Integration Of Biomarkers Research Articles

Validation of Immunotherapy Response Score as Predictive of Pan-solid Tumor Anti-PD-1/PD-L1 Benefit.

This study confirms the utility of the integrative IRS biomarker for predicting anti-PD-L1/PD-1 benefit. IRS significantly improved upon currently available biomarkers, including PD-L1 IHC, TMB, and MSI status. Additional utility for informing on chemotherapy, anti-PD-L1/PD-1, and anti-PD-L1/PD-1 plus chemotherapy treatments decisions is shown.

Relative Ellipsoid Zone Reflectivity in Macular Telangiectasia Type 2.

The relative ellipsoid zone reflectivity (rEZR) has been proposed as an innovative biomarker for photoreceptor integrity. This study evaluates the rEZR in macular telangiectasia type 2 (MacTel) eyes of different disease stages. The mean rEZR (ratio ellipsoid zone [EZ]/external limiting membrane [ELM] reflectivity [arbitrary units {AUs}], grey level range = 0-1) was analyzed for an entire spectral domain optical coherence tomography volume scan (global) and for each subfield of the Early Treatment Diabetic Retinopathy Study (ETDRS) grid (topographic) in patients with MacTel and controls. MacTel disease severity was classified according to Gass and Blodi. Linear mixed-model analysis of 145 eyes of 74 patients and 50 eyes of 25 controls revealed globally lower, yet not statistically significant, rEZR values in MacTel eyes. Topographically, most pronounced decreases were found in stages 3 and 4/5 for the temporal inner (coefficient estimates [CEs] = -25.4 [-38.2; -12.6] and -34.1 [-48.7; -19.6] AU, both: P < 0.001), the inferior inner (-29.9 [-44.6; -15.6] and -35.3 [-52.1; -18.5] AU, both: P < 0.001), the nasal inner (-21.5 [-35.52; -7.4] and -31.6 [-47.6; -15.6] AU, P = 0,003 and P < 0.001), and in the superior inner subfield of stage 4/5 (-25.0 [-42.0; -7.9] AU, P = 0.004). The rEZR showed association with disease severity and the predilection area of MacTel. Given the current understanding of the pathophysiological concept of MacTel, these findings underscore the value of the rEZR as a potential novel biomarker for outer retinal integrity. Longitudinal studies are demanded to better characterize its value as a biomarker for early photoreceptor alterations and disease progression in MacTel.

Phthalate induced hormetic effect reveals susceptibility of gill compared to muscle tissue after depuration in commercially important fish (Etroplus suratensis)

Effect of Bis-2ethylhexyl phthalate (DEHP) on commercially important tropical fish pearl spot has not been demonstrated at environmental concentrations along with depuration. The species is estuarine, juvenile and difficult to maintain but widely consumed and well distributed in tropical estuaries. Antioxidant activity of SOD, CAT and GPx was enhanced on all exposure days for gill and muscle suggesting high oxidative stress, except on day 5. Detoxifying enzyme-GST behaved differentially in gill and muscle tissue after depuration, depicting inhibited activity of GST in gill leading to lipid peroxidation. However, the muscle tissue was able to recover from stress after 7 days of depuration with the help of detoxifying enzymes. Overcompensation of antioxidant activity was observed over disruption of homeostasis defining hormesis effect. Integrated biomarker (IBR) index depicted high toxicity during entire exposure time, but after depuration, gill could not mediate LPO at lowest concentration (10 μg/l) while muscle tissue recovered, suggesting persistence of stress in gill.

Amino Acid-Based Beverage Interventions Ameliorate Exercise-Induced Gastrointestinal Syndrome in Response to Exertional-Heat Stress: The Heat Exertion Amino Acid Technology (HEAAT) Study.

The study aimed to determine the effects of two differing amino acid beverage interventions on biomarkers of intestinal epithelial integrity and systemic inflammation in response to an exertional-heat stress challenge. One week after the initial assessment, participants (n = 20) were randomly allocated to complete two exertional-heat stress trials, with at least 1 week washout. Trials included a water control trial (CON), and one of two possible amino acid beverage intervention trials (VS001 or VS006). On VS001 (4.5g/L) and VS006 (6.4g/L), participants were asked to consume two 237-ml prefabricated doses daily for 7days before the exertional-heat stress, and one 237-ml dose immediately before, and every 20min during 2-hr running at 60% maximal oxygen uptake in 35 °C ambient conditions. A water volume equivalent was provided on CON. Whole blood samples were collected pre-, immediately post-, 1 and 2hr postexercise, and analyzed for plasma concentrations of cortisol, intestinal fatty acid protein, soluble CD14, and immunoglobulin M (IgM) by ELISA, and systemic inflammatory cytokines by multiplex. Preexercise resting biomarker concentrations for all variables did not significantly differ between trials (p > .05). A lower response magnitude for intestinal fatty acid protein (mean [95% CI]: 249 [60, 437]pg/ml, 900 [464, 1,336]pg/ml), soluble CD14 (-93 [-458, 272]ng/ml, 12 [-174, 197]ng/ml), and IgM (-6.5 [-23.0, 9.9]MMU/ml, -10.4 [-16.2, 4.7]MMU/ml) were observed on VS001 and V006 compared with CON (p < .05), respectively. Systemic inflammatory response profile was lower on VS001, but not VS006, versus CON (p < .05). Total gastrointestinal symptoms did not significantly differ between trials. Amino acid beverages' consumption (i.e.,4.5-6.4g/L), twice daily for 7days, immediately before, and during exertional-heat stress ameliorated intestinal epithelial integrity and systemic inflammatory perturbations associated with exercising in the heat, but without exacerbating gastrointestinal symptoms.

