neural Network (NN), and Support Vector Machine (SVM) methodologies. ResultThe present study found that age, hemoglobin (HGB), hematocrit (HCT), platelet count (PLT), lymphocyte (LYM), PLT-LYM ratio (PLR), PLT-High-Density Lipoprotein (HDL) ratio (PHR), HGB-LYM ratio (HLR), red blood cell count (RBC), Neutrophil-HDL ratio (NHR), and PLT-RBC ratio (PRR) were all statistically significant between the two groups (p<0.05). Another important finding was that red cell distribution width (RDW) was a significant predictor for higher LDL levels in women. Furthermore, in men, RDW-PLT ratio (RPR) and PHR were the most important indicators for assessing the elevated LDL levels. ConclusionThe study found that sex increases LDL-C odds in females by 52.9 %, while age and HCT increase it by 4.1 % and 5.5 %, respectively. RPR and PHR were the most influential variables for both genders. Elevated RPR and PHR were negatively correlated with increased LDL levels in men, and RDW levels was a statistically significant factor for women. Moreover, RDW was a significant factor in women for high levels of HDL-C.The study revealed that females have higher LDL-C levels (16 % compared to 14 % of males), with significant differences across variables like age, HGB, HCT, PLT, RLR, PHR, RBC, LYM, NHR, RPR, and key factors like RDW and SII.

8124 Prevalence and Characteristics of Patients with Hypothyroidism in the Danish Blood Donor Study

Abstract Disclosure: N.L. Frisk: None. J.R. Shorter: None. O.B. Pedersen: None. L.T. Dalgaard: None. Introduction: While impaired thyroid function leading to subclinical hypothyroidism and overt hypothyroidism is common in Denmark, the knowledge about the paths by which patients’ progress to impaired thyroid function is limited. Undiagnosed hypothyroidism as well as subclinical hypothyroidism constitute serious risk factors for development of cardio metabolic disease. The Danish Blood Donor Study (DBDS) is a large longitudinal cohort and biobank containing information and samples dating more than 10 years back. Blood donors donate blood every 3-6 months and each time provide a sample for research. Research question: The aim of the study was to obtain up-to-date information about prevalence and characteristics of patients with hypothyroidism in a Danish longitudinal cohort of blood donors. Methodology: The study employed a cross-sectional design. Hypothyroidism was defined based on at least two prescriptions of levothyroxine (LT4) and used for calculations of prevalence. Case numbers were compared to all controls that were currently not being prescribed LT4 nor anti-thyroid drugs (carbimazole, propylthiouracil, thiamazole). We compared cases of hypothyroidism to two different control (ctrl) groups: 1) All the participants of the DBDS having TSH levels in the normal range, and 2) Normothyroid participants matched to hypothyroid cases based on age and sex. Incidence was determined based on DBDS participants developing hypothyroidism after being enrolled into the DBDS during a 10-year follow-up. Men and women were compared separately among cases and controls. Students’ t-test was used to compare cases and controls, and corrected using Bonferroni. Major results: There were 3397 cases of hypothyroidism and 153791 ctrl subjects in the DBDS, giving a prevalence of 2.2%. 85% of cases were female, while among ctrl 50% were female. Average age of cases was 52±13 years (mean±SD) for women and 58±13 for men, while ctrls were 45±13 and 48±14 years, respectively (both P&amp;lt;0.001). BMI among cases were: 25.8±4.7 for women and 26.8±3.9 kg/m2, while cases were 25.1±4.4 and 26.0±3.6, respectively (both P&amp;lt;0.001). TSH levels were, for female cases: 4.6±4.0 iu/mL and 5.7±4.9 for men, while ctrls were 1.8±1.1 and 1.7±1.1, respectively (both P&amp;lt;0.001). Free (F) T4 levels were, for female cases: 14.4±6.4pmol/L and male: 14.0±4.6, while ctrls were: 14.8±4.5 and 15.0±3.9 respectively (P&amp;lt;0.003 for females, P&amp;lt;0.0001 for males), while FT3 levels were for cases: 4.3±1.7 and 4.3±1.4 pmol/L and 4.5±2.0 and 4.7±1.5 for ctrls (both P&amp;lt;0.0001). Conclusion: Hypothyroidism is less prevalent among blood donors than reported in the general Danish population, which is accordance with ‘the healthy donor’ bias. Hypothyroid donors were on average older and with higher BMI than normothyroid controls. Donors with hypothyroidism were generally well regulated, but despite that FT4 and FT3 levels were lower than ctrls. Presentation: 6/1/2024

