High Metabolic Rate Research Articles

Calculating Comfort Indexes and Applying Comfort Models to Predict Thermal Sensation Vote in Sports Centres

Predicting the indoor thermal comfort of people while doing sports might pose challenges, as the combination of high metabolic rate, increased humidity of the space due to physical exercise, and the alternate of more and less intense tasks influence perception. This paper is aimed at comparing environmental data (temperature and relative humidity) and calculating comfort indexes (heat index) and two comfort models (Fanger’s predicted mean value and the adaptive thermal comfort model) with people’s perceptions of the environment. Indoor environmental data for the analysis were collected by monitoring several rooms in eight sports centres in a Mediterranean climate. The thermal sensation votes (TSVs) of the occupants were obtained through an online survey. A detailed explanation of the methodology of the monitoring, creation, and management of the survey and the tools used to analyse the data is provided. Results compare the relation between the TSV and the parameters or indexes calculated. Fanger’s predicted mean vote (PMV) model is not able to correctly predict people’s sensations, neither for low nor for high metabolic rates. Finally, the neutral temperature of the adaptive model for the studied conditions is calculated. Among the studied parameters and indices, temperature exhibits the strongest correlation with the thermal sensation of the occupants. However, occupants did not report a significant sensation regarding humidity in accordance with the objective conditions of the rooms. The heat index also did not show any significant correlation with the TSV. Nevertheless, across a wide range of conditions, including variations in metabolic activities, temperature, and relative humidity, the percentage of thermal dissatisfaction (indicated by “very hot” responses) remains consistently high. Notably, the temperature at which a peak in neutral sensation can be achieved is less than 21° for low metabolic rate activities.

Serum Adropin Levels Are Elevated in Patients With Hyperthyroidism.

Objective: Adropin is a unique hormone, which controls metabolism and energy homeostasis. Hyperthyroidism is a disease with a high metabolic rate that affects both glucose and lipid metabolism. We aimed to investigate the change of adropin levels and the association between adropin levels and clinical parameters in patients with hyperthyroidism. Methods: This cross-sectional study comprised 90 newly diagnosed patients with hyperthyroidism and 90 age- and gender-matched healthy controls. Circulating adropin levels and thyroid hormone levels were evaluated in each participant. Results: Compared with the healthy controls, the hyperthyroid patients had significantly higher levels of serum adropin (p < 0.001). In addition, adropin levels were positively correlated with free triiodothyronine (FT3) and free thyroxine (FT4), whereas they were negatively correlated with thyroid-stimulating hormone (TSH). A multivariate linear regression analysis showed that serum adropin concentrations were independently correlated with FT3 and TSH after adjustment for age, gender, and other confounding factors (FT3: β = 0.231, p < 0.05; TSH: β = -0.301, p < 0.05). Conclusions: Patients with hyperthyroidism had elevated serum adropin levels. And the serum adropin concentrations were independently correlated with the FT3 and TSH levels.

Clearance tests to assess liver function state of animals using compounds with high hepatic metabolism

The article is devoted to the study of the medicinal substances metabolism in the liver and the possibility of using clearance tests with lidocaine and caffeine in veterinary medicine. It has been established that liver is the main organ where metabolism takes place, which is carried out in two stages involving the reactions of microsomal oxidation of fermentable cytochrome P450. Substances with a high metabolic rate undergo presystemic elimination. In liver pathologies, the metabolism of xenobiotics changes, substances with a high metabolism can cause toxic effects with a single application, with a low one – with cumulation. Intravenous clearance test with lidocaine showed that the lower the concentration of metabolites after 15 and 30 minutes, the more unfavorable the prognosis for survival. The test can also be used on dogs. The clearance test with caffeine can be performed intravenously, by respiratory methods or through saliva sampling. The test showed results comparable to the lidocaine test. However, clearance tests are influenced by many factors, so researchers recommend using them as an additional research method.

Lipids in Insect Reproduction: Where, How, and Why.

Modern insects have inhabited the earth for hundreds of millions of years, and part of their successful adaptation lies in their many reproductive strategies. Insect reproduction is linked to a high metabolic rate that provides viable eggs in a relatively short time. In this context, an accurate interplay between the endocrine system and the nutrients synthetized and metabolized is essential to produce healthy offspring. Lipids guarantee the metabolic energy needed for egg formation and represent the main energy source consumed during embryogenesis. Lipids availability is tightly regulated by a complex network of endocrine signals primarily controlled by the central nervous system (CNS) and associated endocrine glands, the corpora allata (CA) and corpora cardiaca (CC). This endocrine axis provides hormones and neuropeptides that significatively affect tissues closely involved in successful reproduction: the fat body, which is the metabolic center supplying the lipid resources and energy demanded in egg formation, and the ovaries, where the developing oocytes recruit lipids that will be used for optimal embryogenesis. The post-genomic era and the availability of modern experimental approaches have advanced our understanding of many processes involved in lipid homeostasis; therefore, it is crucial to integrate the findings of recent years into the knowledge already acquired in the last decades. The present chapter is devoted to reviewing major recent contributions made in elucidating the impact of the CNS/CA/CC-fat body-ovary axis on lipid metabolism in the context of insect reproduction, highlighting areas of fruitful research.