732-P: Biomarkers of Inflammation and Long-Term Microvasculature Integrity in Weight Loss–Induced Prediabetes Remission

The Diabetes Prevention Program Outcomes Study demonstrated that even temporary resolution of prediabetes (remission) to normal glucose regulation (NGR) prevents development of T2D and vascular complications. However, cellular mechanisms are unknown. We have previously shown in the Prediabetes Lifestyle Intervention Study, a German Center for Diabetes Research multicenter study (n = 1105), that lifestyle intervention (LI)-mediated weight loss-induced remission of prediabetes to NGR vs. non-remission is largely driven by improved insulin sensitivity. We hypothesized that these two groups differ by markers of chronic low-grade inflammation. Therefore, we analyzed 31 cytokines implicated in energy metabolism and T2D complications before and after LI in subjects losing ≥5% body weight (n = 113) to compare responders achieving NGR (R, n = 40) to non-responders not achieving NGR (NR, n = 73). Cytokines linked to insulin resistance and T2D such as TNF-α (p = 0.73), IFNγ (p = 0.45) and IL-6 (p = 0.34) did not differ between groups. However, responders showed a significantly stronger reduction of lymphotoxin α (LTα, -0.15 ± 0.29-fold in NR vs. -0.23 ± 0.32 in R, p = 0.02). VCAM (-0.04 ± 0.14 NR vs. -0.08 ±10.9 R, p = 0.02) and ICAM (-0.11 ±0.15 NR vs. -0.16 ± 0.14 R, p = 0.02), which are induced by LTα and have been implied in mediating cardiovascular complications, were also more strongly reduced in responders. To assess if this is linked with long-term microvasculature integrity, we applied optoacoustic mesoscopy up to 5 years after LI (n = 22). Total vessel and junction density and number of junction to endpoint branches (NJEB) were higher in responders at follow-up (NJEB: 154.9 ± 25.3 vs. 186.9 ± 16.1, p &amp;lt; 0.01). These data describe a distinct pattern of reduced low-grade inflammation characterizing remission of prediabetes to NGR. Although limited by low n, this pattern may help explain the positive effects of prediabetes remission on vascular complications. Disclosure A.Sandforth: None. J.Szendroedi: None. S.M.Meyhöfer: Speaker's Bureau; Novo Nordisk, AstraZeneca, Lilly, Amgen Inc., Boehringer-Ingelheim, Novartis. M.Roden: Advisory Panel; Eli Lilly and Company, Consultant; TARGET PharmaSolutions, Inc., Research Support; Boehringer-Ingelheim, Novo Nordisk, Novartis, Sanofi. L.Fritsche: None. N.Stefan: Advisory Panel; Pfizer Inc., Research Support; Sanofi, Speaker's Bureau; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Lilly Diabetes, Novo Nordisk, Sanofi-Aventis Deutschland GmbH. R.Wagner: Advisory Panel; Daiichi Sankyo, Speaker's Bureau; Novo Nordisk, Sanofi. A.Fritsche: Advisory Panel; Novo Nordisk, Lilly, Sanofi, Boehringer-Ingelheim, Speaker's Bureau; AstraZeneca, SYNLAB Holding Deutschland GmbH. R.Jumpertz von schwartzenberg: Other Relationship; Sanofi, Amgen Inc., Lilly, Novo Nordisk. A.L.Birkenfeld: None. S.Katzenstein: None. J.Seissler: None. S.R.Bornstein: None. N.Perakakis: Advisory Panel; Bayer Inc., Other Relationship; Novo Nordisk, Novo Nordisk. S.Kabisch: Other Relationship; Berlin-Chemie AG, Sanofi, Lilly, Boehringer Ingelheim Inc., JuZo Akademie, Research Support; J. Rettenmaier / Söhne, Wilhelm-Doerenkamp Foundation, German Center of Diabetes Research. A.F.Pfeiffer: Advisory Panel; Abbott Diabetes, Speaker's Bureau; Novo Nordisk, Sanofi-Aventis Deutschland GmbH. H.Häring: None. M.Blüher: Advisory Panel; Boehringer Ingelheim Inc., Lilly, Novo Nordisk, Consultant; Novo Nordisk Foundation, Speaker's Bureau; Amgen Inc., AstraZeneca, Bayer Inc., Daiichi Sankyo, Novartis, Sanofi-Aventis Deutschland GmbH.

Fungal translocation measured by serum 1,3-ß-D-glucan correlates with severity and outcome of liver cirrhosis-A pilot study.

