Metabolic Parameters Research Articles

Estrogen restores disordered lipid metabolism in visceral fat of prediabetic mice

BACKGROUND Visceral obesity is increasingly prevalent among adolescents and young adults and is commonly recognized as a risk factor for type 2 diabetes. Estrogen [17β-estradiol (E2)] is known to offer protection against obesity via diverse me-chanisms, while its specific effects on visceral adipose tissue (VAT) remain to be fully elucidated. AIM To investigate the impact of E2 on the gene expression profile within VAT of a mouse model of prediabetes. METHODS Metabolic parameters were collected, encompassing body weight, weights of visceral and subcutaneous adipose tissues (VAT and SAT), random blood glucose levels, glucose tolerance, insulin tolerance, and overall body composition. The gene expression profiles of VAT were quantified utilizing the Whole Mouse Genome Oligo Microarray and subsequently analyzed through Agilent Feature Extraction software. Functional and pathway analyses were conducted employing Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses, respectively. RESULTS Feeding a high-fat diet (HFD) moderately increased the weights of both VAT and SAT, but this increase was mitigated by the protective effect of endogenous E2. Conversely, ovariectomy (OVX) led to a significant increase in VAT weight and the VAT/SAT weight ratio, and this increase was also reversed with E2 treatment. Notably, OVX diminished the expression of genes involved in lipid metabolism compared to HFD feeding alone, signaling a widespread reduction in lipid metabolic activity, which was completely counteracted by E2 administration. This study provides a comprehensive insight into E2's local and direct protective effects against visceral adiposity in VAT at the gene level. CONCLUSION In conclusion, the present study demonstrated that the HFD-induced over-nutritional challenge disrupted the gene expression profile of visceral fat, leading to a universally decreased lipid metabolic status in E2 deficient mice. E2 treatment effectively reversed this condition, shedding light on the mechanistic role and therapeutic potential of E2 in combating visceral obesity.

Relationship between remnant cholesterol and risk of kidney stones in U.S. Adults: a 2007–2016 NHANES analysis

Purpose Remnant cholesterol (RC) is the cholesterol content of triglyceride-rich lipoproteins. This study aimed to investigate the association between RC levels and kidney stones in U.S. adults. Methods Data were obtained from the 2007 to 2016 National Health and Nutrition Examination Survey (NHANES). A total of 10,551 participants with complete data were included and analyzed in this study. Univariate and multivariate logistic regression analysis, restricted cubic spline function, subgroup analysis and mediation analysis were preformed to estimate the independent relationship between RC levels and kidney stones. Results Participants with stone formation had higher levels of RC than those with without stone formation (25.78 ± 13.83 vs 23.27 ± 13.04, p< 0.001). The results of logistic regression analysis and dose-response risk curves revealed a positive nonlinear association between RC levels and risk of kidney stones [univariate: adjusted odds ratio (aOR) =2.388, 95% CI: 1.797–3.173, p< 0.001; multivariate: aOR = 1.424, 95% CI: 1.050–1.929, p = 0.023]. Compared with the discordantly low RC group, the discordantly high RC group was associated with increased risk of kidney stones (aOR = 1.185, 95% CI: 1.013–1.386, p= 0.034). Similar results were demonstrated according to the discordance of different clinical cut points. And metabolic syndrome parameters and vitamin D levels parallelly mediated the association between RC and kidney stone risk. Conclusions Higher RC levels were independently associated with an increased risk of kidney stone incidence.

Impact of the COVID-19 Pandemic on Obesity, Metabolic Parameters and Clinical Values in the South Korean Adult Population

This study aimed to evaluate the effects of the COVID-19 pandemic on obesity, metabolic parameters, and clinical values in the South Korean population. Data from the seventh and eighth National Health and Nutrition Examination Surveys were analyzed, comprising 3560 participants in 2018 (pre-COVID-19) and 3309 participants in 2021 (post-COVID-19). The study focused on adults aged 19 years and older who were overweight (BMI ≥ 25 kg/m2). The results showed a significant increase in waist circumference (approximately 2 cm), BMI (approximately 0.11 kg/m2), systolic blood pressure, fasting blood sugar (1.76 mg/dL higher), and glycated hemoglobin (0.14% higher) in the post-COVID-19 group compared to the pre-COVID-19 group. Additionally, the prevalence of hypercholesterolemia increased by 4% after the COVID-19 pandemic. These findings suggest an increased risk of obesity, abdominal obesity, and metabolic disorders, such as blood sugar disorders, in the post-COVID-19 period. Urine analysis revealed abnormal findings, including occult blood, urobilinogen, hematuria, proteinuria, ketone urea, glycosuria, and bacteriuria. The study highlights the negative impact of lifestyle changes, such as reduced physical activity and social gatherings, on physical vital signs and clinical values during the COVID-19 pandemic.