Exenatide administration time-dependently affects the hepatic circadian clock through glucagon-like peptide-1 receptors in the central nervous system

Accumulating evidence indicates that disruption of the circadian clock contributes to the development of lifestyle-related diseases. We have previously shown that exenatide, a glucagon-like peptide-1 (GLP-1) receptor agonist, can strongly affect the molecular clocks in the peripheral tissues. This study aimed to investigate the effects of its dosing time and the central nervous system-specific GLP-1 receptor knockdown (GLP1RKD) on the hepatic clock in mice treated with exenatide. Male C57BL/6J and GLP1RKD mice were housed under a 12-h/12-h light/dark cycle, and feeding was restricted to either the light period (L-TRF) or the first 4 h in the dark period (D-TRF). In parallel, exenatide was administered 4–5 times, once daily either at the beginning of the dark (ZT 12) or light period (ZT 0), and we assessed the mRNA expression rhythms of clock genes in the liver thereafter. Exenatide administration at ZT 12 counteracted the phase shift effect of the L-TRF on the hepatic clock of wild-type mice, whereas the dosing at ZT 0 enhanced its effect. However, exenatide did not influence the phase of the hepatic clock under D-TRF regardless of the dosing time. The effect of exenatide in wild-type mice weakened in GLP1RKD mice. These results showed that exenatide dosing time-dependently affects the hepatic circadian clock through the central GLP-1 system. Exenatide administration at the beginning of the active period (i.e., in the morning for humans) might prevent disruption of the peripheral clocks caused by irregular eating habits.

8433 Elucidation of the Molecular Basis of Human and Mouse Pancreatic β-Cell Senescence Induced by Hyperglycemia

Abstract Disclosure: K. Iwasaki: None. P. Carapeto: None. C. Aguayo-Mazzucato: None. Background and AIM: Senescent cells accumulate with age and contribute to the development of chronic diseases, including Type 2 Diabetes (T2D). Whereas senescence is an important pathogenic mechanism in diabetes, the role of hyperglycemia as a metabolic driver of pancreatic β-cells has not been clarified. The aim of this study is to elucidate the molecular basis of hyperglycemia-induced pancreatic β-cell senescence using human and rodent islets. Methods: 1) Human islets were cultured for 2 weeks in 20.2 mM high (HG) or 2.8mM low glucose (LG), and analyzed by qPCR and glucose-responsive insulin secretion (GSIS) to explore the molecular basis of senescence in ex vivo. To test the effects of senescent cell removal, senolytics Dasatinib (1μM) and Quercetin (20μM) (DQ) were used. 2) To evaluate the effects of hyperglycemia in vivo, we transplanted mouse and human islets under the kidney capsule of normoglycemic (NG) or streptozocin-induced hyperglycemic (Stz-Db) immunodeficient mice for two weeks. Graft function was evaluated by intraperitoneal glucose tolerance test and cellular identity using qPCR or immunohistochemistry. DQ (5mg/kg/day + 50mg/kg/day) was used to evaluate the effects of removing senescent cells in transplantation (Tx). To investigate the effect of specific removal of p16-positive senescent β-cells in transplanted islets, INK-ATTAC mice islets (p16Ink4a-mediated apoptosis by targeted activation of caspases) were transplanted into Stz-Db and treated with BB homodimer (BB) to remove p16+ cells or vehicle. Results: (1) Human islets from 5 healthy donors cultured in HG had an increased senescence index (mean of senescence markers p16, p21 and HMGB1 mRNA) when compared to LG islets (p&amp;lt;0.05) and lost glucose responsiveness as evaluated by ex vivo GSIS compared to LG (p&amp;lt;0.05). 2) Human islets (1000IEQ) were transplanted to Stz-Db or NG mice. In Stz-Db graft, P21 mRNA significantly increased with decreased expression of β-cell genes when compared to NG. Stz-Db mice treated with DQ (Db-DQ) for 5 days after Tx, significantly decreased expression of senescence index (p&amp;lt;0.05) and increased in β-cell index (mean of β-cell hallmark genes) (p&amp;lt;0.05) at mRNA levels. Stz-Db mice transplanted with INK-ATTAC mice islets had lower fed glucose levels, decreased p16 mRNA, increased expression β-cell hallmark genes and improved insulin secretion ex vivo after removal of p16+ cells. Conclusion: Sustained exposure of human islets to hyperglycemia induced cellular senescence, leading to pancreatic β-cell dysfunction and loss of cellular identity. Furthermore, elimination of senescent cells may protect pancreatic β-cells from hyperglycemia-induced functional decline, which may have potential clinical application in both Type 1 Diabetes and T2D. Presentation: 6/2/2024