Design and Characterization of Oral Mucoadhesive Buccal Films of Empagliflozin

An anti-diabetic drug called Empagliflozin is used to control blood glucose levels in type 2 diabetics. Due to the high rate of hepatic first pass metabolism, it exhibits limited bioavailability. The current study was done to create Mucoadhesive buccal films of Empagliflozin with the aim of increasing bioavailability, patient compliance, and therapeutic efficacy. The solvent casting process used for the preparation of Empagliflozin Mucoadhesive buccal films by using the Mucoadhesive polymers like HPMC K100 and HEC. The prepared films' evaluated for weight variation, thickness, surface pH, uniformity of the drug content, in-vitro residence time, folding durability, in-vitro release, and permeation investigations were all assessed. Formulations (F1-F4) were created by altering the concentrations of various polymers, with F2 and F4 formulations having the highest polymer ratios and the longest-lasting drug release rates. According to characterization results such as in-vitro dissolution experiments, the sustained release formulation F2, F4 shows the best drug release rate, the order of drug release is F1&gt;F3&gt;F2&gt;F4. It was determined that the films could be chosen for the development of buccal films for effective therapeutic applications because they exhibited effective enlargement, a practicable residence duration, and promising controlled drug release.

Systems Engineering Approach to Modeling and Analysis of Chronic Obstructive Pulmonary Disease Part II: Extension for Variable Metabolic Rates.

Recently, we developed a systems engineering model of the human cardiorespiratory system [Kurian et al. ACS Omega2023, 8 (23), 20524-20535. DOI: 10.1021/acsomega.3c00854] based on existing models of physiological processes and adapted it for chronic obstructive pulmonary disease (COPD)-an inflammatory lung disease with multiple manifestations and one of the leading causes of death in the world. This control engineering-based model is extended here to allow for variable metabolic rates established at different levels of physical activity. This required several changes to the original model: the model of the controller was enhanced to include the feedforward loop that is responsible for cardiorespiratory control under varying metabolic rates (activity level, characterized as metabolic equivalent of the task-Rm-and normalized to one at rest). In addition, a few refinements were made to the cardiorespiratory mechanics, primarily to introduce physiological processes that were not modeled earlier but became important at high metabolic rates. The extended model is verified by analyzing the impact of exercise (Rm > 1) on the cardiorespiratory system of healthy individuals. We further formally justify our previously proposed adaptation of the model for COPD patients through sensitivity analysis and refine the parameter tuning through the use of a parallel tempering stochastic global optimization method. The extended model successfully replicates experimentally observed abnormalities in COPD-the drop in arterial oxygen tension and dynamic hyperinflation under high metabolic rates-without being explicitly trained on any related data. It also supports the prospects of remote patient monitoring in COPD.

Effects of temperature on metabolic rate during metamorphosis in the alfalfa leafcutting bee.

Spring conditions, especially in temperate regions, may fluctuate abruptly and drastically. Environmental variability can expose organisms to temperatures outside of their optimal thermal ranges. For ectotherms, sudden changes in temperature may cause short- and long-term physiological effects, including changes in respiration, morphology, and reproduction. Exposure to variable temperatures during active development, which is likely to occur for insects developing in spring, can cause detrimental effects. Using the alfalfa leafcutting bee, Megachile rotundata, we aimed to determine if oxygen consumption could be measured using a new system and to test the hypothesis that female and male M. rotundata have a thermal performance curve with a wide optimal range. Oxygen consumption of M. rotundata pupae was measured across a large range of temperatures (6-48°C) using an optical oxygen sensor in a closed respirometry system. Absolute and mass-specific metabolic rates were calculated and compared between bees that were extracted from their brood cells and those remaining in the brood cell to determine whether pupae could be accurately measured inside their brood cells. The metabolic response to temperature was non-linear, which is an assumption of a thermal performance curve; however, the predicted negative slope at higher temperatures was not observed. Despite sexual dimorphism in body mass, sex differences only occurred in mass-specific metabolic rates. Higher metabolic rates in males may be attributed to faster development times, which could explain why there were no differences in absolute metabolic rate measurements. Understanding the physiological and ecological effects of thermal environmental variability on M. rotundata will help to better predict their response to climate change.