The value of dynamic FDG PET/CT in the differential diagnosis of lung cancer and predicting EGFR mutations

Objectives18F-fluorodeoxyglucose (FDG) PET/CT has been widely used for the differential diagnosis of cancer. Semi-quantitative standardized uptake value (SUV) is known to be affected by multiple factors and may make it difficult to differentiate between benign and malignant lesions. It is crucial to find reliable quantitative metabolic parameters to further support the diagnosis. This study aims to evaluate the value of the quantitative metabolic parameters derived from dynamic FDG PET/CT in the differential diagnosis of lung cancer and predicting epidermal growth factor receptor (EGFR) mutation status.MethodsWe included 147 patients with lung lesions to perform FDG PET/CT dynamic plus static imaging with informed consent. Based on the results of the postoperative pathology, the patients were divided into benign/malignant groups, adenocarcinoma (AC)/squamous carcinoma (SCC) groups, and EGFR-positive (EGFR+)/EGFR-negative (EGFR-) groups. Quantitative parameters including K1, k2, k3, and Ki of each lesion were obtained by applying the irreversible two-tissue compartmental modeling using an in-house Matlab software. The SUV analysis was performed based on conventional static scan data. Differences in each metabolic parameter among the group were analyzed. Wilcoxon rank-sum test, independent-samples T-test, and receiver-operating characteristic (ROC) analysis were performed to compare the diagnostic effects among the differentiated groups. P < 0.05 were considered statistically significant for all statistical tests.ResultsIn the malignant group (N = 124), the SUVmax, k2, k3, and Ki were higher than the benign group (N = 23), and all had-better performance in the differential diagnosis (P < 0.05, respectively). In the AC group (N = 88), the SUVmax, k3, and Ki were lower than in the SCC group, and such differences were statistically significant (P < 0.05, respectively). For ROC analysis, Ki with cut-off value of 0.0250 ml/g/min has better diagnostic specificity than SUVmax (AUC = 0.999 vs. 0.70). In AC group, 48 patients further underwent EGFR testing. In the EGFR (+) group (N = 31), the average Ki (0.0279 ± 0.0153 ml/g/min) was lower than EGFR (-) group (N = 17, 0.0405 ± 0.0199 ml/g/min), and the difference was significant (P < 0.05). However, SUVmax and k3 did not show such a difference between EGFR (+) and EGFR (-) groups (P>0.05, respectively). For ROC analysis, the Ki had a cut-off value of 0.0350 ml/g/min when predicting EGFR status, with a sensitivity of 0.710, a specificity of 0.588, and an AUC of 0.674 [0.523–0.802].ConclusionAlthough both techniques were specific, Ki had a greater specificity than SUVmax when the cut-off value was set at 0.0250 ml/g/min for the differential diagnosis of lung cancer. At a cut-off value of 0.0350 ml/g/min, there was a 0.710 sensitivity for EGFR status prediction. If EGFR testing is not available for a patient, dynamic imaging could be a valuable non-invasive screening method.

Metabolic network analysis of pre-ASD newborns and 5-year-old children with autism spectrum disorder

Classical metabolomic and new metabolic network methods were used to study the developmental features of autism spectrum disorder (ASD) in newborns (n = 205) and 5-year-old children (n = 53). Eighty percent of the metabolic impact in ASD was caused by 14 shared biochemical pathways that led to decreased anti-inflammatory and antioxidant defenses, and to increased physiologic stress molecules like lactate, glycerol, cholesterol, and ceramides. CIRCOS plots and a new metabolic network parameter, V°\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\dot{{{\\boldsymbol{V}}}}\\!$$\\end{document}net, revealed differences in both the kind and degree of network connectivity. Of 50 biochemical pathways and 450 polar and lipid metabolites examined, the developmental regulation of the purine network was most changed. Purine network hub analysis revealed a 17-fold reversal in typically developing children. This purine network reversal did not occur in ASD. These results revealed previously unknown metabolic phenotypes, identified new developmental states of the metabolic correlation network, and underscored the role of mitochondrial functional changes, purine metabolism, and purinergic signaling in autism spectrum disorder.