VCAM-1 targeted nanocarriers of shRNA-Smad3 mitigate endothelial-to-mesenchymal transition triggered by high glucose concentrations and osteogenic factors in valvular endothelial cells

Endothelial to mesenchymal transition (EndMT) of valvular endothelial cells (VEC) is a key process in the development and progression of calcific aortic valve disease (CAVD). High expression of the Smad3 transcription factor is crucial in the transition process. We hypothesize that silencing Smad3 could hinder EndMT and provide a novel treatment for CAVD. We aimed at developing nanoparticles encapsulating short-hairpin (sh)RNA sequences specific for Smad3 targeted to the aortic valve. We synthesized VCAM-1-targeted lipopolyplexes encapsulating shRNA-Smad3 plasmid (V-LPP/shSmad3) and investigated their potential to reduce the EndMT of human VEC. VEC incubation in a medium containing high glucose concentrations and osteogenic factors (HGOM) triggers EndMT and increased expression of Smad3. Exposed to lipopolyplexes, VEC took up efficiently the V-LPP/shSmad3. The latter reduced the EndMT process in VEC exposed to HGOM by downregulating the expression of αSMA and S100A4 mesenchymal markers and increasing the expression of the CD31 endothelial marker. In vivo, V-LPP/shSmad3 accumulated in the aortic root and aorta of a murine model of atherosclerosis complicated with diabetes, without affecting the liver and kidney function. The results suggest that targeting activated VEC with lipopolyplexes to silence Smad3 could be an effective, novel treatment for CAVD mediated by the EndMT process.

8561 Association Of Alopecia And Hirsutism With Severity Of Depression In A Sample Of Hispanic Women With Polycystic Ovary Syndrome

Abstract Disclosure: C.M. Casas Loyola: None. Y.G. Rivera-Rodriguez: None. B. Marin Rodriguez: None. J.A. Roque Torres: None. L.A. Gonzalez Rodriguez: Research Investigator; Self; Lilly USA, LLC. J. Romaguera: None. Purpose: Polycystic ovary syndrome (PCOS), a highly prevalent endocrine disorder in females has been associated with several chronic diseases. Females with PCOS have been found with a higher prevalence of mental disorders. Depression and its severity have been associated with the development and progression of cardiovascular disease. We aimed to assess depression severity and its association with PCOS related comorbidities such as alopecia and hirsutism. Methods: A cross sectional study of females aged 21-45 years was conducted in the endocrinology clinics at the RCM-Clinics. PCOS was diagnosed using the Rotterdam criteria, hirsutism was defined by modified Ferriman-Gallwey score (mFG ≥ 9), alopecia was defined using the Ludwig scale and Depression using the Patient Health Questionnaire (PHQ9). Severity of depression and presence of alopecia and hirsutism were compared among groups. Results: A total of 112 patients were included in this study (85 patients PCOS+ and 27 patients PCOS-). Mean age was 32 ± 6 years. Severity of depression in PCOS- patients was: 44% none to minimal, 30% mild and 27% moderate to severe. Severity of depression in PCOS+ patients was: 28% none to minimal, 35% mild and 36% moderate to severe. Participants with alopecia and PCOS+ had a greater percentage of moderate to severe depression (58%) compared to the control group without alopecia (30%) (p value&amp;lt;0.05). No differences were observed between hirsutism and severity of depression among groups. Conclusion: Our study showed an association between alopecia and severity of depression in patients with PCOS+. The presence of hirsutism was not associated to severity of depression. Currently, there are more available treatments for hirsutism than for alopecia. For this reason, patients with hirsutism have more opportunities to manage their condition than patients with alopecia, which often require more invasive procedures. The presence of alopecia can be considered a risk factor for developing major depressive disorder in patients with PCOS. Treatment of PCOS-related abnormalities should be emphasized soon after diagnosis. Evaluation of mental health is imperative in our PCOS patients. Presentation: 6/3/2024

