Concomitant Elevation Research Articles

High-intensity interval training with blood-flow restriction enhances sprint and maximal aerobic power in male endurance athletes.

We investigated the concurrent impact of HIIT and blood-flow restriction (BFR) as a novel approach to further enhance maximal aerobic and anaerobic physiology and performances in trained athletes. In a randomized controlled trial, eighteen endurance-trained males (V ̇O2peak 65.6±5.1 ml.min-1.kg-1) included three sessions of HIIT per week (sets of 15-s efforts at 100% maximal aerobic power, interspersed by 15-s recovery) into their usual training for three weeks, either with restriction imposed on both lower limbs at 50-70% of arterial occlusion pressure (BFR group, n=10) or without (CTL group, n=8), and were tested for sprint and endurance exercise performance. The total mechanical work developed during a 30-sec Wingate test increased only in BFR (3.6%, P=0.02). During the Wingate, changes in near-infrared spectroscopy-derived vastus lateralis muscle oxygenation (Δ(deoxy[Hb+Mb]), % arterial occlusion) were attenuated after BFR training (-8.8%, P=0.04). The maximal aerobic power measured during an incremental cycling test increased only in BFR (4.5%, P=0.0004), but there was no change in V ̇O2peak among groups. Both groups improved 5-km cycling time trial performance, but BFR displayed a concomitant greater elevation in [H+] (11%, P=0.02). Changes in other blood variables (e.g., pH, lactate, bicarbonate and potassium ion concentration, hemoglobin) were not different between groups. Combining short-duration HIIT performed at 100% aerobic power with BFR elicited greater changes in sprint performance and maximal aerobic power in endurance athletes, associated with locomotor muscle metabolic adaptations but no meaningful effect on cardiorespiratory fitness.

Abstract 4132152: Cardiovascular Procedures for Hospitalized Patients with Hypertrophic Cardiomyopathy requiring Valvular Heart Repair/Replacement or Coronary Artery Revascularizations: A Risk-Stratified Analysis of a Large National Database

Background: Hypertrophic cardiomyopathy (HCM) is associated with increased mortality mainly due to sudden cardiac arrest. However, it is not clear how HCM affects in-hospital mortality among patients hospitalized due to other cardiovascular conditions requiring intervention. Methods: National Inpatient Sample (NIS) database was queried from 2016 to 2020 to identify hospitalized patients with a diagnosis of HCM. Patients with HCM were stratified based on their concomitant cardiovascular conditions necessitating interventions. Results: Data pertinent to 278,995 admission cases with HCM was analyzed. Of this, 15,035 cases had concomitant non-ST elevation MI (NSTEMI), and 1,230 cases had ST-elevation MI (STEMI). Additionally, 15,100 cases were diagnosed with aortic valve diseases (AVD), 33,580 had concomitant mitral valve diseases (MVD), 5,580 cases had tricuspid valve diseases (TVD), and 16,815 cases had pulmonary valve diseases (PVD). Cardiovascular procedures were more common among HCM patients with concomitant STEMI (43.5%) followed by HCM patients with AVD (17.1%) and HCM patients with NSTEMI (16.9%). Stratification of mortality rate based on cardiovascular procedures and the underlying indication revealed CABG to have the highest mortality rate for HCM patients with STEMI (25%), followed by PCI for HCM patients with STEMI and HFrEF (12.5%). HCM patients with NSTEMI undergoing revascularization had higher mortality when PCI was performed for HFrEF cases and when CABG was performed for HFpEF cases. For HCM patients with AVD requiring repair or replacement, TAVR was superior to SAVR if performed in patients with HFpEF but was inferior among HFrEF subgroup in terms of in-hospital mortality. For subgroup of HCM patients with MVD, transcatheter replacement was associated with a lower mortality than surgical repair regardless of concomitant heart failure. Data was insufficient for HCM patients with concomitant TVD or PVD undergoing repair or replacement procedures. Conclusions: Among hospitalized patients with HCM, concomitant HFrEF but not HFpEF is associated with a significantly higher mortality rate regardless of the underlying cardiovascular conditions requiring revascularization or heart valvular repair. A more comprehensive preoperative risk assessment could delineate the ideal procedures for HCM patients with certain comorbidities and specific need.