On a global scale, liver cirrhosis is attributable to ~1 million deaths per year. This systemic disease comes along with diverse sequelae, including microbiota alterations, increased gut permeability and translocation of microbial components into the systemic circulation. Alongside the extensively studied influence of bacterial translocation and its host-pathogen interactions, far less is known about the role and impact of fungal components once having crossed the intestinal barrier. Including 70 patients with different aetiologies of liver cirrhosis, we investigated the relationship between fungal translocation, measured by 1,3-β-D-glucan (BDG), and biomarkers of gut integrity, inflammation and severity/outcome of liver disease. Patients with cirrhosis Child-Pugh class (CPC)-B were more likely to have positive serum BDG (aOR 5.4, 95% CI 1.2-25.2) compared to patients with cirrhosis CPC-A. BDG showed a moderate positive correlation with several markers of inflammation (sCD206, sCD163, Interleukin 8, interferon-gamma-induced protein). Mortality differed significantly between patients with positive versus negative BDG (log-rank test, p = 0.015). The multivariable Cox regression model yielded an aHR of 6.8 (95% CI 1.8-26.3). We observed trends for increased fungal translocation depending on the severity of liver cirrhosis, an association of BDG with an inflammatory environment and the adverse effects of BDG on disease outcome. In order to gain more in-depth knowledge about (fungal-)dysbiosis and its detrimental consequences in the setting of liver cirrhosis, these trends need to be studied in more detail including prospective sequential testing in larger cohorts together with mycobiome analyses. This will further elucidate complex host-pathogen interactions and potentially introduce points of application for therapeutic interventions.

Nano-TiO2 aggravates the adverse effect of pentachlorophenol on antioxidant and immune response in anti-predatory mussels

Nano-TiO2 can act as a vector to organic compounds, such as pentachlorophenol (PCP) posing a potential threat to the marine ecosystems. Studies showed that nano pollutant toxicity can be modulated by abiotic factors, but little is known about the potential influence of biotic stressors (such as predators) on the physiological responses to pollutants in marine organisms. We explored the effects of n-TiO2 and PCP on the mussel Mytilus coruscus in the presence of its natural predator, the swimming crab Portunus trituberculatus. Exposure to n-TiO2, PCP, and predation risk showed interactive effects on antioxidant and immune parameters of the mussels. Elevated activities of catalase (CAT), glutathione peroxidase (GPX), acid phosphatase (ACP) and alkaline phosphatase (AKP), suppressed activity of superoxide dismutase (SOD), lower levels of glutathione (GSH) and increased malondialdehyde (MDA) levels indicated dysregulation of the antioxidant system and immune stress induced by single PCP or n-TiO2 exposure. Integrated biomarker (IBR) response values showed the effect of PCP was concentration dependent. Of the two used n-TiO2 sizes (25 and 100 nm), larger particles induced higher antioxidant and immune disturbances indicating higher toxicity possibly due to higher bioavailability. Compared to single PCP exposure, the combination of n-TiO2 and PCP enhanced the imbalance of SOD/CAT and GSH/GPX and led to elevated oxidative lesions and activation of immune-related enzymes. Overall, the combined impacts of pollutants and biotic stress exhibited a greater magnitude of adverse effects on antioxidant defense and immune parameters in mussels. The toxicological effects of PCP were exacerbated in the presence of n-TiO2, and the deleterious impact of these stressors was further amplified under predator-induced risk after prolonged (28 days) exposure. However, the underlying physiological regulatory mechanisms governing the interplay of these stressors and predatory cues on mussels remain elusive, warranting further investigation.

Size-dominated biotoxicity of microplastics laden with benzophenone-3 and ciprofloxacin: Enhanced integrated biomarker evaluation on mussels

Microplastics (MPs) are emerging pollutants with diverse sizes in aquatic environments. This paper investigates the toxicity of micron- and nano-scale polystyrene (50 μm, 5 μm, 0.5 μm) loaded with 2-hydroxy-4-methoxy-benzophenone (BP-3) and ciprofloxacin (CIP) by eight biomarker responses in mussels, perna viridis. The mussels were exposed to MPs and chemicals for 7 days before 7 days of depuration. Eight biomarkers were measured to determine biotoxicity over time by using the weighted integrated biomarkers index evaluation (EIBR). Mussels exposed to MPs on a daily basis demonstrated a cumulative toxic effect. The toxicity of MPs for mussels was inversely related to the size at which they can be ingested. Then toxicity was reversed when exposure was halted. EIBR mold has shown a significant difference in the biotoxicity of each biological level under different exposure scenarios. In general, the mussel toxicity influenced by BP-3 and CIP exposure without an adsorbent was insignificant. MPs laden with them increased the toxicity of mussels. Under condition of lower concentration of ECs (Emerging contaminants), the presence of MPs as a component of a combined pollutant in water dominated the biotoxicity for mussels. The EIBR assessment further validated that the biotoxicity of mussels was size-dependent. Its application simplified the biomarkers’ response index and enhanced the accuracy of evaluation by weighing on molecular, cellular and physiological level. Specifically, mussels were physiologically sensitive to nano-scale plastics, with nano-scale plastics causing a higher level of cellular immunity destruction and genotoxicity than micron-scale plastics. Enzymatic antioxidant systemswere upregulated based on size-differential plastics; however, the total antioxidant effect of non-enzymatic defenses appeared to be least affected by the size effect.