6807 Evaluation of Tobacco Exposure and Teprotumumab Efficacy: Pooled Results from Acute TED Clinical Trials

Abstract Disclosure: S. Ugradar: Consulting Fee; Self; Acelyrin. S.T. Wester: Advisory Board Member; Self; Amgen Inc. Consulting Fee; Self; Immunovant, Lassen. Research Investigator; Self; Amgen Inc, Sling, Immunovant. R. Holt: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. Q. Fu: Employee; Self; Amgen Inc. Stock Owner; Self; Amgen Inc. G.J. Kahaly: Consulting Fee; Self; Amgen Inc. Research Investigator; Self; Amgen Inc. Introduction: Tobacco exposure is a known risk factor for Thyroid Eye Disease (TED) development and severity. Here, we compare outcomes with teprotumumab in smokers versus non-smokers as reported in pooled clinical trials in patients with acute TED. Methods: Patients ≥18 years old from two placebo-controlled trials and an open-label extension in the US and EU (Phase 2, NCT01868997; OPTIC, NCT03298867; OPTIC-X, NCT03461211) and one placebo-controlled trial in Japan (OPTIC-J, jRCT2031210453) with Graves’ disease and recent onset (≤9 month duration) active TED (Clinical activity score, CAS≥4), were included. Patients received eight infusions of teprotumumab over 21 weeks, with the final study visit at Week 24 (three weeks after final dose). Statistical analyses were conducted to test differences in responder rates for proptosis (≥2mm, primary outcome), diplopia (Bahn-Gorman scale≥1), clinical activity score (CAS, 2-point improvement), and Overall response (proptosis + CAS), as well as proptosis mm change and Graves’ Ophthalmopathy Quality of Life (GO-QOL, range 0-100) score change. Cochran-Mantel-Haenszel tests were conducted to test the difference in responder rate for proptosis, diplopia, CAS, and Overall responder rate between smokers and non-smokers stratified by study (Phase 2, OPTIC, OPTIC-X, and OPTIC-J). Mixed Model for Repeated Measures was conducted to test the difference in the mean change in proptosis and GO-QOL. Results: Baseline characteristics and TED characteristics between teprotumumab-treated smokers (N=32, mean age 51 years, 75% female) and non-smokers (N=116), mean age 49.5 years, 68% female were similar. No significant differences were seen in proptosis (78.1% vs 83.6%, P=.585), diplopia (55.6% vs 70.2%, P=.175), CAS (73.3% vs 59.3%, P=.145), Overall (73.3% vs 76.1%, P=.814) responses and GO-QOL least squares mean (LSM) change (17.3 vs 17.0, P=.927) between smokers and non-smokers. The magnitude of LSM proptosis mm change was similar (-2.82 vs -3.23 mm, P=.19). Conclusion: In this post-hoc assessment, proptosis response rates with teprotumumab were comparable in smokers and non-smokers at Week 24. Teprotumumab produced clinically relevant decreases in proptosis, CAS, Overall response, diplopia, and improvements in quality of life over the study period of 24 weeks in both groups. These improvements were comparable to those seen in the overall teprotumumab-treated patient populations with TED. Smoking is a known risk factor for more severe TED but does not significantly affect response to teprotumumab. Public Presentation: 6/2/2024

8327 Risk Of Chronic Kidney Disease In Subjects With Metabolic Dysfunction-Associated Fatty Liver Disease Or Metabolic Dysfunction-Associated Steatotic Liver Disease: A Retrospective Study