Enhancing the Segmentation Accuracy of the Otsu Method for Calculating Blood Vessel Rupture Volumes in CT-Scan Images

The precise quantification of cerebral hemorrhage volume assumes paramount significance, given its consequential impact on subsequent medical interventions. While antecedent scholarly endeavors have undertaken cerebral hemorrhage volume computations, the attendant accuracy remains amenable to refinement. The main contribution to this research is the development of a rectangle algorithm using the Otsu method, which can be used to calculate the total volume of brain hemorrhage in CT-Scan images of the human brain. The present investigation seeks to augment the segmentation paradigm inherent to the Otsu method, thereby advancing the precision of cerebral hemorrhage volume assessments. The Otsu method is conceived with the purpose of automating the segmentation of the hemorrhagic domain through the determination of threshold values. The refinement of the Otsu method’s accuracy is effectuated by the formulation of an algorithm aimed at maximizing the mean discrepancy between object and background intensities within the object image, predicated upon the ascertained threshold values. These determined thresholds subsequently govern the transformation of grayscale images into binary format, achieved through the quotient of the threshold value and the mean variance, thereby amplifying segmentation precision. The incorporation of variance and mean values in the binarization of grayscale images affords adaptability in threshold modulation commensurate with the intensity spectrum of the image. The research corpus leverages CT-Scan images sourced from RSUP M. Djamil Padang, West Sumatra, encompassing a compendium of 100 image slices culled from a quintet of patients. Empirical findings attest to the fortification of the Otsu method in the segmentation milieu, substantiating the augmentation of threshold value accuracy. This enhancement is conspicuously manifest in the outcomes of segmentation tests, underscoring the superior efficacy of the Otsu method in discerning between objects and backgrounds. The corollary effect is a discernibly more accurate computation of volumes employing the Otsu-T methodology. The import of this research rests in its successful establishment of automated threshold values and the concomitant elevation of segmentation precision.

Effects of endoscopic lobectomy and conventional lobectomy on psychological and sleep quality in patients with papillary thyroid microcarcinoma-a prospective observational study.

Both endoscopic thyroid lobectomy and conventional thyroid lobectomy are effective modalities for treating papillary thyroid microcarcinoma (PTMC). However, their respective psychological and sleep quality ramifications in patients remain largely unexplored. Patients diagnosed with PTMC who underwent thyroid lobectomy at our institution between July 15, 2021, and July 15, 2022, were prospectively recruited. Psychological distress and sleep quality were assessed at five intervals (hospital admission, hospital discharge, and 1, 3, and 6 months posttreatment) utilizing four validated scales. The PTMC patients who completed the questionnaires diligently were subsequently categorized into either the endoscopic thyroid lobectomy group (trial group) or the conventional thyroid lobectomy group (control group). A propensity score matching (PSM) cohort was then established to examine longitudinal and cross-sectional alterations in psychological parameters. Out of 602 eligible PTMC patients, 560 individuals completed all the questionnaires diligently during the follow-up period (response rate: 93.02%). This cohort comprised 176 patients (31.43%) who underwent endoscopic thyroid lobectomy and 384 patients (68.57%) who underwent conventional thyroid lobectomy. Following PSM, a comprehensive set of 176 matched patient pairs was successfully established. Both groups of patients exhibited a decline in sleep quality throughout the 6-month postoperative follow-up period; however, patients in the control group experienced concomitant elevation in anxiety levels. The PSQI scores of patients in the control group were markedly higher than those in the trial group across all follow-up time points, whereas the HAMA, HADS, and HEI scale scores did not significantly differ between the two groups. In terms of sleep quality and psychological well-being, endoscopic thyroid lobectomy is superior to conventional thyroid lobectomy for PTMC patients.

Bladder cancer associated with elevated heavy metals: Investigation of probable carcinogenic pathways through mitochondrial dysfunction, oxidative stress and mitogen-activated protein kinase

ObjectiveCarcinogenic mechanisms of heavy metals/ trace elements (HMTE) in bladder cancer (BC) are exactly unknown. Mitochondrial dysfunction (MD), oxidative stress (OS), and mitogen-activated protein kinases (MAPK) are probable carcinogenic mechanisms. The purpose is to investigate probable carcinogenic pathways of HMTE in BC using six MD genes, seven OS markers, and p38-MAPK. MethodsStudy included 125 BC/radical cystectomy (RC) patients between October 2020 and October 2022, and 72 controls. Exclusion criteria included previous neoplasm, chemo- or radiotherapy. Two samples (cancer/noncancer) were taken from RC specimens. Tissues/plasma/urine cadmium (Cd), lead (Pb), cobalt (Co), nickel (Ni), strontium (Sr), aluminium (Al), zinc (Zn), boron (B) were measured by ICP-OES. Tissue MD genes (mt-CO3, mt-CYB, mt-ATP 6, mt-ATP8, mt-CO1, mt-ND1), and serum OS markers (8-OHdG, MDA, 3-NT, AGEs, AOPP, ROS, SOD2), p38-MAPK were assessed by RT-PCR, and ELISA, respectively. ResultsBC and adjacent tissue showed higher (Al, Co, Pb, Ni, Zn, Cd,Sr), lower B concentrations, compared to controls. High tissue concentrations (Cd, Co, Pb, Ni, Sr) were associated with higher MD genes, OS, MAPK and lower SOD2 levels. The same differences were greater in 41 patients with concomitant elevation of two or more HMTE. Noninclusion of BC-related oncogenes (e.g. RAS) is a limitation. ConclusionsEvidence suggests that high BC tissue (Cd, Co, Pb, Ni, Si) concentrations are associated with over-expressed MD genes, OS, p38-MAPK and low SOD2. These findings provide important understanding keys of probable carcinogenic pathways in BC associated with HMTE. So, efforts should be performed to minimize and counteract exposure to toxic HMTE.