Effects of dietary palm oil on nutritional indices of Diatraea saccharalis (Lepidoptera: Crambidae) for Cotesia flavipes (Hymenoptera: Braconidae) production

Cotesia flavipes parasitizes Diatraea saccharalis, a pest that causes major losses to sugarcane production. The mass production of C. flavipes and its subsequent release onto sugarcane is one form of biological control of D. saccharalis. An essential factor for successfully fighting this pest is the development of host diets that can increase the efficiency of C. flavipes production. Palm oil contains saturated fatty acids, unsaturated fatty acids, and polyunsaturated linoleic acid. However, little is known about the effects of palm oil on C. flavipes production in the laboratory. Different concentrations of palm oil were added to the D. saccharalis diet and its nutritional indices were analyzed. Subsequently, the production and sex ratio of C. flavipes were determined. Our results indicated that the addition of higher palm oil concentrations to an artificial diet generated a high relative consumption rate (RCR) in D. saccharalis, and consequently a high relative metabolic rate (RMR), which resulted in a lower production of the parasitoid. In contrast, the lowest palm oil concentration in the artificial diet generated a low RMR and resulted in high-efficiency conversion of ingested food (ECI), enabling D. saccharalis to yield more C. flavipes. This suggests that palm oil influences the quantity of D. saccharalis ingested, which determines the number of C. flavipes that will be generated. In this study, supplementation of a D. saccharalis diet with 0.25% palm oil increased the production of C. flavipes. Therefore, this level of palm oil supplementation can aid in the production of C. flavipes on a laboratory-scale. Further research, including increasing the number of parasitoids, must be performed to mass-produce the augmentative releases of C. flavipes to manage D. saccharalis.

Metabolic Interplay in the Tumor Microenvironment: Implications for Immune Function and Anticancer Response.

Malignant tumors exhibit rapid growth and high metabolic rates, similar to embryonic stem cells, and depend on aerobic glycolysis, known as the "Warburg effect". This understanding has enabled the use of radiolabeled glucose analogs in tumor staging and therapeutic response assessment via PET scans. Traditional treatments like chemotherapy and radiotherapy target rapidly dividing cells, causing significant toxicity. Despite immunotherapy's impact on solid tumor treatment, gaps remain, leading to research on cancer cell evasion of immune response and immune tolerance induction via interactions with the tumor microenvironment (TME). The TME, consisting of immune cells, fibroblasts, vessels, and the extracellular matrix, regulates tumor progression and therapy responses. TME-targeted therapies aim to transform this environment from supporting tumor growth to impeding it and fostering an effective immune response. This review examines the metabolic disparities between immune cells and cancer cells, their impact on immune function and therapeutic targeting, the TME components, and the complex interplay between cancer cells and nontumoral cells. The success of TME-targeted therapies highlights their potential to achieve better cancer control or even a cure.

Higher metabolic rate during sedentary, eucaloric conditions predicts long-term weight gain: The role of ethnic differences on adjusted energy expenditure

Higher metabolic rate during sedentary, eucaloric conditions predicts long-term weight gain: The role of ethnic differences on adjusted energy expenditure

Characterization of brain metabolism, volume, and vasculature of the 5xFAD mouse model of Alzheimer’s Disease across lifespan.

AbstractBackgroundThe MODEL‐AD Consortium seeks to develop the next generation of Alzheimer’s Disease models based on human data. A popular model of familial AD is the 5xFAD mouse, characterized by early amyloid‐β deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic features over its lifespan.MethodMale and female 5xFAD and WT littermates underwent in vivo 18F‐FDG‐PET imaging at 4, 6, and 12 months of age to evaluate regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent “vessel painting” that labels all cerebral vessels with a fluorescent dye. “Vessel painted” brains were analyzed for vascular characteristics such as vessel density, junction density, vessel length, network complexity, number of collaterals and vessel diameter.ResultsOur analyses revealed that vessel length, vessel and junction densities increased from 4 to 12 months on the cortical surface in both 5xFAD and WT mice. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but their diameters were significantly increased only in 5xFAD mice. MCA average vessel length was decreased in 5xFAD mice compared to WT. Analysis of 18F‐FDG cortical uptake found significant interactions between WT and 5xFAD mice spanning 4‐12 months of age in retrosplenial, somatosensory and visual cortices. Broadly, 5xFAD males had increased 18F‐FDG uptake at 12 months of age compared to WT mice. In most cortical regions, female 5xFAD mice had reduced FDG uptake compared to WT across the lifespan. In males these metabolic increases coincided with decreased vessel characteristics.ConclusionThe 5xFAD mouse exhibits AD‐like cognitive deficits with age that are associated with increasing amyloid‐β deposition. No significant differences were found in cortical vascular features although males and females exhibited opposite effects in 18F‐FDG uptake. The MCA supplies blood to large portions of the motor cortex and increased vessel lengths and decreased collaterals along with higher metabolic rates in 5xFAD mice may be related to increasing behavioral deficits via metabolic insufficiency or other mechanisms.