Abstract Disclosure: E. Rhee: None. H. Kwon: None. S. Park: None. W. Lee: None. Background: Recently, the term non-alcoholic fatty liver disease (NAFLD) is replaced by a new term, metabolic dysfunction-associated liver disease (MASLD), with a new definition made by a modified Delphi process led by three large pan-national liver associations. In this study, we aimed to analyze the risk for chronic kidney disease (CKD) development in those with MASLD defined by the new definition and metabolic dysfunction-associated fatty liver disease (MAFLD). Methods: Among 52,606 participants (mean age 35.4 years) in the health checkup program from 2002 to 2019, in whom at least 10 health checkups were performed, after strict exclusion, 48,751 participants were enrolled and analyzed the development of CKD defined by estimated glomeruls filtration lower than 60 mL/min/1.73m2) during a median of 14.7 years of follow-up. The presence of MAFLD was defined by presence of hepatic steatosis plus one of the three criteria of overweight or obese, type 2 diabetes or presence of ≥2 metabolic risk abnormalities. MASLD was defined by presence of hepatic steatosis plus at least 1 of 5 cardiometabolic risk factors. Results: At baseline, 12,773(26.2%) participants had MAFLD and 35,359(74.58%) had MASLD. During the follow-up period, 849(1.7%) participants developed CKD. In participants with MAFLD, 345(2.7%) participants developed CKD, and in participants with MASLD, 609(1.7%) developed CKD. After adjustment for age and sex, the hazard ratio(HR) of CKD was 1.44 (95% confidence interval [CI] 1.25-1.66) for MAFLD, and 1.25(95% CI 1.07-1.47) for MASLD. Both definition predicted development of CKD nicely (Harrell’s C-index: 0.79(0.77-0.81) for MAFL and MASLD) Conclusions: The participants with MAFLD and MASLD showed significantly increased risk for CKD during a median of 15 years of follow-up. Both criteria showed nice predictability for CKD. Presentation: 6/1/2024

The role of 1q abnormalities in multiple myeloma: Genomic insights, clinical implications, and therapeutic challenges

Chromosome 1q copy number variations, collectively termed +1q, are 1 of the most common cytogenetic abnormalities in multiple myeloma. 1q abnormalities are associated with overexpression of a high-risk gene signature promoting cell proliferation, apoptosis resistance, genomic instability, and treatment resistance, and acquisition or expansion of +1q subclones mediate disease development and relapse. While there remains significant controversy as to whether the presence of +1q is itself an independent driver of poor prognosis or is simply a marker of other high-risk features, +1q has recently been incorporated into multiple prognostic scoring models as a new high-risk cytogenetic abnormality. In this review, we present possible underlying genetic mechanisms of high-risk disease in +1q myeloma, implications for subclonal development, its role in modifying the tumor microenvironment, current evidence for clinical significance in newly-diagnosed and relapsed patients, and current controversies in +1q classification and prognostication.

Tryptophan Metabolism Disorder-Triggered Diseases, Mechanisms, and Therapeutic Strategies: A Scientometric Review.

Tryptophan is widely present in foods such as peanuts, milk, and bananas, playing a crucial role in maintaining metabolic homeostasis in health and disease. Tryptophan metabolism is involved in the development and progression of immune, nervous, and digestive system diseases. Although some excellent reviews on tryptophan metabolism exist, there has been no systematic scientometric study as of yet. This review provides and summarizes research hotspots and potential future directions by analyzing annual publications, topics, keywords, and highly cited papers sourced from Web of Science spanning 1964 to 2022. This review provides a scientometric overview of tryptophan metabolism disorder-triggered diseases, mechanisms, and therapeutic strategies. The gut microbiota regulates gut permeability, inflammation, and host immunity by directly converting tryptophan to indole and its derivatives. Gut microbial metabolites regulate tryptophan metabolism by activating specific receptors or enzymes. Additionally, the kynurenine (KYN) pathway, activated by indoleamine-2, 3-dioxygenase (IDO) and tryptophan 2, 3-dioxygenase, affects the migration and invasion of glioma cells and the development of COVID-19 and depression. The research and development of IDO inhibitors help to improve the effectiveness of immunotherapy. Tryptophan metabolites as potential markers are used for disease therapy, guiding clinical decision-making. Tryptophan metabolites serve as targets to provide a new promising strategy for neuroprotective/neurotoxic imbalance affecting brain structure and function. In summary, this review provides valuable guidance for the basic research and clinical application of tryptophan metabolism.

The Multifaceted Roles of Hippo-YAP in Cardiovascular Diseases.