P53-dependent crosstalk between DNA replication integrity and redox metabolism mediated through a NRF2-PARP1 axis.

Mechanisms underlying p53-mediated protection of the replicating genome remain elusive, despite the quintessential role of p53 in maintaining genomic stability. Here, we uncover an unexpected function of p53 in curbing replication stress by limiting PARP1 activity and preventing the unscheduled degradation of deprotected stalled forks. We searched for p53-dependent factors and elucidated RRM2B as a prime factor. Deficiency in p53/RRM2B results in the activation of an NRF2 antioxidant transcriptional program, with a concomitant elevation in basal PARylation in cells. Dissecting the consequences of p53/RRM2B loss revealed a crosstalk between redox metabolism and genome integrity that is negotiated through a hitherto undescribed NRF2-PARP1 axis, and pinpoint G6PD as a primary oxidative stress-induced NRF2 target and activator of basal PARylation. This study elucidates how loss of p53 could be destabilizing for the replicating genome and, importantly, describes an unanticipated crosstalk between redox metabolism, PARP1 and p53 tumor suppressor pathway that is broadly relevant in cancers and can be leveraged therapeutically.

Musculoskeletal Symptoms and Misdiagnoses in Children With Acute Myeloid Leukaemia: A Nationwide Cohort Study.

Childhood cancer often presents with non-specific signs and symptoms that might mimic non-malignant disorders including musculoskeletal diseases, potentially leading to rheumatic and orthopaedic misdiagnoses. We aimed to compare clinical presentation, diagnostic interval and survival in paediatric acute myeloid leukaemia (AML) with and without initial musculoskeletal symptoms. This nationwide retrospective, cohort study reviewed medical records of 144 children below 15 years diagnosed with AML in Denmark from 1996 to 2018. Musculoskeletal symptoms occurred in 29% (42/144) of children with AML and 8% (11/144) received an initial musculoskeletal misdiagnosis, being mainly non-specific and pain-related. The children with and without musculoskeletal symptoms did not differ markedly up to the diagnosis of AML and blood counts were affected equally in both groups. However, the children with prior musculoskeletal symptoms were more likely to have elevated levels of LDH and ferritin. Furthermore, they revealed a tendency towards a longer total interval (median 53 days vs. 32 days, p = 0.07), but the overall survival did not differ. AML should be considered as an underlying cause in children with unexplained musculoskeletal symptoms and abnormal blood counts. Concomitant elevation of LDH and ferritin should strengthen the suspicion.

SP6.6 - Examining the Immunomodulatory Effects of Fibrosis Induced by Radiation Using Adipose-derived Stem Cells

Abstract Background and Introduction Radiation-induced fibrosis (RIF) is a complication of radiotherapy in the treatment of head and neck cancer. RIF is characterised by the formation of fibrous tissue and is associated with significant morbidity. Autologous fat grafting (AFG) is a promising approach for treating RIF, and adipose-derived stem cells (ADSC) have been identified as key contributors to this therapeutic effect. Method The experimental group included subjecting human-derived fibroblasts (iHDF) to radiation, whereas the control group remained radiation-free. Both groups were then treated with ADSC-controlled medium and co-cultured with ADSC. The amounts of important immunomodulators produced by iHDF cells were then collected and evaluated using enzyme-linked immunosorbent assays (ELISA) and real-time reverse transcription-polymerase chain reaction (RT-PCR). Results Co-cultured iHDF samples demonstrated a slight reduction in CCL2 concentrations compared to untreated iHDF samples (p = 0.0006). The iHDF co-culture samples exhibit a marginal elevation in CCL3 levels compared to the untreated iHDF samples (p = 0.0247). The co-culture samples of iHDF demonstrate a substantial and measurable elevation in IL-8 levels compared to the untreated iHDF samples (p = 0.027). The expression of Col1A1 is decreased in iHDF samples in comparison to control groups. Discussion CCL2 is implicated in the recruitment of ADSCs to specific locations. The elevated production of IL-8 in ADSC samples is associated with the pro-angiogenic characteristics of ADSC secretions, which promote healing in fibrotic tissue. Conclusion ADSCs were shown to possess anti-fibrotic properties via stimulating pro-angiogenic factors. However, experimental data indicates a concomitant elevation in pro-inflammatory factors. Further research is needed to explore the in-vivo effects of ADSC.