Characterization of brain metabolism, volume, and vasculature of the 5xFAD mouse model of Alzheimer’s Disease across lifespan

AbstractBackgroundThe MODEL‐AD Consortium seeks to develop the next generation of Alzheimer’s Disease models based on human data. A popular model of familial AD is the 5xFAD mouse, characterized by early amyloid‐ß deposition and cognitive decrements. Despite numerous studies, the 5xFAD mouse has not been comprehensively phenotyped for vascular and metabolic features over its lifespan.MethodMale and female 5xFAD and WT littermates underwent in vivo 18F‐FDG‐PET imaging at 4, 6, and 12 months of age to evaluate regional glucose metabolism. A separate cohort of mice (4, 8, 12 months) underwent “vessel painting” that labels all cerebral vessels with a fluorescent dye. “Vessel painted” brains were analyzed for vascular characteristics such as vessel density, junction density, vessel length, network complexity, number of collaterals and vessel diameter.ResultOur analyses revealed that vessel length, vessel and junction densities increased from 4 to 12 months on the cortical surface in both 5xFAD and WT mice. The number of collateral vessels between the middle cerebral artery (MCA) and the anterior and posterior cerebral arteries decreased with age but their diameters were significantly increased only in 5xFAD mice. MCA average vessel length was decreased in 5xFAD mice compared to WT. Analysis of 18F‐FDG cortical uptake found significant interactions between WT and 5xFAD mice spanning 4‐12 months of age in retrosplenial, somatosensory and visual cortices. Broadly, 5xFAD males had increased 18F‐FDG uptake at 12 months of age compared to WT mice. In most cortical regions, female 5xFAD mice had reduced FDG uptake compared to WT across the lifespan. In males these metabolic increases coincided with decreased vessel characteristics.ConclusionThe 5xFAD mouse exhibits AD‐like cognitive deficits with age that are associated with increasing amyloid‐ß deposition. No significant differences were found in cortical vascular features although males and females exhibited opposite effects in 18F‐FDG uptake. The MCA supplies blood to large portions of the motor cortex and increased vessel lengths and decreased collaterals along with higher metabolic rates in 5xFAD mice may be related to increasing behavioral deficits via metabolic insufficiency or other mechanisms.

Potential of psychrotolerant rhizobacteria for the growth promotion of wheat (Triticum aestivum L.).

Wheat is the second most important staple crop grown and consumed worldwide. Temperature fluctuations especially the cold stress during the winter season reduces wheat growth and grain yield. Psychrotolerant plant growth-promoting rhizobacteria (PGPR) may improve plant stress-tolerance in addition to serve as biofertilizer. The present study aimed to isolate and identify PGPR, with the potential to tolerate cold stress for subsequent use in supporting wheat growth under cold stress. Ten psychrotolerant bacteria were isolated from the wheat rhizosphere at 4°C and tested for their ability to grow at wide range of temperature ranging from -8°C to 36°C and multiple plant beneficial traits. All bacteria were able to grow at 4°C to 32°C temperature range and solubilized phosphorus except WR23 at 4°C, whereas all the bacteria solubilized phosphorus at 28°C. Seven bacteria produced indole-3-acetic acid at 4°C, whereas all produced indole-3-acetic acid at 28°C. Seven bacteria showed the ability to fix nitrogen at 4°C, while all the bacteria fixed nitrogen at 28°C. Only one bacterium showed the potential to produce cellulase at 4°C, whereas four bacteria showed the potential to produce cellulase at 28°C. Seven bacteria produced pectinase at 4°C, while one bacterium produced pectinase at 28°C. Only one bacterium solubilized the zinc at 4°C, whereas six bacteria solubilized the zinc at 28°C using ZnO as the primary zinc source. Five bacteria solubilized the zinc at 4°C, while seven bacteria solubilized the zinc at 28°C using ZnCO3 as the primary zinc source. All the bacteria produced biofilm at 4°C and 28°C. In general, we noticed behavior of higher production of plant growth-promoting substances at 28°C, except pectinase assay. Overall, in vitro testing confirms that microbes perform their inherent properties efficiently at optimum temperatures rather than the low temperatures due to high metabolic rate. Five potential rhizobacteria were selected based on the in vitro testing and evaluated for plant growth-promoting potential on wheat under controlled conditions. WR22 and WR24 significantly improved wheat growth, specifically increasing plant dry weight by 42% and 58%, respectively. 16S rRNA sequence analysis of WR22 showed 99.78% similarity with Cupriavidus campinensis and WR24 showed 99.9% similarity with Enterobacter ludwigii. This is the first report highlighting the association of C. campinensis and E. ludwigii with wheat rhizosphere. These bacteria can serve as potential candidates for biofertilizer to mitigate the chilling effect and improve wheat production after field-testing.