The Hippo-yes-associated protein (YAP) signaling pathway plays a crucial role in cell proliferation, differentiation, and death. It is known to have impact on the progression and development of cardiovascular diseases (CVDs) as well as in the regeneration of cardiomyocytes (CMs). However, further research is needed to understand the molecular mechanisms by which the Hippo-YAP pathway affects the pathological processes of CVDs in order to evaluate its potential clinical applications. In this review, we have summarized the recent findings on the role of the Hippo-YAP pathway in CVDs such as myocardial infarction, heart failure, and cardiomyopathy, as well as its in CM development. This review calls attention to the potential roles of the Hippo-YAP pathway as a relevant target for the future treatment of CVDs.

Chronic Exposure to Petroleum-Derived Hydrocarbons Alters Human Skin Microbiome and Metabolome Profiles: A Pilot Study.

Petroleum-derived substances, like industrial oils and grease, are ubiquitous in our daily lives. Comprised of petroleum hydrocarbons (PH), these substances can come into contact with our skin, potentially causing molecular disruptions and contributing to the development of chronic disease. In this pilot study, we employed mass spectrometry-based untargeted metabolomics and 16S rRNA gene sequencing analyses to explore these effects. Superficial skin samples were collected from subjects with and without chronic dermal exposure to PH at two anatomical sites: the fingers (referred to as the hand) and arms (serving as an intersubject variability control). Exposed hands exhibited higher bacterial diversity (Shannon and Simpson indices) and an enrichment of oil-degrading bacteria (ODB), including Dietzia, Paracoccus, and Kocuria. Functional prediction suggested enriched pathways associated with PH degradation in exposed hands vs non-exposed hands, while no differences were observed when comparing the arms. Furthermore, carboxylic acids, glycerophospholipids, organooxygen compounds, phenol ethers, among others, were found to be more abundant in exposed hands. We observed positive correlations among multiple ODB and xenobiotics, suggesting a chemical remodeling of the skin favorable for ODB thriving. Overall, our study offers insights into the complex dysregulation of bacterial communities and the chemical milieu induced by chronic dermal exposure to PH.

Post-viral lung diseases: the microbiota as a key player

Viral infections of the respiratory tract can lead to chronic lung injury through immunopathological mechanisms that remain unclear. Communities of commensal bacteria colonizing the respiratory tract, known as the respiratory tract microbiota, are altered in viral infections, which can contribute to inflammation, lung epithelial damage and subsequent development of lung disease. Emerging evidence on post-viral lung injury suggests an interplay between viral infections, immune responses and airway microbiota composition in the development of viral-induced lung diseases. In this review, we present the clinical characteristics of post-viral lung injury, along with the underlying immunopathological mechanisms and host-bacteria interactions, with a focus on influenza virus, respiratory syncytial virus and coronaviruses. Additionally, considering the important role of the airway microbiota in viral-induced pulmonary sequelae, we suggest key areas for future research on respiratory microbiota involvement in the development of post-viral lung diseases.

CDT1 is a Potential Therapeutic Target for the Progression of NAFLD to HCC and the Exacerbation of Cancer

Aims: This study aimed to identify potential therapeutic targets in the progression from non-alcoholic fatty liver disease (NAFLD) to hepatocellular carcinoma (HCC), with a focus on genes that could influence disease development and progression. Background: Hepatocellular carcinoma, significantly driven by non-alcoholic fatty liver disease, represents a major global health challenge due to late-stage diagnosis and limited treatment options. This study utilizes bioinformatics to analyze data from GEO and TCGA, aiming to uncover molecular biomarkers that bridge NAFLD to HCC. Through identifying critical genes and pathways, our research seeks to advance early detection and develop targeted therapies, potentially improving prognosis and personalizing treatment for NAFLD-HCC patients. Objective: Identify key genes that differ between NAFLD and HCC; Analyze these genes to understand their roles in disease progression; Validate the functions of these genes in NAFLD to HCC transition. Methods: Initially, we identified a set of genes differentially expressed in both NAFLD and HCC using second-generation sequencing data from the GEO and TCGA databases. We then employed a Cox proportional hazards model and a Lasso regression model, applying machine learning techniques to the large sample data from TCGA. This approach was used to screen for key disease-related genes, and an external dataset was utilized for model validation. Additionally, pseudo-temporal sequencing analysis of single-cell sequencing data was performed to further examine the variations in these genes in NAFLD and HCC. Results: The machine learning analysis identified IGSF3, CENPW, CDT1, and CDC6 as key genes. Furthermore, constructing a machine learning model for CDT1 revealed it to be the most critical gene, with model validation yielding an ROC value greater than 0.80. The single-cell sequencing data analysis confirmed significant variations in the four predicted key genes between the NAFLD and HCC groups. Conclusion: Our study underscores the pivotal role of CDT1 in the progression from NAFLD to HCC. This finding opens new avenues for early diagnosis and targeted therapy of HCC, highlighting CDT1 as a potential therapeutic target.