Safety and effectiveness of LEO stents for dual stent-assisted embolization combined with IA and IV intra-procedural infusion of tirofiban in the treatment of wide-necked intracranial bifurcation aneurysms.

To evaluate the safety and efficacy of employing LEO stents in dual stent-assisted embolization (DSAE) for wide-necked intracranial bifurcation aneurysms, and to assess the effectiveness of combined IA and IV intra-procedural infusion of tirofiban in mitigating perioperative complications. Clinical data and follow-up images from 562 patients with wide-necked intracranial bifurcation aneurysms treated at First Affiliated Hospital of Army Medical University from 2018-2022 were collected. Among them, 65 received DSAE with LEO stents. The study observed treatment success rates, procedure-related complications, perioperative thromboembolic events (TEs) and hemorrhagic events (HEs), immediate postoperative modified Raymond-Roy classification (mRR), and follow-up imaging. Glasgow Outcome Scale (GOS) at discharge and clinical follow-ups were recorded. The study enrolled 65 patients (mean age: 56.77 ± 10.07) with wide-necked intracranial bifurcation aneurysms. Among them, 58 had unruptured aneurysms, 7 ruptured (Hunt-Hess II-III). All aneurysms were successfully embolized without significant stent or bleeding complications. Only one case had intraoprative thrombosis; two postoperative ischemic incidents occurred within three days, no severe bleeding events. Immediate imaging showed modified Raymond-Roy classification: mRRC I (92.3%), mRRC II (4.6%), mRRC III b (3.1%). A total of 43 patients were followed up postoperatively with DSA. Among them, 41 patients exhibited mRRC I, while 2 patients exhibited mRRC II. No aneurysm was recanalized. Discharge GOS: GOS 5-60, GOS 4-1, GOS 3-4. One patient, GOS 1, died from lung cancer; others improved. The utilization of LEO stents for dual stent-assisted embolization of wide-necked intracranial bifurcation aneurysms demonstrated remarkable success and safety, yielding favorable postoperative outcomes and no instances of aneurysm recurrence. The concomitant administration of perioperative antiplatelet medications alongside IA and IV intra-procedural infusion of tirofiban effectively attenuated thromboembolic events (TEs) without concomitant elevations in bleeding risks.

Improved Interpretation of Pulmonary Artery Wedge Pressures through Left Atrial Volumetry-A Cardiac Magnetic Resonance Imaging Study.

The pulmonary artery wedge pressure (PAWP) is regarded as a reliable indicator of left ventricular end-diastolic pressure (LVEDP), but this association is weaker in patients with left-sided heart disease (LHD). We compared morphological differences in cardiac magnetic resonance imaging (CMR) in patients with heart failure (HF) and a reduced left ventricular ejection fraction (LVEF), with or without elevation of PAWP or LVEDP. We retrospectively identified 121 patients with LVEF < 50% who had undergone right heart catheterization (RHC) and CMR. LVEDP data were available for 75 patients. The mean age of the study sample was 63 ± 14 years, the mean LVEF was 32 ± 10%, and 72% were men. About 53% of the patients had an elevated PAWP (>15 mmHg). In multivariable logistic regression analysis, NT-proBNP, left atrial ejection fraction (LAEF), and LV end-systolic volume index independently predicted an elevated PAWP. Of the 75 patients with available LVEDP data, 79% had an elevated LVEDP, and 70% had concomitant PAWP elevation. By contrast, all but one patient with elevated PAWP and half of the patients with normal PAWP had concomitant LVEDP elevation. The Bland-Altman plot revealed a systematic bias of +5.0 mmHg between LVEDP and PAWP. Notably, LAEF was the only CMR variable that differed significantly between patients with elevated LVEDP and a PAWP ≤ or >15 mmHg. In patients with LVEF < 50%, a normal PAWP did not reliably exclude LHD, and an elevated LVEDP was more frequent than an elevated PAWP. LAEF was the most relevant determinant of an increased PAWP, suggesting that a preserved LAEF in LHD may protect against backward failure into the lungs and the subsequent increase in pulmonary pressure.

Biomarker Periodic Repolarization Dynamics Indicates Enhanced Risk for Arrhythmias and Sudden Cardiac Death in Myocardial Infarction in Pigs.