EXTH-48. PROTOPORPHYRIN IX LEVELS IN PATIENTS’ PLASMA, BLOOD, AND BRAIN TUMOR BY A VALIDATED LC-MS/MS METHOD

Abstract BACKGROUND Protoporphyrin IX (PPIX) is an intermediate molecule in the heme biosynthesis pathway. Cancer cells, having a higher metabolic rate than normal cells, accumulate PPIX when an exogenous dose of its precursor, 5-aminolevulinic acid (5-ALA), is administered. 5-ALA is currently approved by the U.S. FDA for the visualization of high-grade gliomas (HGG) and fluorescence guided surgery. 5-ALA and PPIX are also central to experimental treatments of photodynamic and sonodynamic therapy for HGG patients. Accurate quantitation of PPIX in brain tumor, plasma, and blood is necessary to evaluate its pharmacokinetics and hence optimize its therapeutic benefit in the context of experimental therapies and tumor visualization. METHODS Plasma was used as a matrix for PPIX quantitation in plasma and brain homogenate. Brain homogenates (1:7) were prepared in 5 mM ammonium formate containing 0.2% formic acid. A separate plasma curve was used for blood quantitation. Before protein precipitation, blood and corresponding calibrators were diluted five times with water. PPIX was extracted from human plasma, blood, and brain homogenate samples using methanol containing PPIX-d6 (internal standard). Sample preparation was performed under low light conditions (&amp;lt; 5 lux). Chromatographic separation of the analyte was achieved isocratically on Phenomenex Kinetex™ EVO C18 column, with a total run time of 3.5 min. Analyte detection was performed on Sciex QTRAP 6500+ MS/MS detector. RESULTS The method was validated for 1-2000 nmol/L range. Using plasma as a surrogate matrix, the maximum coefficient of variation for intra- and inter-day precision and accuracy were within acceptable ranges for all matrices. CONCLUSIONS A new rapid and sensitive LC-MS/MS method was successfully validated for the PPIX quantitation in human plasma, blood, and brain. It is currently used in a sonodynamic therapy clinical trial (NCT04559685) to evaluate PPIX pharmacokinetic profile in plasma and blood, and to determine levels in brain tumors of HGG patients.

Resource Patchiness as a Resolution to the Food Paradox in the Sea.

AbstractAverage concentrations of biota in the ocean are low, presenting a critical problem for ocean consumers. High-resolution sampling, however, demonstrates that the ocean is peppered with narrow hot spots of organism activity. To determine whether these resource aggregations could provide a significant solution to the ocean's food paradox, a conceptual graphical model was developed that facilitates comparisons of the role of patchiness in predator-prey interactions across taxa, size scales, and ecosystems. The model predicts that predators are more reliant on aggregated resources for foraging success when the average concentrations of resources is low, the size discrepancy between predator and prey is great, the predator has a high metabolic rate, and/or the predator's foraging time is limited. Size structure differences between marine and terrestrial food webs and a vast disparity in the overall mean density of their resources lead to the conclusion that high-density aggregations of prey are much more important to the survival of oceanic predators than their terrestrial counterparts, shaping the foraging decisions that are available to an individual and setting the stage on which evolutionary pressures can act. Patches of plenty may be rare, but they play an outsized role in behavioral, ecological, and evolutionary processes, particularly in the sea.

Exploring the genetic landscape of neurotransmitter alterations in hypoxic-ischemic encephalopathy: A personalized medicine perspective

\textbf{Background:} Hypoxic-ischemic encephalopathy (HIE) is a neurological condition due to perinatal asphyxia, affecting brain areas with high metabolic rates and active myelination processes. The HIE has various origins and can be challenging to diagnose and treat. This study aimed to determine the origin of the clinical phenotype of patients who met the criteria for perinatal asphyxia at birth from personalized medicine. \textbf{Methods:} We evaluated 28 patients classified according to the SARNAT scale (i.e., clinical staging of HIE) and neurological anomalies by MRI scans. We used a next-generation sequencing panel for genes related to neurotransmitters and analyzed the statistical association between sequelae and other clinical variables using Fisher’s exact test. We also evaluated odds ratios (OR) with 95\% confidence intervals by binary logistic regression analysis adjusted for SARNAT, seizure, MRI scans, and genetic findings. \textbf{Results:} We identified 11 patients with neurotransmitter-related genetic alterations, such as glycine encephalopathy. Three had pathogenic variants (ALDH7A1, AMT, and SLC1A4), and eight had uncertain significance (TH, DBH, MYH2, CGH1, SLC6A5, ABAT, ALDH5A1, GLRB). One patient had 8p11.2 deletion, 14q11.2 deletion, and 10q11.22 duplication. Statistical analyses indicated that the presence or absence of mutations had a statistically significant association with sequelae (p-value = 0.054). Patients with a pathogenetic or uncertain mutation are associated with an increased risk of neurological sequelae (OR: 6.43; 95\% CI: 1.2 – 51.5; p-value = 0.044) regardless of clinical conditions such as the presence of seizures, severity of encephalopathy, alterations in the RMI or hypothermia therapy. \textbf{Conclusions:} Our findings suggest that neurotransmitter alterations are a critical factor significantly increasing the risk of HIE-related sequelae. Identifying these genetic alterations could lead to earlier and more precise diagnosis and treatment of HIE patients.