The impact of PET/CT and brain MRI for metastasis detection among patients with clinical T1-category lung cancer: Findings from a large-scale cohort study

Abstract Purpose [18F]-FDG PET/CT and brain MRI are common approaches to detect metastasis in patients of lung cancer. Current guidelines for the use of PET/CT and MRI in clinical T1-category lung cancer lack risk-based stratification and require optimization. This study stratified patients based on metastatic risk in terms of the lesions' size and morphological characteristics. Methods The detection rate of metastasis was measured in different sizes and morphological characteristics (solid and sub-solid) of tumors. To confirm the cut-off value for discriminating metastasis and overall survival (OS) prediction, the receiver operating characteristic (ROC) analysis was performed based on PET/CT metabolic parameters (SUVmax/SUVmean/SULpeak/MTV/TLG), followed by Kaplan–Meier analysis for survival in post-operation patients with and without PET/CT plus MRI. Results 2,298 patients were included. No metastasis was observed in patients with solid nodules &lt; 8.0 mm and sub-solid nodules &lt; 10.0 mm. The cut-off of PET/CT metabolic parameters on discriminating metastasis were 1.09 (SUVmax), 0.26 (SUVmean), 0.31 (SULpeak), 0.55 (MTV), and 0.81 (TLG), respectively. Patients undergoing PET/CT plus MRI exhibited longer OS compared to those who did not receive it in solid nodules ≥ 8.0 mm &amp; sub-solid nodules ≥ 10.0 mm (HR, 0.44; p &lt; 0.001); in solid nodules ≥ 8.0 mm (HR, 0.12; p&lt;0.001) and in sub-solid nodules ≥ 10.0 mm (HR; 0.61; p=0.075), respectively. Compared to patients with metabolic parameters lower than cut-off values, patients with higher metabolic parameters displayed shorter OS: SUVmax (HR, 12.94; p &lt; 0.001), SUVmean (HR, 11.33; p &lt;0.001), SULpeak (HR, 9.65; p &lt; 0.001), MTV (HR, 9.16; p = 0.031), and TLG (HR, 12.06; p &lt; 0.001). Conclusion The necessity of PET/CT and MRI should be cautiously evaluated in patients with solid nodules &lt; 8.0 mm and sub-solid nodules &lt; 10.0 mm, however, these examinations remained essential and beneficial for patients with solid nodules ≥ 8.0 mm and sub-solid nodules ≥ 10.0 mm.

Real-World Clinical Experience of Oral Semaglutide in a Secondary Diabetes Clinic in the UK: A Retrospective Observational Study.

Oral semaglutide improves cardiovascular risk factors in people with type 2 diabetes (T2D) in clinical trials, though real-world evidence is limited. We aimed to determine the real-world impact of oral semaglutide on routinely collected clinical data in our practice. People with T2D initiated on oral semaglutide in secondary care diabetes clinics at two hospital sites in Wales (United Kingdom) were included. Data were collected on reasons for oral semaglutide initiation and changes in bodyweight, blood pressure, glycemic control, and lipid profiles over follow-up at 3-6months, and at 6-12months. Data were collected to determine the safety of oral semaglutide. Seventy-six patients were included, with a median age 59.3 [51.4-67.6] years, and 38 (50.0%) patients were female. The most common reasons for oral semaglutide were need for weight loss and improved glycemia (69.8%), and improved glycemia alone (25.0%). Oral semaglutide associated with significantly reduced bodyweight (- 3.3kg), body mass index (BMI) (-0.9kg/m2), glycated hemoglobin (HbA1c) (- 11mmol/mol), and total cholesterol (- 0.4mmol/l) by 3-6months follow-up. At 6-12months, there was a significant reduction in systolic blood pressure (- 7.0mmHg), in addition to sustained reductions in other metabolic parameters. By 12months, 18 (23.6%) patients had discontinued the drug, largely resulting from gastrointestinal disturbance, but there were no serious events in this cohort. Oral semaglutide was effective in improving cardiovascular risk factors in this real-world population living with T2D, and no serious events were identified related to oral semaglutide in this patient group.

Transient brain structure changes after high phenylalanine exposure in adults with phenylketonuria.