Tau influences the severity of delusions in older persons with early‐stage cognitive decline

AbstractBackgroundThe relationship between delusional severity and structural brain changes in patients with cognitive decline is unclear. In prior work by our group, we conducted texture and volume analysis of Normal Appearing Brain Matter (NABM) using FLAIR MRI sequences in a cognitively impaired delusional cohort. Our results demonstrated that with more severe delusions, greater global brain disease burden and tissue degeneration in NABM is apparent. In this study we examined the relationship between our findings and neurodegenerative biomarkers, ApoE4 and plasma tau.MethodsA total of 42 patients with Alzhiemer’s disease (AD) or Mild Cognitive Impairment (MCI) with delusions as identified by the Neuropsychiatric Inventory‐Quick version (NPI‐Q) were selected from the Alzheimer’s Disease Neuroimaging Initiative (ADNI). From fluid‐attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI) images, Brain extraction and intensity standardization alghorthims were applied to extract the normal‐appearing brain matter (NABM). Three biomarkers were measured from the NABM region, which included volume and two texture features called integrity and damage that measure the structural integrity of tissue and tissue damage. Statistical analysis included a multivariable stepwise regression of each biomarker as a dependent variable across delusional severity groups 1 (lowest severity) to 3 (highest severity) and the inclusion of sex, age, education, ApoE4 and plasma tau as co‐variates.ResultsData were gathered on the 42 participants representing 164 MRI scans. Significant associations were found between baseline plasma tau, delusional severity group 3 for the NABM integrity and volume biomarkers (p&lt;.05). Additionally, ApoE4 homozygotes were signficantly associated to NABM volume, integrity and damage, though no association was found with delusional severity.ConclusionThese findings suggest that plasma tau may be linked to both delusional severity and structural alterations within the NABM while ApoE4 status is more strongly associated with structural alterations in the NABM with no effect on delusional severity. Further longitudinal studies are required to establish plasma tau associated mechanisms of delusional severity.

Association of Body Mass Index and Waist Circumference With Imaging Metrics of Brain Integrity and Functional Connectivity in Children Aged 9 to 10 Years in the US, 2016-2018

Aside from widely known cardiovascular implications, higher weight in children may have negative associations with brain microstructure and neurodevelopment. To evaluate the association of body mass index (BMI) and waist circumference with imaging metrics that approximate brain health. This cross-sectional study used data from the Adolescent Brain Cognitive Development (ABCD) study to examine the association of BMI and waist circumference with multimodal neuroimaging metrics of brain health in cross-sectional and longitudinal analyses over 2 years. From 2016 to 2018, the multicenter ABCD study recruited more than 11 000 demographically representative children aged 9 to 10 years in the US. Children without any history of neurodevelopmental or psychiatric disorders were included in this study, and a subsample of children who completed 2-year follow-up (34%) was included for longitudinal analysis. Children's weight, height, waist circumference, age, sex, race and ethnicity, socioeconomic status, handedness, puberty status, and magnetic resonance imaging scanner device were retrieved and included in the analysis. Association of preadolescents' BMI z scores and waist circumference with neuroimaging indicators of brain health: cortical morphometry, resting-state functional connectivity, and white matter microstructure and cytostructure. A total of 4576 children (2208 [48.3%] female) at a mean (SD) age of 10.0 years (7.6 months) were included in the baseline cross-sectional analysis. There were 609 (13.3%) Black, 925 (20.2%) Hispanic, and 2565 (56.1%) White participants. Of those, 1567 had complete 2-year clinical and imaging information at a mean (SD) age of 12.0 years (7.7 months). In cross-sectional analyses at both time points, higher BMI and waist circumference were associated with lower microstructural integrity and neurite density, most pronounced in the corpus callosum (fractional anisotropy for BMI and waist circumference at baseline and second year: P < .001; neurite density for BMI at baseline: P < .001; neurite density for waist circumference at baseline: P = .09; neurite density for BMI at second year: P = .002; neurite density for waist circumference at second year: P = .05), reduced functional connectivity in reward- and control-related networks (eg, within the salience network for BMI and waist circumference at baseline and second year: P < .002), and thinner brain cortex (eg, for the right rostral middle frontal for BMI and waist circumference at baseline and second year: P < .001). In longitudinal analysis, higher baseline BMI was most strongly associated with decelerated interval development of the prefrontal cortex (left rostral middle frontal: P = .003) and microstructure and cytostructure of the corpus callosum (fractional anisotropy: P = .01; neurite density: P = .02). In this cross-sectional study, higher BMI and waist circumference among children aged 9 to 10 years were associated with imaging metrics of poorer brain structure and connectivity as well as hindered interval development. Future follow-up data from the ABCD study can reveal long-term neurocognitive implications of excess childhood weight. Imaging metrics that had the strongest association with BMI and waist circumference in this population-level analysis may serve as target biomarkers of brain integrity in future treatment trials of childhood obesity.