Epcoritamab SC + GemOx Leads to High Complete Metabolic Response Rates in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma Ineligible for Autologous Stem Cell Transplant: Updated Results from Epcore NHL-2

Background: Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who fail or are ineligible for autologous stem cell transplant (ASCT) have poor outcomes with standard chemotherapy, and novel, effective therapeutic options are needed. A retrospective analysis showed that treatment with rituximab and gemcitabine + oxaliplatin (GemOx) in a transplant-ineligible population resulted in a complete response rate of 33% in the overall population; among patients refractory to previous therapy, 10% achieved complete response (Cazelles et al, Leuk Lymphoma 2021). Epcoritamab, a subcutaneously administered (SC) CD3xCD20 bispecific antibody, has demonstrated deep, durable responses with a manageable safety profile as a single agent in patients with R/R DLBCL. Based on these data, epcoritamab SC was approved by the US FDA for the treatment of adults with R/R DLBCL, not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma, after ≥2 lines of systemic therapy. In the EPCORE ™ NHL-2 phase 1/2 trial (NCT04663347), epcoritamab + GemOx treatment showed encouraging preliminary efficacy with overall expected and manageable safety in patients with R/R DLBCL who failed or were ineligible for ASCT. Here, we present updated results with longer follow-up. Methods: Adults with R/R CD20 + DLBCL who had failed or were ineligible for ASCT were enrolled. Patients received epcoritamab SC in 28-d cycles (Cs) as follows: weekly, C1-3; every 2 weeks, C4-9; every 4 weeks, C≥10 until progressive disease or unacceptable toxicity. Patients received GemOx every 2 weeks in C1-4. Step-up epcoritamab dosing (step-up doses 1 and 2 followed by 48-mg full doses) and corticosteroid prophylaxis were required in C1 to mitigate CRS. The primary endpoint was overall response rate (ORR) as assessed by PET-CT per Lugano criteria. Results: A total of 34 patients (median age, 71 y; range, 47-87) with a median follow-up of 20.3 mo (range, 1.0+ to 26.8) received epcoritamab SC 48 mg + GemOx on or prior to August 24, 2022. At the data cutoff date (April 24, 2023), treatment was ongoing in 35% of patients. A majority of patients (68%) had stage III or IV disease, 53% had primary refractory disease, 38% were refractory to ≥2 consecutive lines of prior therapy, and 79% were refractory to the last line of therapy. The median number of prior lines of treatment was 2 (range, 1-6); 11 patients (32%) had 3 or more prior lines of treatment. A total of 7 patients (21%) had prior CAR T, and 5 patients (15%) had previously received ASCT. The most common treatment-emergent AEs (TEAEs) of any grade (G) were thrombocytopenia/decreased platelet count (68%), diarrhea (59%), anemia (56%), CRS (56%), and neutropenia/decreased neutrophil count (56%). This trial was conducted amid the COVID-19 pandemic and 32% of patients experienced COVID-19. Most CRS events were low grade (53% G1-2; 3% G3) and primarily occurred following the first full dose (C1D15); no incidence of CRS resulted in epcoritamab discontinuation, and all events resolved. ICANS (G1) was reported in 1 patient; this event resolved in 2 d. No clinical tumor lysis syndrome was reported. There were 10 G5 TEAEs; in 2 cases, the contribution of epcoritamab could not be ruled out by the investigator (small intestinal perforation and multiple organ dysfunction syndrome; both patients had multiple confounding factors). The ORR was 91% (31/34), with 59% (20/34) of patients achieving complete metabolic response (CMR). Median times to response and CMR were 1.5 mo and 2.6 mo, respectively. The ORR and CMR rates were 94% and 39% among patients with primary refractory disease, 89% and 78% among patients ≥75 y of age, and 90% and 50% among patients with IPI ≥3 ( Table). Response rates were comparable for patients with and without prior CAR T treatment: ORR of 86% and CMR rate of 57% among patients with prior CAR T; ORR of 93% and CMR rate of 59% among CAR T-naive patients. Conclusions: Epcoritamab SC + GemOx led to high CMR rates in this difficult-to-treat R/R DLBCL population ineligible for transplant with high unmet medical need. No new safety signals were identified, and the safety profile was consistent with those of the individual drugs. These data are encouraging and underline the versatility of epcoritamab SC for the treatment of R/R DLBCL. Additional data and subgroup analyses will be presented.