Periodic repolarization dynamics (PRD) is an electrocardiographic biomarker that captures repolarization instability in the low frequency spectrum and is believed to estimate the sympathetic effect on the ventricular myocardium. High PRD indicates an increased risk for postischemic sudden cardiac death (SCD). However, a direct link between PRD and proarrhythmogenic autonomic remodeling has not yet been shown. We investigated autonomic remodeling in pigs with myocardial infarction (MI)-related ischemic heart failure induced by balloon occlusion of the left anterior descending artery (n=17) compared with pigs without MI (n=11). Thirty days after MI, pigs demonstrated enhanced sympathetic innervation in the infarct area, border zone, and remote left ventricle paralleled by altered expression of autonomic marker genes/proteins. PRD was enhanced 30 days after MI compared with baseline (pre-MI versus post-MI: 1.75±0.30 deg2 versus 3.29±0.79 deg2, P<0.05) reflecting pronounced autonomic alterations on the level of the ventricular myocardium. Pigs with MI-related ventricular fibrillation and SCD had significantly higher pre-MI PRD than pigs without tachyarrhythmias, suggesting a potential role for PRD as a predictive biomarker for ischemia-related arrhythmias (no ventricular fibrillation versus ventricular fibrillation: 1.50±0.39 deg2 versus 3.18±0.53 deg2 [P<0.05]; no SCD versus SCD: 1.67±0.32 deg2 versus 3.91±0.63 deg2 [P<0.01]). We demonstrate that ischemic heart failure leads to significant proarrhythmogenic autonomic remodeling. The concomitant elevation of PRD levels in pigs with ischemic heart failure and pigs with MI-related ventricular fibrillation/SCD suggests PRD as a biomarker for autonomic remodeling and as a potential predictive biomarker for ventricular arrhythmias/survival in the context of MI.

Can high-sensitivity C-reactive protein be a routine trans-diagnostic biomarker for thoughts of death and suicidal attempts?

IntroductionSeveral studies have shown an association between suicidal behavior and increased C-reactive-protein (CRP) levels (Ghayour-Mobarhan M. et al. Comb Chem High Throughput Screen 2022; 25 1047-1057) although most studies evaluated the association between CRP levels and suicidal ideation in depressed patients (Olié E. et al. Eur Neuropsychopharmacol 2015; 25 1824-31).ObjectivesOur study assessed baseline high-sensitivity CRP (hsCRP) levels in a cohort of adult inpatients affected by severe mental illness (SMI) and their association with Mini-International Neuropsychiatric Interview-5 subscale suicidality (MINI-5-s).MethodsA naturalistic, observational, cross-sectional study was carried out by retrospectively recruiting 127 adult SMI inpatients, excluding patients with an organic pathology. HsCRP levels were assessed at the ward admission. To assess the suicidal behaviour all patients filled the same day the MINI-5-s.Results The number of patients with hsCRP&gt;3mg/l were significantly higher among those with thoughts of death (p=0.002) and suicidal attempt (p=0.026). No statistically significant associations were observed between hsCRP levels and other suicidality dimensions.Limitations: Small sample size, heterogeneous diagnoses, lack of diagnostic sub-analysis, cross-sectional design, and lack of a healthy control group.ConclusionsThe study reveals a transdiagnostic association between inflammation, thoughts of death and suicidal attempt in SMI inpatients. Our preliminary findings could support a routine introduction of hsCRP measurement, due to its relatively low cost, possible utility in trans- diagnostically suicide risk assessment. Large-scale clinical trials would be recommended to evaluate the effects of early anti-inflammatory therapy in patients with death ideation and/or suicidal attempt and concomitant low-grade hsCRP elevation. HsCRP could potentially represent an early biomarker for suicidal risk.Disclosure of InterestNone Declared

Intramuscular injection of mesenchymal stem cells augments basal muscle protein synthesis after bouts of resistance exercise in male mice.

Skeletal muscle mass is critical for activities of daily living. Resistance training maintains or increases muscle mass, and various strategies maximize the training adaptation. Mesenchymal stem cells (MSCs) are multipotent cells with differential potency in skeletal muscle cells and the capacity to secrete growth factors. However, little is known regarding the effect of intramuscular injection of MSCs on basal muscle protein synthesis and catabolic systems after resistance training. Here, we measured changes in basal muscle protein synthesis, the ubiquitin-proteasome system, and autophagy-lysosome system-related factors after bouts of resistance exercise by intramuscular injection of MSCs. Mice performed three bouts of resistance exercise (each consisting of 50 maximal isometric contractions elicited by electrical stimulation) on the right gastrocnemius muscle every 48 h, and immediately after the first bout, mice were intramuscularly injected with either MSCs (2.0 × 106 cells) labeled with green fluorescence protein (GFP) or vehicle only placebo. Seventy-two hours after the third exercise bout, GFP was detected only in the muscle injected with MSCs with concomitant elevation of muscle protein synthesis. The injection of MSCs also increased protein ubiquitination. These results suggest that the intramuscular injection of MSCs augmented muscle protein turnover at the basal state after consecutive resistance exercise.