Integrative biomarker response - Threshold (IBR-T): Refinement of IBRv2 to consider the reference and threshold values of biomarkers

The Integrated Biomarker Response (IBR) is one of the most used index in biomonitoring, especially the IBRv2 integrating a reference condition. However, some limitations remain for its routine and large-scale use. The IBRv2 is proportional to the total number of biomarkers, is dependent on the nature of biomarkers and considers all biomarkers modulations, even small and biologically non-significant. In addition, IBRv2 relies on reference values but the references are often different between each study, making it difficult to compare results between studies and/or campaigns. To overcome these limitations, the present work proposed a new index called IBR-T (“Integrated Biomarker Response – Threshold”) which considers the threshold values of biomarkers by limiting the calculation of the IBR value to biomarkers with significant modulations. The IBRv2 and the IBR-T were calculated and compared on four datasets from active biomonitoring campaigns using Dreissena polymorpha, a bivalve widely used in freshwater biomonitoring studies. The comparison between indices has demonstrated that the IBR-T presents a better correlation (0.907 < r2 < 0.998) with the percentage of biomarkers significantly modulated than the IBRv2 (0.002 < r2 < 0.759). The IBRv2 could not be equal to 0 (0.915 < intercept <1.694) because the value was dependent on the total number of biomarkers, whereas the IBR-T reached 0 when no biomarker was significantly modulated, which appears more biologically relevant. The final ranking of sites was different between the two index and the IBR-T ranking tends to be more ecologically relevant that the IBRv2 ranking. This IBR-T have shown an undeniable interest for biomonitoring and could be used by environmental managers to simplify the interpretation of large datasets, directly interpret the contamination status of the site, use it to decision-making, and finally to easily communicate the results of biomonitoring studies to the general public.

Cognitive Function During Pregnancy In Multiple Sclerosis: Is There A Decline In Processing Speed? (P9-3.004)

Cognitive Function During Pregnancy In Multiple Sclerosis: Is There A Decline In Processing Speed? (P9-3.004)

Relationship Between White Matter Hyperintensities and Blood Biomarkers of Axonal Injury and White Matter Integrity (P14-7.002)

Relationship Between White Matter Hyperintensities and Blood Biomarkers of Axonal Injury and White Matter Integrity (P14-7.002)

Modulation of gut microbiota and intestinal immune response in gilthead seabream (Sparus aurata) by dietary bile salt supplementation.

Given their role in lipid digestion, feed supplementation with bile salts could be an economic and sustainable solution to alterations in adiposity and intestinal inflammation generated by some strategies currently used in aquaculture. An important part of the metabolism of bile salts takes place in the intestine, where the microbiota transforms them into more toxic forms. Consequently, we aimed to evaluate the gut immune response and microbial populations in gilthead seabream (Sparus aurata) fed a diet supplemented with a blend of bile salts with proven background as a regulator of lipid metabolism and fat content. After the 90-day feeding trial, a differential modulation of the microbiota between the anterior and posterior intestine was observed. While in the anterior intestine the relative abundance of Desulfobacterota doubled, in the posterior intestine, the levels of Firmicutes increased and Proteobacteria, Actinobacteriota, and Campylobacterota were reduced when supplementing the diet with bile salts. Even so, only in the anterior intestine, there was a decrease in estimated richness (Chao1 and ACE indices) in presence of dietary bile salts. No significant differences were displayed in alpha (Shannon and Simpson indices) nor beta-diversity, showing that bile sales did not have a great impact on the intestinal microbiota. Regarding the gene expression profile in 2 h postprandial-fish, several changes were observed in the analyzed biomarkers of epithelial integrity, nutrient transport, mucus production, interleukins, cell markers, immunoglobulin production and pathogen recognition receptors. These results may indicate the development of an intestinal immune-protective status to tackle future threats. This work also suggests that this immune response is not only regulated by the presence of the dietary bile salts in the intestine, but also by the microbial populations that are in turn modulated by bile salts. After a fasting period of 2 days, the overall gene expression profile was stabilized with respect to fish fed the unsupplemented diet, indicating that the effect of bile salts was transient after short periods of fasting. On the balance, bile salts can be used as a dietary supplement to enhance S. aurata farming and production without compromising their intestinal health.

Higher CSF/serum free-T4 ratio is associated with improvement of quality of life during treatment with L-thyroxine.