Phenylketonuria is a rare metabolic disease resulting from a deficiency of the enzyme phenylalanine hydroxylase. Recent cross-sectional evidence suggests that early-treated adults with phenylketonuria exhibit alterations in cortical grey matter compared to healthy peers. However, the effects of high phenylalanine exposure on brain structure in adulthood need to be further elucidated. In this double-blind, randomised, placebo-controlled crossover trial, we investigated the impact of a four-week high phenylalanine exposure on the brain structure and its relationship to cognitive performance and metabolic parameters in early-treated adults with phenylketonuria. Twenty-eight adult patients with early-treated classical phenylketonuria (19-48 years) underwent magnetic resonance imaging before and after the four-week phenylalanine and placebo interventions (four timepoints). Structural T1-weighted images were preprocessed and evaluated using DL+DiReCT, a deep-learning-based tool for brain morphometric analysis. Cortical thickness, white matter volume, and ventricular volume were compared between the phenylalanine and placebo periods. Brain phenylalanine levels were measured using 1H spectroscopy. Blood levels of phenylalanine, tyrosine, and tryptophan were assessed at each of the four timepoints, along with performance in executive functions and attention. Blood phenylalanine levels were significantly higher after the phenylalanine period (1441µmol/L) than after the placebo period (873µmol/L, P<0.001). Morphometric analyses revealed a statistically significant decrease in cortical thickness in 17 out of 60 brain regions after the phenylalanine period compared to placebo. The largest decreases were observed in the right pars orbitalis (point estimate=-0.095mm, P<0.001) and the left lingual gyrus (point estimate=-0.070mm, P<0.001). Bilateral white matter and ventricular volumes were significantly increased after the phenylalanine period. However, the structural alterations in the Phe-placebo group returned to baseline measures following the washout and placebo period. Additionally, elevated blood and brain phenylalanine levels were related to increased bilateral white matter volume (rs=0.43 to 0.51, P≤0.036) and decreased cortical thickness (rs=-0.62 to -0.39, not surviving FDR correction) after the phenylalanine and placebo periods. Moreover, decreased cortical thickness was correlated with worse cognitive performance after both periods (rs=-0.54 to -0.40, not surviving FDR correction). These findings provide evidence that a four-week high phenylalanine exposure in adults with phenylketonuria results in transient reductions of the cortical grey matter and increases in white matter volume. Further research is needed to determine the potential long-term impact of high phenylalanine levels on brain structure and function in adults with phenylketonuria.

Dimethyl Sulfoxide (DMSO) as a Potential Source of Interference in Research Related to Sulfur Metabolism—A Preliminary Study

Dimethyl sulfoxide (DMSO), an organosulfur compound, is widely used as the gold standard solvent in biological research. It is used in cell culture experiments and as a component of formulations in in vivo studies. Unfortunately, parameters related to sulfur metabolism are often not taken into account when using DMSO. Therefore, in this work we aim to show that the addition of DMSO to the culture medium (even in amounts commonly considered acceptable) alters some parameters of sulfur metabolism. For this study, we used three cell lines: a commercially available Caco-2 line (HTB-37, ATCC) and two lines created as part of our early studies (likewise previously described in the literature) to investigate the anomalies of sulfur metabolism in mucopolysaccharidosis. As the negative effects of DMSO on the cell membrane are well known, additional experiments with the partial loading of DMSO into polymerosomes (poly(ethylene glycol) methyl ether-block-poly(lactide-co-glycolide), PEG-PLGA) were performed to eliminate these potentially disruptive effects. The results show that DMSO is a source of interference in studies related to sulfur metabolism and that there are not just simple effects that can be corrected in the final result by subtracting control values, since complex synergisms are also observed.

Strength-endurance training and liraglutide treatment: impact on metabolic parameters in middle-aged ovariectomized female rats

Strength-endurance training and liraglutide treatment: impact on metabolic parameters in middle-aged ovariectomized female rats

Eating behavior patterns, metabolic parameters, and circulating levels of oxytocin in patientswith obesity: a prospective pilot study

Eating behavior patterns, metabolic parameters, and circulating levels of oxytocin in patientswith obesity: a prospective pilot study

The effect of denosumab treatment on metabolic and inflammatory parameters in postmenopausal osteoporosis

The effect of denosumab treatment on metabolic and inflammatory parameters in postmenopausal osteoporosis

Impact of one-anastomosis gastric bypass and laparoscopic sleeve gastrectomy on metabolic parameters in morbidly obese patients: A comparative review.

Objective: To compare one-anastomosis gastric bypass and laparoscopic sleeve gastrectomy in morbidly obese patients in terms of frequency of dyslipidemia, mean AST, mean ALT, mean HbA1C and mean FPG. Study Design: Randomized Controlled Trial Setting: Department of General Surgery, Allied Hospital, Faisalabad. Period: October 20, 2022, to June 20, 2023, Methods: Morbidly obese individuals were randomly assigned to either undergo laparoscopic sleeve gastrectomy (Group A) or one-anastomosis gastric bypass (Group B). The study, led by a consultant with 3 years of post-fellowship experience, conducted comprehensive patient assessments, including BMI calculations and metabolic profiling. Monthly follow-ups continued until the 6th month, after which lipid profiles, alanine transaminase (ALT), aspartate transaminase (AST), hemoglobin A1C (HbA1C) and fasting plasma glucose (FPG), results were obtained from the hospital pathology lab. The comparative analysis revealed superior outcomes in Group B, the one-anastomosis gastric bypass cohort, as compared to Group A (laparoscopic sleeve gastrectomy), spanning multiple parameters. Results: The mean FPG in Group A was 5.52±0.26, compared to 5.56±0.25 in Group B. Mean HbA1c was 6.65±0.24 in Group A and 6.26±0.19 in Group B. AST levels were comparable, with 24.13±3.31 in Group A and 24.23±3.48 in Group B, yielding a p-value of 0.896. Similarly, ALT levels showed no significant difference between the groups (24.55±3.46 in Group A and 23.92±3.35 in Group B, p-value=0.414). Conclusion: One-anastomosis gastric bypass demonstrated superior efficacy over laparoscopic sleeve gastrectomy in morbidly obese patients, showcasing favorable outcomes in terms of dyslipidemia, AST, ALT, HbA1C, and FPG.