Predictive Value of Post-operative Cardiac Troponin I and Lactate Levels After Ventricular Septal Defect Closure

Objectives: Although the mortality rate of primary ventricular septal defect (VSD) closure surgery has been reduced to &lt;0.5% in many centers, low cardiac output syndrome and multi-organ failure syndrome development in the post-operative period are still the most common causes of mortality and morbidity. The use of biochemical markers in the early period can be used as effective predictors for reducing mortality and morbidity. In this study, the effect of post-operative serum lactate and cardiac troponin I (cTNI) levels on hospital mortality in patients who underwent primary closure of VSD was investigated retrospectively. Methods: The effect of lactate and cTNI values on hospital mortality in 52 patients who underwent surgical repair for VSD was investigated. Serum lactate levels of all patients in the first 6 h after the operation; on the first post-operative day, cTNI values were examined retrospectively. Serum lactate levels exceeding 3.5 mmol/ lt and cTNI values exceeding 35 ng/mL were determined as the cut-off points. Results: Serum lactate level and cTNI increase were found to be statistically different in the mortality group (p&lt;0.05). It was shown that increased cTNI was associated with weight, left ventricular end-diastolic diameter, and cardiopulmonary bypass time (p&lt;0.05). Serum lactate levels were 4.1±0.5 mmol/lt in the non-mortality group and 15.3±8.3 mmol/lt in the mortality group, and the difference was statistically significant (p&lt;0.05). Hospital mortality was observed in 6 patients. Conclusion: In patients undergoing VSD closure surgery, serum lactate levels measured in the first 6 h postoperatively and cTNI levels measured on the first post-operative day are associated with hospital mortality. Concomitant elevations of lactate and cTNI values in patients after VSD closure should suggest to take caution and early supportive treatments to reduce mortality.

Abstract 62: Intra-tumor persistence of activated anti-mesothelin hYP218 CAR T cells is associated with increased efficacy in gastric and colorectal cancers

Abstract Purpose: Patients with gastric and colorectal cancers that have progressed after standard therapies have poor prognosis. Given the high expression of mesothelin in these tumor types, we examined the potential utility of the anti-mesothelin hYP218 CAR T cells to treat these cancers. Experimental Design: Cell surface mesothelin expression in a panel of gastric and colorectal cancer cell-lines was analyzed using flow cytometry. In vitro efficacy of hYP218 CAR T cells against these cell lines was evaluated using cytotoxicity and cytokine release assays. In vivo efficacy of hYP218 CAR T cells was studied using gastric (HGC27) and colorectal (SW48) tumor xenografts in NSG mice. NSG mice were injected with 1 × 106 cancer cells and the tumors were allowed to grow until they reached a volume of 80-100mm³, after which the mice were treated with either 5 × 106 hYP218 CAR T cells, 5 × 106 untransduced T cells, or saline and monitored over time. Persistence of CAR T cells in the tumor was evaluated over time and expression of activation and exhaustion markers were studied. Results: hYP218 CAR T cells demonstrated strong cytotoxic activity against mesothelin positive gastric and colorectal cancer cell lines and exhibited increased pro-inflammatory cytokine production. In both the HGC27 and SW48 tumor models hYP218 CAR T cells demonstrated significant reduction in tumor volume and overall survival compared to mice treated with untransduced T cells or saline. CAR T cells isolated from tumors of both the xenograft models, at day 40 after treatment, displayed higher expression levels of activation markers CD39 and CD69 when compared to the infused product. Furthermore, a concomitant elevation in the levels of effector cytokines, TNF-α and IFN-γ, was detected in the blood of treated mice demonstrating the functional capacity of the CAR T cells to not only persist but also to maintain an activated state. Conclusions: hYP218 CAR T cells show anti-tumor efficacy against gastric and colorectal tumor xenografts due to increased accumulation of activated CAR T cells in the tumor and warrants further investigation for treatment of patients with these cancers. Citation Format: Sameer A. Mir, Abhilash Venugopalan, Jingli Zhang, Mana Kamana Khanal, Chaido Stathopoulou, Manjistha Sengupta, Qun Jiang, Raffit Hassan. Intra-tumor persistence of activated anti-mesothelin hYP218 CAR T cells is associated with increased efficacy in gastric and colorectal cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 62.