Up to 20% of individuals with primary hypothyroidism treated with L-thyroxine still suffer from severe symptoms. These are supposedly brain derived and involve both cognitive and emotional domains. Previously, no consistent relationship has been found between thyroid hormones (TH) or TSH levels in blood and quality of life (QoL). Recently, we reported an association between cerebrospinal fluid (CSF)/serum free-thyroxine (f-T4) ratio and QoL, in juvenile hypothyroid patients. Here, we investigated if CSF/serum f-T4 ratio and QoL estimates correlate also during L-thyroxine treatment. Moreover, the CSF biomarker neurogranin (Ng) was used as a biomarker for synaptic function and integrity in clinical research. Ng is partially controlled by TH and therefore we investigated the relationship between QoL parameters and Ng levels. Patients diagnosed with primary hypothyroidism were investigated using vital parameters, serum and CSF analyses of TH, TSH, Ng and QoL questionnaires. Similar procedures were performed after 6 months of treatment. The most marked associations with QoL were found for CSF/serum f-T4 ratio, which was strongly related to several QoL parameters such as the mental subscore of SF-36 (r = 0.83, p < .0005). Ng, which did not differ from that in our healthy controls, was lower in some patients during treatment and higher in others. However, the change in Ng during treatment was significantly correlated with QoL parameters including the mental subscore of SF-36 (r = -0.86, p < .0001). In addition, the CSF/serum f-T4 ratio correlated with the change in Ng (r = -0.75, p = .001). Our results suggest that the ratio between CSF and serum f-T4 is an important biomarker for QoL during treatment of patients with primary hypothyroidism, so far in research, but in the future maybe also in clinical settings. Moreover, this ratio also correlates with the changes in Ng levels during L-thyroxine treatment, further supporting the impact of the TH balance between serum and CSF on QoL.

Abstract 2700: ORM-6151: A first-in-class CD33-antibody enabled GSPT1 degrader for AML

Abstract Targeted protein degraders (TPDs) have expanded the breadth of therapeutic options through both their catalytic mechanism of action and ability to degrade previously “undruggable” target proteins. Prior reports of small-molecule GSPT1 degraders such as CC-90009 in AML demonstrate potent anti-tumor cytotoxicity, but with a potentially narrow therapeutic index. To increase the efficacy vs. tolerability window of TPDs and improve drug delivery, we introduce TPD-Squared (TPD2 TM), a dual-targeted protein degradation approach of combining the catalytic mechanism of targeted protein degradation with the precision of tumor-targeting therapeutic antibodies. We have previously shown in vitro and in vivo efficacy with a HER2-targeted TPD2 conjugate: ORM-5029. Following on that success, we generated conjugates using a CD33-targeting antibody (OR000283) produced by engineering the FAb (H&amp;L) sequences from gemtuzumab onto an IgG1 Fc with N297A variant to inhibit Fc-γR binding. Medicinal chemistry optimization of linker-payloads led to the identification of ORM-6151, which is composed of SMol006, a highly potent GSPT1 degrader conjugated to OR000283 via a novel β-glucuronide releasable linker. ORM-6151 treatment in CD33-expressing cell lines showed picomolar activity with 10-1000-fold greater potency compared to several GSPT1 degrader molecules, including CC-90009 or Mylotarg, and had robust activity in Mylotarg-resistant lines (AML193 and Kasumi6). ORM-6151 also exhibited picomolar potency in in vitro cytotoxicity to primary relapsed/refractory AML patient blasts, with better potency than CC-90009 and Mylotarg. We evaluated ORM-6151 in several in vivo disseminated xenograft models and observed robust efficacy following a single treatment at doses as low as 0.1 mg/kg. Tumor growth inhibition correlated with the degree and duration of GSPT1 depletion and changes in the expression of previously described integrated stress response biomarker genes. In summary, ORM-6151 is a promising, potential therapy for AML and currently in preclinical development as a first-in-class targeted protein degrader therapy with CD33-targeted delivery. Citation Format: James Palacino, Pedro Lee, Hangyeol Jeong, Yeonjoon Kim, Yoojin Song, Uttapol Permpoon, Wesley Wong, Chen Bai, Nathan Fishkin, Khuloud Takouri, Eunjun Yu, Yong Yi, Anna Skaletskaya, Min-Soo Kim, Da-Yeong Kim, Dong-Ki Choi, Peter U. Park. ORM-6151: A first-in-class CD33-antibody enabled GSPT1 degrader for AML [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2700.

Abstract 1392: Integrative biomarker analysis of regorafenib plus nivolumab (RegoNivo) in unresectable hepatocellular carcinoma (uHCC): A multicenter phase 2 RENOBATE trial