Follistatin as a Potential Biomarker for Identifying Metabolically Healthy and Unhealthy Obesity: A Cross-Sectional Study

Metabolically healthy obesity (MHO) refers to obese individuals with a favorable metabolic profile, without severe metabolic abnormalities. This study aimed to investigate the potential of follistatin, a regulator of metabolic balance, as a biomarker to distinguish between metabolically healthy and unhealthy obesity. This cross-sectional study included 30 metabolically healthy and 32 metabolically unhealthy individuals with obesity. Blood samples were collected to measure the follistatin levels using an enzyme-linked immunosorbent assay (ELISA). While follistatin did not significantly differentiate between metabolically healthy (median 41.84 [IQR, 37.68 to 80.09]) and unhealthy (median 42.44 [IQR, 39.54 to 82.55]) individuals with obesity (p = 0.642), other biochemical markers, such as HDL cholesterol, triglycerides, C-peptide, and AST, showed significant differences between the two groups. Insulin was the most significant predictor of follistatin levels, with a coefficient of 0.903, followed by C-peptide, which exerted a negative influence at −0.624. Quantile regression analysis revealed nuanced associations between the follistatin levels and metabolic parameters in different quantiles. Although follistatin may not serve as a biomarker for identifying MHO and metabolically unhealthy obesity, understanding the underlying mechanisms that contribute to metabolic dysfunction could provide personalized strategies for managing obesity and preventing associated complications.

Abstract PO3-27-01: Prediction of pathological complete response to neoadjuvant treatment in loco-regional advancedbreast cancer by using advanced PET/CT metabolic parameters

Abstract Prediction of pathological complete response to neoadjuvant treatment in loco-regional advanced breast cancer by using advanced PET/CT metabolic parameters. Abstract: Background: The standard treatment for locally advanced breast cancer (LABC) is neoadjuvant systemic therapy followed by surgery. The usefulness of FDG PET/CT for evaluating the treatment efficacy in breast cancer is well established; however, the role of quantitative functional PET/CT parameters, such as the metabolic tumor volume (MTV) and total lesion glycolysis (TLG), remains inconclusive. The aim of this study was to determine the correlation between quantitative functional parameters derived from PET/CT in LABC patients at staging and the response to neoadjuvant therapy. Methods: Seventy-eight consecutive patients (aged 25-82 y) with confirmed LABC (stages II-III) who underwent PET/CT as a part of their staging assessment and received neoadjuvant therapy followed by surgery were retrospectively included in this study. All patients underwent an FDG PET/CT at staging; and values of SUV max, SUV mean, MTV, and TLG were determined from the PET/CT studies. The patients were divided into two groups, based on the completeness of histopathologic response to neoadjuvant therapy, both in the primary tumor and axillary lymph nodes. Clinical, imaging and demographic data were collected from patient’s medical record. Results: A complete pathologic response (pCR) was achieved in 33/78 (42%) patients. Among patients with ER/PR positive, Her2-neu negative tumors, in 23/27 (85%) patients only partial pathologic response was reached; 91% of patients with ER/PR negative, Her2-neu positive and 43% of Triple-negative patients had complete pathological? response. For the primary breast tumor response, a higher SUV max, 10.7±5.34 for pCR vs. 7.24±4.62 for non-pCR group was measured, p-value=0.003; threshold value of 6.625. A higher SUV mean in the primary tumor resulted in a significantly higher rate of pCR, 5.95±2.36 vs 4,4±2.16, p=0.004, with a threshold value of 5.795. Neither MTV, not TLG were predictive parameters of the primary tumor response. For lymph nodes response, SUV max and SUV mean had no role in the prediction of pCR. Statistically significant difference however, was found between pCR and non-pCR in MTV values in the involved lymph nodes, with a median =2.13 cm³ [0-7.85] in pCR group vs 5.43 cm³ [3.11-15.3] in non-pCR, p=0.01 (threshold value 2.375) as well as in TLG measurements, with a median of 4.64 [0-19.8] vs. 12.7 [3.21-23.1], p=0.047, (25-75 IQR). Conclusion: Primary breast tumor SUV max/mean values have a significant correlation with the treatment response and threshold values were found. Low MTV and TLG measurements in lymph nodes may predict pCR. Neither MTV nor TLG had were found to have a significant role in the prediction of the primary tumor response. Citation Format: Maisun Shamya, Olga Kagna, Zohar Keidar, Tala Palchan-Hazan, Salem Billan, Roxolyana Abdah-Bortnyak. Prediction of pathological complete response to neoadjuvant treatment in loco-regional advancedbreast cancer by using advanced PET/CT metabolic parameters [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-27-01.