Epcoritamab SC + R-Mini-CHOP Leads to High Complete Metabolic Response Rates in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma Ineligible for Full-Dose R-CHOP: First Disclosure from Arm 8 of the Epcore NHL-2 Trial

Background: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) is a standard of care for previously untreated (1L) diffuse large B-cell lymphoma (DLBCL); however, some patients are not candidates for full-dose R-CHOP due to advanced age, frailty, or underlying comorbidities. For these patients, various attenuated treatment regimens have been evaluated, with low-dose R-CHOP (R-mini-CHOP) being widely adopted as a standard 1L regimen. However, outcomes are suboptimal, with overall response rates (ORRs) and complete metabolic response (CMR) rates around 70% and 40-60%, respectively, and a 2-y progression-free survival rate of only 47%, leaving substantial room for improvement. Epcoritamab, a subcutaneous (SC) CD3xCD20 bispecific antibody, was approved by the US FDA for the treatment of adults with relapsed or refractory DLBCL, not otherwise specified, including DLBCL arising from indolent lymphoma, and high-grade B-cell lymphoma after ≥2 lines of systemic therapy. In the 1L setting in patients with high-risk DLBCL, epcoritamab SC with full-dose R-CHOP had a favorable safety profile and showed promising efficacy, including an ORR of 100% (Falchi et al, ASCO 2023). Here we report initial data from arm 8 of the EPCORE™ NHL-2 study (NCT04663347; phase 1/2) evaluating epcoritamab SC + R-mini-CHOP in 1L DLBCL. Methods: Adults with 1L CD20 + DLBCL who were not considered candidates for full-dose R-CHOP due to age ≥75 y or age ≥65 y with comorbidities (reduced left ventricular ejection fraction, history of myocardial infarction [&amp;gt;6 mo prior to enrollment], exertional chest pain, arrhythmia [grade ≤2], hypertension requiring treatment, or diabetes) were enrolled. Patients received epcoritamab SC (QW, cycles 1-2 [21 d each]; Q3W, cycles 3-6 [21 d each]; Q4W, cycles 7-8 [28 d each]) with R-mini-CHOP in cycles 1-6 (Q3W). A safety run-in was conducted to confirm acceptability of the safety profile. The primary endpoint of arm 8 was ORR as assessed by PET-CT per Lugano criteria. Results: As of April 24, 2023, 28 patients had received epcoritamab SC 48 mg + R-mini-CHOP. The median age was 81 y, 14 patients (50%) had IPI 3-5, 10 patients (36%) had bulky disease (&amp;gt;6 cm), and 15 patients (54%) had stage IV disease. At the data cutoff, median follow-up was 6.2 mo (range, 2.5+ to 11.7), with 9 patients (32%) having completed treatment and 15 patients (54%) still on treatment. R-mini-CHOP median relative dose intensity was ≥94%. There were no dose-limiting toxicities. The most common treatment-emergent AEs (TEAEs) of any grade were cytokine release syndrome (CRS; 43%), neutropenia (32%), fatigue (25%), anemia (21%), constipation (21%), and hypokalemia (21%). TEAEs decreased over time; 3 patients (11%) discontinued epcoritamab SC due to TEAEs. One grade 5 TEAE (cytomegalovirus infection reactivation) was recorded. CRS events were primarily low grade (grade 1-2: 39%, grade 3: 4%, grade ≥4: 0%), timing was predictable, and a majority of events were observed after the first full dose (cycle 1, day 15); all events resolved, with a median time to resolution of 3 d (range, 1-7). No ICANS events were reported. All 20 efficacy-evaluable patients had a response (ORR, 100%), with 17 patients (85%) achieving CMR. Median time to response was 1.4 mo ( Figure). At both month 6 and month 9, most patients who achieved CMR remained in CMR, suggesting durability of response. The study is ongoing and updated results will be presented. Conclusions: Epcoritamab SC + R-mini-CHOP showed encouraging efficacy with high response rates in patients with 1L DLBCL who cannot tolerate full-dose R-CHOP, including elderly, frail, and high-risk patients. There were no new safety signals, and findings were consistent with previously reported data, supporting the feasibility of the combination. These results warrant further investigation of epcoritamab-based therapies in 1L DLBCL.