Abstract Regorafenib plus nivolumab (RegoNivo) combination has shown promising anti-cancer activity in multiple cancer types. REBNOBATE trial is a single-arm multicenter phase 2 trial of first-line RegoNivo in patients (pts) with uHCC (NCT04310709). Here we report the clinical outcomes of the RENOBATE study and integrative biomarker analysis using circulating tumor DNA (ctDNA) and single cell RNA sequencing (scRNA-seq) analysis. Method: Adult pts with ECOG PS 0 or 1, BCLC stage B or C, and no prior systemic therapy were eligible for the study. Pts received nivolumab 480 mg iv, every 4 wks, and regorafenib 80 mg daily po, 3 wks on/1 wk off, every 4 wks. Tumor response was assessed according to RECIST v1.1 every 8 wks. ctDNA analysis was performed using the Guardant 360 CDx (n=42). scRNA-seq was performed using PBMCs at baseline (e.g., C1D1) and on treatment (eg., C1D15) from early progression (EP) group (14 pts with PD or tumor burden increases towards PD on the 1st evaluation) and long-term response (LR) group (15 pts with PR or SD &amp;gt; 6 months). Results: 42 pts were enrolled. Response rates were 31.0% and median progression-free survival (was 7.4 mo (95% CI, 4.2-13.0) and 1-year OS rate was 80.5% (95% CI, 63.0-90.3%). Aberrations of Wnt/β-Catenin and PI3K/mTOR pathways identified in ctDNA were not associated with efficacy outcomes. scRNA-seq revealed that genes upregulated in immune cells on C1D15 (vs. C1D1) were associated with immune activation and regulation of angiogenesis. Unsupervised clustering identified 13 immune subsets; among them, classical monocyte showed the most prominent changes in their proportion and gene expression profiles. After RegoNivo treatment, CD8 clusters had enhanced expressions of genes related to cytotoxicity, tissue homing (i.e., CXCR6, CX3CR1, and CXCR3) and proliferation (MKI67), and monocyte clusters showed an enrichment of the gene signatures representing polarization towards M1-related features. Importantly, the enrichment of cytotoxic features of the T cell clusters and M1-polarizing features of monocyte clusters were more pronounced in LR group than in EP group. From the analysis of differentially expressed genes monocyte clusters between the EP and LR groups, a surface molecule ‘X’ was identified as a potential biomarker involved in resistance to RegoNivo. RegoNivo showed promising efficacy outcomes in pts with uHCC. Through scRNA-seq of serial PBMCs, we identified enhanced cellular immune responses induced by RegoNivo and a potential predictive marker for immunotherapy in pts with uHCC. Our study highlighted that regorafenib might synergize with anti-PD-1 in pts with uHCC. Association between differential features of T cell and monocyte clusters induced by this combination and distinct clinical outcomes highlights the importance of immune-modulation in HCC pts suggesting a potential to further harness these signals Citation Format: Hyung-Don Kim, Seyoung Jung Jung, Baek-Yeol Ryoo, Min-Hee Ryu, Beodeul Kang, Hong Jae Chon, Jung Yong Hong, Ho Yeong Lim, Jeong Seok Lee, June-Young Koh, Changhoon Yoo. Integrative biomarker analysis of regorafenib plus nivolumab (RegoNivo) in unresectable hepatocellular carcinoma (uHCC): A multicenter phase 2 RENOBATE trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1392.

Abstract 3238: Integrative biomarker analysis of regorafenib plus nivolumab (RegoNivo) in unresectable hepatocellular carcinoma (uHCC): A multicenter phase 2 RENOBATE trial

Abstract RegoNivo combination has shown promising anti-cancer activity in multiple cancer types. REBNOBATE is a single-arm multicenter phase 2 trial of first-line RegoNivo in patients (pts) with uHCC (NCT04310709). In this study, we present the final clinical outcomes of RENOBATE and integrative biomarker analysis. Pts with &amp;gt;19 years, ECOG PS 0 or 1, BCLC stage B or C, and no prior systemic therapy were eligible. Pts received Nivo 480 mg iv, every 4 wks, and Rego 80 mg daily po, 3 wks on/1 wk off, every 4 wks. Tumor response was assessed according to RECIST v1.1 every 8 wks. ctDNA analysis was performed using the Guardant 360 CDx platform (n=42). scRNA-seq was performed using peripheral blood mononuclear cells (PBMCs) at baseline (e.g., C1D1, n=28) and C1D15 (n=19) from early progression (EP) group (pts with PD or tumor burden increases towards PD on the first evaluation) and long-term response (LR) group (pts with PR or SD &amp;gt; 6 months). A total of 42 pts was enrolled. Response rates were 31.0% and median progression-free survival (PFS) was 7.4 mo (95% CI, 4.2-13.0) and 1-year OS rate was 80.5% (95% CI, 63.0-90.3%). Aberrations of Wnt/β-Catenin and PI3K/mTOR pathways identified in ctDNA were not associated with efficacy outcomes. scRNA-seq revealed that genes upregulated in immune cells on C1D15 (vs. baseline) were associated with immune activation and regulation of angiogenesis. Unsupervised clustering identified 13 immune subets; among them, classical monocyte showed most prominent changes in their proportion and gene expression profiles. After RegoNivo treatment, CD8 T cell clusters had enhanced expressions of genes related to cytoxicity, tissue homing (i.e., CXCR6, CX3CR1, and CXCR3) and proliferation (MKI67), and monophaghocyte clusters showed an enrichment of the gene signatures representing polarization towards M1-related features. Importantly, enrichment of cytotoxic features of the T cell clusters and M1-polarizing features of monophagocyte clusters were more pronounced in LR group than in EP group. From the analysis of differentially expressed genes monophagocyte clusters between the EP and LR groups, a surface molecule ‘X’ was identified as a potential biomarker involved in resistance to RegoNivo. RegoNivo showed promising efficacy outcomes in pts with uHCC. Through scRNA-seq of serial PBMCs, we identified enhanced cellular immune responses induced by RegoNivo and found a potential predictive marker for immunotherapy in pts with uHCC. Our study highlighted that Rego, a multikinase inhibitor, might synergize with anti-PD-1 in pts with uHCC. Association between differential features of T cell and monophagocyte clusters induced by this combination and distinct clinical outcomes highlights the importance of immune-modulation in HCC pts and suggests a potential to further harness these signals. Citation Format: Hyung-Don Kim, Seyoung Jung, Baek-Yeol Ryoo, Min-Hee Ryu, Beodeul Kang, Hong Jae Chon, Jung Yong Hong, Ho Yeong Lim, Jeong Seok Lee, June-Young Koh, Changhoon Yoo. Integrative biomarker analysis of regorafenib plus nivolumab (RegoNivo) in unresectable hepatocellular carcinoma (uHCC): A multicenter phase 2 RENOBATE trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3238.