Changes in metabolic parameters and serum YKL-40 levels in Chinese rheumatoid arthritis patients during tocilizumab therapy.

To investigate the metabolic changes during therapy of tocilizumab (TCZ) and methotrexate (MTX) in non-diabetic rheumatoid arthritis (RA) patients and for the first time explore the associations between metabolic parameters and serum YKL-40 (sYKL-40) levels. We enrolled active non-diabetic RA patients who were refractory to MTX. Patients received intravenous TCZ (8mg/kg) once every 4weeks combined with MTX for 24weeks. Metabolic parameters and sYKL-40 levels were measured before TCZ infusion at baseline, week 4, week 12, and week 24. Correlations were assessed by the Spearman's rank correlation analysis. A total of 91 non-diabetic RA patients were enrolled in this study. At week 24, we observed a significant elevation in body mass index (BMI), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) levels. In contrast, there was a significant decrease in TC/HDL‑C ratio. No apparent changes in insulin resistance were found. Additionally, we detected a significant reduction in sYKL-40 levels during the study. At week 24, changes in sYKL-40 levels showed a significant negative correlation (r = -0.334, p = 0.002) with changes in TC levels. The combined therapy of TCZ and MTX resulted in a significant increase in BMI and lipid levels, while an evident decrease in the TC/HDL‑C ratio and sYKL-40 levels in RA patients. Additionally, there was a significant correlation between the decrease in sYKL-40 levels and the increase in TC levels during treatment with TCZ and MTX. Key Points • Lipid levels elevated significantly and sYKL-40 levels decreased obviously after therapy of TCZ combined with MTX in Chinese RA patients. • There was a significant correlation between the increase in TC levels and the decrease in sYKL-40 levels during treatment with TCZ and MTX in RA patients.

Abstract RF02-07: Precocious modulation of metabolic and immunological parameters predicts tumor response to fasting-mimicking diet plus chemotherapy in patients with early stage TNBC