Measurement of cumulative high-sensitivity C-reactive protein and monocyte to high-density lipoprotein ratio in the risk prediction of type 2 diabetes: a prospective cohort study

BackgroundConverging data have suggested that monocytic inflammation and C-reactive protein (CRP) are biologically intertwined processes and are involved in diabetogenesis. This study aimed to investigate the association between systemic inflammation assessed by joint cumulative high-sensitivity C-reactive protein (CumCRP) and monocyte to high-density lipoprotein ratio (CumMHR) and incident type 2 diabetes (T2D) and their predictive value for T2D in a general population.MethodsA total of 40,813 nondiabetic participants from a prospective real-life cohort (Kailuan Study, China) were followed biennially from 2010/2011 until December 31, 2020. Multivariable Cox regression analyses were conducted to evaluate the adjusted hazard ratios (aHRs) of incident diabetes.ResultsDuring a median follow-up of 7.98 (IQR: 5.74–8.87) years, 4848 T2D cases developed. CumMHR and CumCRP were alone or jointly associated with incident T2D after adjusting for potential confounders. Elevated CumMHR levels significantly increased the risk of incident diabetes in each CumCRP strata (P-interaction: 0.0278). Participants with concomitant elevations in CumMHR and CumCRP levels had the highest risk (aHR: 1.71, 95% CI 1.52–1.91) compared to both in the low strata. Notably, the coexposure-associated T2D risk was modified by age, sex, hypertension, dyslipidemia, and prediabetes status. C-statistics increased from 0.7377 to 0.7417 when CumMHR and CumCRP were added into the multivariable-adjusted model, with a net reclassification improvement (%) of 12.39 (9.39–15.37) (P < 0.0001).ConclusionsCumulative hsCRP and MHR were both independently and jointly associated with an increased risk of T2D and their addition to established risk factors should improve risk prediction and reclassification of diabetes.

Cardiac Metabolism.

The heart is composed of a heterogeneous mixture of cellular components perfectly intermingled and able to integrate common environmental signals to ensure proper cardiac function and performance. Metabolism defines a cell context-dependent signature that plays a critical role in survival, proliferation, or differentiation, being a recognized master piece of organ biology, modulating homeostasis, disease progression, and adaptation to tissue damage. The heart is a highly demanding organ, and adult cardiomyocytes require large amount of energy to fulfill adequate contractility. However, functioning under oxidative mitochondrial metabolism is accompanied with a concomitant elevation of harmful reactive oxygen species that indeed contributes to the progression of several cardiovascular pathologies and hampers the regenerative capacity of the mammalian heart. Cardiac metabolism is dynamic along embryonic development and substantially changes as cardiomyocytes mature and differentiate within the first days after birth. During early stages of cardiogenesis, anaerobic glycolysis is the main energetic program, while a progressive switch toward oxidative phosphorylation is a hallmark of myocardium differentiation. In response to cardiac injury, different signaling pathways participate in a metabolic rewiring to reactivate embryonic bioenergetic programs or the utilization of alternative substrates, reflecting the flexibility of heart metabolism and its central role in organ adaptation to external factors. Despite the well-established metabolic pattern of fetal, neonatal, and adult cardiomyocytes, our knowledge about the bioenergetics of other cardiac populations like endothelial cells, cardiac fibroblasts, or immune cells is limited. Considering the close intercellular communication and the influence of nonautonomous cues during heart development and after cardiac damage, it will be fundamental to better understand the metabolic programs in different cardiac cells in order to develop novel interventional opportunities based on metabolic rewiring to prevent heart failure and improve the limited regenerative capacity of the mammalian heart.

Elevated High-Sensitivity C-Reactive Protein Level Enhances the Impact of Lipoprotein(a) on Platelet Reactivity in PCI Patients Treated with Clopidogrel.