Metabolic syndrome biomarkers relate to rate of cognitive decline in MCI and dementia stages of Alzheimer’s disease

BackgroundThe relationship between biomarkers of metabolic syndrome and insulin resistance, plasma triglyceride/HDL cholesterol (TG/HDL-C) ratio, on the rate of cognitive decline in mild cognitive impairment (MCI) and dementia stages of Alzheimer’s disease (AD) is unknown. The role of peripheral and cerebrospinal fluid (CSF) levels of Apolipoprotein A1 (ApoA1), a key functional component of HDL, on cognitive decline also remains unclear among them. Here we evaluate baseline plasma TG/HDL-C ratio and CSF and plasma ApoA1 levels and their relation with cognitive decline in the MCI and Dementia stages of AD.Patients and methodsA retrospective longitudinal study (156 participants; 106 MCI, 50 AD dementia) from the Alzheimer’s Disease Neuroimaging Initiative, with an average of 4.0 (SD 2.8) years follow-up. Baseline plasma TG/HDL-C, plasma, and CSF ApoA1 and their relationship to inflammation and blood–brain barrier (BBB) biomarkers and longitudinal cognitive outcomes were evaluated. Multivariable linear mixed effect models were used to assess the effect of baseline analytes with longitudinal changes in Mini-Mental State Exam (MMSE), Clinical Dementia Rating–Sum of Boxes (CDR-SB), and Logical Memory delayed recall (LM) score after controlling for well-known covariates.ResultsA total of 156 participants included 98 women, 63%; mean age was 74.9 (SD 7.3) years. At baseline, MCI and dementia groups did not differ significantly in TG/HDL-C (Wilcoxon W statistic = 0.39, p = 0.39) and CSF ApoA1 levels (W = 3642, p = 0.29), but the dementia group had higher plasma ApoA1 than the MCI group (W = 4615, p = 0.01). Higher TG/HDL-C ratio was associated with faster decline in CDR-SB among MCI and dementia groups. Higher plasma ApoA1 was associated with faster decline in MMSE and LM among MCI, while in contrast higher CSF ApoA1 levels related to slower cognitive decline in MMSE among MCI. CSF and plasma ApoA1 also show opposite directional correlations with biomarkers of BBB integrity. CSF but not plasma levels of ApoA1 positively correlated to inflammation analytes in the AGE-RAGE signaling pathway in diabetic complications (KEGG ID:KO04933).ConclusionsBiomarkers of metabolic syndrome relate to rate of cognitive decline among MCI and dementia individuals. Elevated plasma TG/HDL-C ratio and plasma ApoA1 are associated with worse cognitive outcomes in MCI and dementia participants. CSF ApoA1 and plasma ApoA1 likely have different roles in AD progression in MCI stage.

Evaluation of Scapholunate Injury and Repair with Dynamic (4D) CT: A Preliminary Report of Two Cases.

Background In predynamic or dynamic scapholunate (SL) instability, standard diagnostic imaging may not identify SL interosseous ligament (SLIL) injury, leading to delayed detection and intervention. This study describes the use of four-dimensional computed tomography (4DCT) in identifying early SLIL injury and following injured wrists to 1-year postoperatively. Description of Technique 4DCT acquires a series of three-dimensional volume data with high temporal resolution (66 ms). 4DCT-derived arthrokinematic data can be used as biomarkers of ligament integrity. Patients and Methods This study presents the use of 4DCT in a two-participant case series to assess changes in arthrokinematics following unilateral SLIL injury preoperatively and 1-year postoperatively. Patients were treated with volar ligament repair with volar capsulodesis and arthroscopic dorsal capsulodesis. Arthrokinematics were compared between uninjured, preoperative injured, and postoperative injured (repaired) wrists. Results 4DCT detected changes in interosseous distances during flexion-extension and radioulnar deviation. Generally, radioscaphoid joint distances were greatest in the uninjured wrist during flexion-extension and radioulnar deviation, and SL interval distances were smallest in the uninjured wrist during flexion-extension and radioulnar deviation. Conclusion 4DCT provides insight into carpal arthrokinematics during motion. Distances between the radioscaphoid joint and SL interval can be displayed as proximity maps or as simplified descriptive statistics to facilitate comparisons between wrists and time points. These data offer insight into areas of concern for decreased interosseous distance and increased intercarpal diastasis. This method may allow surgeons to assess whether (1) injury can be visualized during motion, (2) surgery repaired the injury, and (3) surgery restored normal carpal motion. Level of Evidence Level IV, Case series.