Abstract Background: Preclinical studies showed that severely calorie restricted fasting-mimicking diets (FMDs) enhance the antitumor efficacy of chemotherapy (CT) or immunotherapy (IO) in murine triple negative breast cancer (TNBC) models. These effects are mediated by a combination of blood glucose reduction and positive immunomodulatory effects. Moreover, combining fasting and metformin produced synergistic anticancer effects in a broad range of tumor models. The BREAKFAST trial was designed to investigate if FMD, plus/minus metformin, could increase the antitumor activity of neoadjuvant CT in patients with stage I-III TNBC. Methods: BREAKFAST (NCT04248998) is a randomized, non-comparative, phase II, pilot trial that enrolled stage I-III (cT&amp;gt;1 cm) TNBC patients (pts) candidate to receive 4 cycles of neoadjuvant CT with doxorubicin-cyclophosphamide every 3 weeks, followed by 12 cycles of weekly paclitaxel. Pts were randomized 1:1 to receive: CT plus 5-day FMD every 3 weeks, up to 8 cycles (arm A); CT plus FMD plus daily metformin (1700 mg) (arm B). The primary study endpoint was the rate of pCR in either experimental arm. Secondary/exploratory endpoints included safety, compliance, and biomarker analyses based on blood metabolomics and tumor transcriptomics analyses at different timepoints. Results: Between June 2020 and February 2022 we enrolled 30 pts. Then, the study was interrupted after the introduction of chemo-immunotherapy (CT-IO) as a standard neoadjuvant therapy for early stage TNBC pts. Among 30 pts, 13 were treated with CT plus FMD, while 17 pts received CT plus FMD plus metformin. Overall, pCR rate was 56.6%, i.e., significantly higher than pCR rates reported with anthracycline-taxane CT alone in previous phase II/III trials (26-39%), with no significant differences among treatment arms (p=0.49). The FMD acutely reduced blood glucose, insulin and LDH levels, which reflects a reduction in systemic and/or tumor glucose metabolism. Of note, precocious LDH reduction was more pronounced in patients undergoing pCR. RNA-seq analysis of tumor samples revealed a significant downmodulation of glycolysis and TCA cycle pathways after one treatment cycle, paralleled by an increase of intratumor activated T cells, memory T cells and NK cells, as estimated by deconvolution analyses of tumor transcriptomic data. Of note, these changes were observed only in patients achieving pCR. While intratumor metabolic changes were similar in the two treatment arms, the modulation of intratumor immunity was more pronounced in patients not receiving metformin. Conclusion: Preoperative CT plus cyclic FMD (plus/minus metformin) results in excellent pCR rates in localized TNBC patients. Early on-treatment downregulation of systemic and intratumor metabolic parameters related to glucose metabolism predicts pCR, and this is independent of metformin use. Based on results of this study, we recently initiated a large, multicentric trial, namely the BREAKFAST-2 (NCT05763992) study, which will investigate if adding cyclic FMD to neoadjuvant CT-IO increases pCR rates in ~ 145 pts with stage II-III TNBC. Citation Format: Francesca Ligorio, Giovanni Fucà, Andrea Vingiani, Fabio Iannelli, Riccardo Lobefaro, Leonardo Provenzano, Lucrezia Zanenga, Cristina Ferraris, Antonino Belfiore, Silvia Brich, Alessia Bertolotti, Gianfranco Scaperrotta, Catherine Depretto, Antonia Martinetti, Elisa Sottotetti, Paola Antonia Corsetto, Giulia Valeria Bianchi, Giuseppe Capri, Secondo Folli, Saverio Minucci, Marco Foiani, Massimiliano Pagani, Giancarlo Pruneri, Filippo De Braud, Claudio Vernieri. Precocious modulation of metabolic and immunological parameters predicts tumor response to fasting-mimicking diet plus chemotherapy in patients with early stage TNBC [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr RF02-07.

Long-term uroseptic and metabolic effects of a herbal medicinal preparation in women with type 2 diabetes taken gliflosins

Background. The problem of urinary tract infections, including recurrent cystitis, and the choice of effective and safe means of treatment and prevention, taking into account the increasing burden of antibiotic resistance, are extremely relevant. Aim. To evaluate the effectiveness and safety of the herbal medicine Canephron® N for the prevention of exacerbations of recurrent cystitis and its effect on metabolic parameters in patients with type 2 diabetes mellitus taking sodium glucose cotransporter type 2 inhibitors. Material and methods. A prospective, randomized, open-label, parallel group study of 60 women without exacerbation of recurrent cystitis. The main group took the drug Canephron® N for 3 months, 2 tablets 3 times a day, and for the next 3 months they were monitored without taking the drug. The main evaluation parameters were: frequency of cystitis relapses, albumin/creatinine ratio in the morning urine, glomerular filtration rate, plasma lipid profile, glycemia and malondialdehyde in low-density lipoproteins. Results. 3 months after the end of taking the drug Canephron® N, patients in the main group maintained a positive effect in reducing exacerbations of cystitis – 3.3 times less relapses of the disease (3 and 10%, respectively; p=0.038). The urine albumin/creatinine ratio, lipid profile, glycemia and malondialdehyde in low-density lipoproteins after a 3-month treatment period had positive dynamics, but in the long-term period they corresponded to the values at the inclusion stage, both in the main and control groups. Conclusion. Prophylactic use of the herbal drug Canephron® N for 3 months is safe and reduces the frequency of relapses of cystitis in women with chronic cystitis against the background of diabetes mellitus taking sodium glucose cotransporter type 2 inhibitors, this effect persists for 3 months after discontinuation of the drug. Positive metabolic effects are associated with taking Canephron® N and are gradually leveled out when it is discontinued.

Abstract PO5-14-01: Weight loss and omega-3 polyunsaturated fatty acid intervention in overweight and obese peri- and postmenopausal women with increased breast cancer risk modifies the gut microbiome and is associated with circulating biomarkers