Recently, the effect of Lipoprotein(a) [Lp(a)] on thrombogenesis has aroused great interest, while inflammation has been reported to modify the Lp(a)-associated risks through an unidentified mechanism. This study aimed to evaluate the association between platelet reactivity with Lp(a) and high-sensitivity C-reactive protein (hs-CRP) levels in percutaneous intervention (PCI) patients treated with clopidogrel. Data were collected from 10,724 consecutive PCI patients throughout the year 2013 in Fuwai Hospital. High on-treatment platelet reactivity (HTPR) and low on-treatment platelet reactivity (LTPR) were defined as thrombelastography (TEG) maximum amplitude of adenosine diphosphate-induced platelet (MAADP) > 47 mm and < 31 mm, respectively. 6615 patients with TEG results were finally enrolled. The mean age was 58.24 ± 10.28 years and 5131 (77.6%) were male. Multivariable logistic regression showed that taking Lp(a) < 30 mg/dL and hs-CRP < 2 mg/L as the reference, isolated Lp(a) elevation [Lp(a) ≥ 30 mg/dL and hs-CRP < 2 mg/L] was not significantly associated with HTPR (P = 0.153) or LTPR (P = 0.312). However, the joint elevation of Lp(a) and hs-CRP [Lp(a) ≥ 30 mg/dL and hs-CRP ≥ 2 mg/L] exhibited enhanced association with both HTPR (OR:1.976, 95% CI 1.677-2.329) and LTPR (OR:0.533, 95% CI 0.454-0.627). The isolated elevation of Lp(a) level was not an independent indicator for platelet reactivity, yet the concomitant elevation of Lp(a) and hs-CRP levels was significantly associated with increased platelet reactivity. Whether intensified antiplatelet therapy or anti-inflammatory strategies could mitigate the risks in patients presenting combined Lp(a) and hs-CRP elevation requires future investigation.

Glutathione Depletion and Concomitant Elevation of Susceptibility in Patients with Parkinson's Disease: State-of-the-Art MR Spectroscopy and Neuropsychological Study.

Parkinson's disease (PD) is characterized by extrapyramidal motor disturbances and nonmotor cognitive impairments which impact activities of daily living. Although the etiology of PD is still obscure, autopsy reports suggest that oxidative stress (OS) is one of the important factors in the pathophysiology of PD. In the current study, we have investigated the impact of OS in PD by measuring the antioxidant glutathione (GSH) levels from the substantia nigra (SN), left hippocampus (LH) and neurotransmitter γ-amino butyric acid (GABA) levels from SN region. Concomitant quantitative susceptibility mapping (QSM) from SN and LH was also acquired from thirty-eight PD patients and 30 age-matched healthy controls (HC). Glutathione levels in the SN region decreased significantly and susceptibility increased significantly in PD compared to HC. Nonsignificant depletion of GABA was observed in the SN region. GSH levels in the LH region were depleted significantly, but LH susceptibility did not alter in the PD cohort compared to HC. Neuropsychological and physical assessment demonstrated significant impairment of cognitive functioning in PD patients compared to HC. GSH depletion was negatively correlated to motor function performance. Multivariate receiver operating characteristic (ROC) curve analysis on the combined effect of GSH, GABA, and susceptibility in the SN region yielded an improved diagnostic accuracy of 86.1% compared to individual diagnostic accuracy based on GSH (65.8%), GABA (57.5%), and susceptibility (69.6%). This is the first comprehensive report in PD demonstrating significant GSH depletion as well as concomitant iron enhancement in the SN region.

Abstract 18209: The Association Between Lp(a) and Low-Density Plaque Volume is Not Modified by CRP

BACKGROUND: Inconsistent data have suggested an interaction between Lp(a) and hs-CRP levels, putting patients with concomitant elevation at the greatest risk for atherosclerotic cardiovascular events. To date, the association between Lp(a), systemic inflammation as measured by hs-CRP, and coronary plaque phenotype has not been unraveled. METHODS: Among consecutive asymptomatic patients evaluated for primary prevention of coronary artery disease, we explored the associations between Lp(a), hs-CRP and coronary atherosclerosis using atherosclerosis imaging-quantitative coronary CT angiography (AI-QCT; Cleerly Labs, Cleerly Inc., Denver,CO). The associations between Lp(a), hs-CRP and the AI-QCT outcomes defined as percent atheroma volume (PAV) as well as percent low-density non-calcified plaque volume (LD-NCPV) were assessed using multivariable linear regression adjusted for clinical risk factors. RESULTS: The mean age of the 373 included patients was 56.2 ± 8.9 years, 71.6% were male, and 54.2% was on statin therapy. Mean±SD LDL-C was 106 ± 41 mg/dl, median (IQR) Lp(a) was 31 (11, 89) nmol/L, while median hs-CRP levels were 0.8 (0.4, 1.8) mg/L. In the multivariable-adjusted analysis, Lp(a) levels were significantly associated with an increase in PAV (0.367 increase in PAV per 100 nmol/l increase in Lp(a), p=0.026) and percent LD-NCPV (0.018 increase in PAV per 100 nmol/l increase in Lp(a), p=0.031). However, there was no effect of adding hs-CRP to the models (p=0.446), and we observed no direct relationship between hs-CRP and PAV (p=0.446) or percent LD-NCPV (0.871). Table 1. CONCLUSIONS: Lp(a) is associated with low-density non-calcified plaque and total coronary plaque burden. The current study found no impact of hs-CRP on these associations, nor were hs-CRP levels associated with plaque burden.