Bone-protective effects of neutralizing angiopoietin-like protein 4 monoclonal antibody in rheumatoid arthritis

Despite recent advances, rheumatoid arthritis (RA) patients remain refractory to therapy. Dysregulated overproduction of angiopoietin-like 4 protein (ANGPTL4) is thought to be contributed to the disease development. ANGPTL4 was initially identified as a regulator of lipid metabolism, which is hydrolyzed to N-terminal (nANGPTL4) and C-terminal (cANGPTL4) fragments in vivo. cANGPTL4 is involved in several non-lipid-related processes, including angiogenesis and inflammation. The present study revealed that the level of ANGPTL4 was markedly elevated in the sera and synovial tissues from patients with RA versus controls. The administration of a neutralizing antibody against cANGPTL4 (anti-cANGPTL4 Ab) resulted in the inhibition of inflammatory processes and bone loss in animal models of collagen-induced arthritis (CIA) and adjuvant-induced arthritis (AIA). Transcriptomic and proteomic profiling of synovial tissues from AIA model indicated that the anti-cANGPTL4 Ab inhibited fibroblast-like synoviocytes (FLS) immigration and inflammatory-induced osteoclastogenesis. Mechanistically, the anti-cANGPTL4 Ab has been shown to inhibit TNF-α-induced inflammatory cascades in RA-FLS through the sirtuin 1/nuclear factor-κB signaling pathway. Moreover, the anti-cANGPTL4 Ab was found to block FLS invasion- and immigration-induced osteoclast activation. Collectively, these findings identify ANGPTL4 as a prospective biomarker for the diagnosis of RA, and targeting cANGPTL4 may represent a potential therapeutic strategy.

Different diseases, different needs: Patient preferences for gene therapy in lysosomal storage disorders, a probabilistic threshold technique survey

BackgroundGene therapy is currently in development for several monogenetic diseases including lysosomal storage disorders. Limited evidence is available on patient preferences for gene therapy in this population. In this study, we compare gene therapy-related risk tolerance between people affected by three lysosomal storage diseases currently faced with different therapeutic options and prognoses.MethodsA survey including the probabilistic threshold technique was developed in which respondents were asked to choose between gene therapy and the current standard of care. The attributes included to establish participants’ risk tolerance were previously identified in focus groups of affected people or their representatives, namely: risk of mild side effects, severe side effects, the need for additional medication, and the likelihood of long-term effectiveness. The survey was distributed among people receiving outpatient care for type 1 Gaucher disease (good prognosis with current treatment options), Fabry disease (varying prognosis with current treatment options, XY-genotype on average more severely affected than XX), and parents representing people with severe forms of mucopolysaccharidosis type III A/B (poor prognosis, no disease-specific therapy available).ResultsA total of 85 surveys were completed (15 Gaucher disease respondents, 62 Fabry disease respondents (17 self-identifying male), eight parents of ten people with mucopolysaccharidosis type III). Disease groups with higher disease severity trended towards higher risk tolerance: Gaucher disease respondents were most cautious and predominantly preferred the current standard of care as opposed to MPS III representatives who were more risk tolerant. Respondents with Fabry disease were most heterogeneous in their risk tolerance, with male participants being more risk tolerant than female participants. Long-term effectiveness was the attribute in which respondents tolerated the least risk.ConclusionsPeople affected by a lysosomal storage disease associated with a poorer prognosis and less effective current treatment options trended towards more risk tolerance when choosing between gene therapy and the current standard of care. This study shows the importance of involvement of patient preferences before and during the development process of new treatment modalities such as gene therapy for rare diseases, to ensure that innovative therapies align with the wishes and needs of people affected by these diseases.