Infection Causes Trade-Offs between Development and Growth in Larval Amphibians.

AbstractTrade-offs between life history traits are context dependent; they vary depending on environment and life stage. Negative associations between development and growth often characterize larval life stages. Both growth and development consume large parts of the energy budget of young animals. The metabolic rate of animals should reflect differences in growth and developmental rates. Growth and development can also have negative associations with immune function because of their costs. We investigated how intraspecific variation in growth and development affected the metabolism of larval amphibians and whether intraspecific variation in growth, development, and metabolic rate could predict mortality and viral load in larvae infected with ranavirus. We also compared the relationship between growth and development before and after infection with ranavirus. We hypothesized that growth and development would affect metabolism and predicted that each would have a positive correlation with metabolic rate. We further hypothesized that allocation toward growth and development would increase ranavirus susceptibility and therefore predicted that larvae with faster growth, faster development, and higher metabolic rates would be more likely to die from ranavirus and have higher viral loads. Finally, we predicted that growth rate and developmental rate would have a negative association. Intraspecific variation in growth rate and developmental rate did not affect metabolism. Growth rate, developmental rate, and metabolism did not predict mortality from ranavirus or viral load. Larvae infected with ranavirus exhibited a trade-off between developmental rate and growth rate that was absent in uninfected larvae. Our results indicate a cost of ranavirus infection that is potentially due to both the infection-induced anorexia and the cost of infection altering priority rules for resource allocation.

18 Regional patterns of mitochondrial function using phosphorus magnetic resonance spectroscopy in older adults at-risk for Alzheimer’s disease.

Objective:The brain is reliant on mitochondria to carry out a host of vital cellular functions (e.g., energy metabolism, respiration, apoptosis) to maintain neuronal integrity. Clinically relevant, dysfunctional mitochondria have been implicated as central to the pathogenesis of Alzheimer’s disease (AD). Phosphorous magnetic resonance spectroscopy (31p MRS) is a non-invasive and powerful method for examining in vivo mitochondrial function via high energy phosphates and phospholipid metabolism ratios. At least one prior 31p MRS study found temporal-frontal differences for high energy phosphates in persons with mild AD. The goal of the current study was to examine regional (i.e., frontal, temporal) 31p MRS ratios of mitochondrial function in a sample of older adults at-risk for AD. Given the high energy consumption in temporal lobes (i.e., hippocampus) and preferential age-related changes in frontal structure-function, we predicted 31p MRS ratios of mitochondrial function would be greater in temporal as compared to frontal regions.Participants and Methods:The current study leveraged baseline neuroimaging data from an ongoing multisite study at the University of Florida and University of Arizona. Participants were older adults with memory complaints and a first-degree family history of AD [N = 70; mean [M] age [years] = 70.9, standard deviation [SD] =5.1; M education [years] = 16.2, SD = 2.2; M MoCA = 26.5, SD = 2.4; 61.4% female; 91.5% non-latinx white]. To achieve optimal sensitivity, we used a single voxel method to examine 31p MRS ratios (bilateral prefrontal and left temporal). Mitochondrial function was estimated by computing 5 ratios for each voxel: summed adenosine triphosphate to total pooled phosphorous (ATP/TP; momentary energy), ATP to inorganic phosphate (ATP/Pi; energy consumption), phosphocreatine to ATP (PCr/ATP; energy reserve), phosphocreatine to inorganic phosphate (PCr/Pi; oxidative phosphorylation), and phosphomonoesters to phosphodiesters (PME/PDE; cellular membrane turnover rate). All ratios were corrected for voxel size and cerebrospinal fluid fraction. Separate repeated measures analyses of variance controlling for scanner site differences (RM ANCOVAs) were performed.Results:31p MRS ratios were unrelated to demographic characteristics and were not included as additional covariates in analyses. Results of separate RM ANCOVAs revealed all 31p MRS ratios of mitochondrial function were greater in left temporal relative to bilateral prefrontal voxel: ATP/TP (p &lt; .001), ATP/Pi (p = .001), PCr/ATP (p = .004), PCr/Pi (p = .004), and PME/PDE (p = .017). Effect sizes (partial eta squared) ranged from 0.6-.20.Conclusions:Consistent and extending one prior study, all 31p MRS ratios of mitochondrial function were greater in temporal as compared to frontal regions in older adults at-risk for AD. This may in part be related to the intrinsically high metabolic rate of the temporal region and preferential age-related changes in frontal structure-function. Alternatively, findings may reflect the influence of unaccounted factors (e.g., hemodynamics, auditory stimulation). Longitudinal study designs may inform whether patterns of mitochondrial function across different brain regions are present early in development, occur across the lifespan, or some combination. In turn, this may inform future studies examining differences in mitochondrial function (as measured using 31p MRS) in AD.