Abstract Background: Obesity-associated gut microbiome dysbiosis is thought to increase risk for postmenopausal breast cancer through alteration of estrogen metabolism and an increase in pro-inflammatory microbe abundance. Many studies have reported an increase in the Firmicutes/Bacteroidetes phyla ratio as a biomarker of obesity and is associated with adverse metabolic outcomes. Marine omega-3 eicosapentaenoic (EPA) and docosahexaenoic (DHA) fatty acids are thought to have favorable metabolic and inflammation resolving properties resulting in reduced risk for several epithelial cancers. One possible mechanism is the effect of EPA and DHA on the gut microbiome. We assessed the effect of weight loss and/or omega-3 supplementation on the gut microbiome and circulating molecular breast cancer risk factors. Methods: 46 peri/postmenopausal overweight and obese women at increased risk for breast cancer were enrolled into a weight-loss intervention and after 2 weeks randomized to 3.25 g/day combined EPA and DHA or placebo (PMC8416797). Fecal samples were collected at 0, 2-weeks and 6-months, with matched fecal samples for all timepoints available for 26 patients. Fecal samples at 6-months were available for 34 patients. 12M read depth metagenomic sequencing was performed on DNA isolated from feces to determine shifts in the gut microbiome. Fasting and non-fasting blood was also collected for circulating biomarker analysis. Body composition by DXA scan were also performed at baseline and 6-month time points. Results: Mean baseline BMI was 32 kg/m2. There was no significant difference between arms in age, baseline BMI, % body fat, or baseline Firmicutes/Bacteroidetes ratio. We identified gut microbiota species (A. hadrus and P. faecium) that correlated with metabolic parameters (% body fat, adiponectin/leptin ratio, and fasting insulin), species (P. dorei and B. ovatus) that correlated with estradiol levels, and mucin-degrading species (D. formicigenerans and R. gnavus) whose abundance correlated with inflammation (as measured by circulating monocyte-chemoattractant protein 1 (MCP-1)). Median 6-month weight change for all randomized subjects was -10% from baseline. Favorable change in the Firmicutes/Bacteroidetes ratio was associated both with the degree of weight loss and with omega-3 supplementation, although significant species modification differed between weight loss and omega-3 PUFA groups. Women with both &amp;gt;10% weight loss and omega-3 supplementation had a significantly reduced Firmicutes abundance and lower Firmicute/Bacteroidetes ratio than other groups. Species abundance shifts appear to differ between weight loss and omega-3 supplementation with 3 species modified by weight loss and 12 species shifted by omega-3 PUFA administration. Omega-3 PUFA supplementation significantly reduced proportional abundance of Dorea formicigenerans, which was a microbe associated with inflammation. Conclusions: Omega-3 supplementation at 3.25 g/day compared to placebo had a greater net effect on changing the gut microbiome in overweight and obese women at increased risk for breast cancer undergoing a weight loss intervention. Change in the gut microbiome may serve as a useful response biomarker in Phase II prevention trials of omega-3 fatty acid and weight loss. Citation Format: Katherine L. Cook, Erin Giles, Amy Kreutzjans, Shahid Umar, Christie Befort, Bruce Kimler, Stephen Hursting, Carol Fabian. Weight loss and omega-3 polyunsaturated fatty acid intervention in overweight and obese peri- and postmenopausal women with increased breast cancer risk modifies the gut microbiome and is associated with circulating biomarkers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-14-01.

Risk Assessment of Diabetes Mellitus during and after Pregnancy in Women with Prolactinomas.

Prolactin (PRL) is a crucial mediator of gluco-insulinemic metabolism. Dissecting glucose metabolism during and after pregnancy in patients with prolactinomas. 52 patients treated with cabergoline (CAB) were evaluated before conception, during pregnancy and up to 10 years after delivery. During pregnancy, CAB was discontinued, while it was restarted in 57.7 % of patients after delivery, due to recurrent hyperprolactinemia (RH). Hormonal (serum PRL) and metabolic (HbA1c, fasting glucose/FG, glucose tolerance) parameters were assessed. During pregnancy, PRL gradually increased, while FG remained stable. An inverse correlation between PRL and FG was found in the first (p=0.032) and third (p=0.048) trimester. PRL percent increase across pregnancy was inversely correlated with third trimester FG. Serum PRL before conception emerged as predictive biomarker of third trimester FG (τ=2.603; p=0.048). Elderly patients with lower HbA1c at first trimester and lower FG at 3 years postpartum, delivered infants with reduced birth weight. Breastfeeding up to 6 months correlated with lower FG at 4 and 10 years postpartum. A positive correlation between BMI and FG at 10 years after delivery (p=0.03) was observed, particularly in overweight/obese patients requiring higher CAB doses. Patients with RH who had to restart CAB showed shorter breastfeeding duration and higher FG at 2 years postpartum. Low PRL levels before pregnancy may be detrimental to FG during pregnancy. CAB duration and dose may influence long-term glucose tolerance, besides family history and BMI. Pre-conceptional metabolic management should be recommended to reduce the risk of gestational and type 2 diabetes mellitus.