Significant Differences In Activity Research Articles

Identification of the Biomechanical Response of the Muscles That Contract the Most during Disfluencies in Stuttered Speech.

Stuttering, affecting approximately 1% of the global population, is a complex speech disorder significantly impacting individuals' quality of life. Prior studies using electromyography (EMG) to examine orofacial muscle activity in stuttering have presented mixed results, highlighting the variability in neuromuscular responses during stuttering episodes. Fifty-five participants with stuttering and 30 individuals without stuttering, aged between 18 and 40, participated in the study. EMG signals from five facial and cervical muscles were recorded during speech tasks and analyzed for mean amplitude and frequency activity in the 5-15 Hz range to identify significant differences. Upon analysis of the 5-15 Hz frequency range, a higher average amplitude was observed in the zygomaticus major muscle for participants while stuttering (p < 0.05). Additionally, when assessing the overall EMG signal amplitude, a higher average amplitude was observed in samples obtained from disfluencies in participants who did not stutter, particularly in the depressor anguli oris muscle (p < 0.05). Significant differences in muscle activity were observed between the two groups, particularly in the depressor anguli oris and zygomaticus major muscles. These results suggest that the underlying neuromuscular mechanisms of stuttering might involve subtle aspects of timing and coordination in muscle activation. Therefore, these findings may contribute to the field of biosensors by providing valuable perspectives on neuromuscular mechanisms and the relevance of electromyography in stuttering research. Further research in this area has the potential to advance the development of biosensor technology for language-related applications and therapeutic interventions in stuttering.

Gene and Protein Expression of Placental Nutrient-Stress Sensor Proteins in Fetal Growth Restriction

Fetal growth restriction (FGR) and low birth weight increase the risk of non-communicable diseases such as type 2 diabetes and heart failure in adulthood. Placental insufficiency is widely considered a major contributor to FGR. Two crucial placental proteins involved in nutrient and stress sensing—O-linked N-acetylglucosamine transferase (OGT) and mechanistic target of rapamycin (mTOR) kinase—play roles in post-translational protein modification and protein translation, influencing cellular growth and metabolism in response to maternal stress, hypoxia, and nutritional status in the placenta. In our study, we examined the gene and protein profiles of OGT and mTOR in FGR and control placentae, comparing those appropriate for gestational age (AGA), while also considering potential confounding effects of fetal sex and delivery mode. Our findings revealed no significant differences in gene expression, protein levels, or activity of OGT, OGA, mTOR, or their associated markers between female AGA and FGR cesarean placentae, nor between female AGA and male AGA cesarean placentae. Additionally, the mode of delivery in female AGA placentae did not affect the levels or activity of these proteins. Overall, our study did not observe significant differences in nutrient sensor protein expression after stratifying by FGR, sex, and delivery mode. Nevertheless, these unbiased results provide a more comprehensive understanding of the complexities of placental gene expression involving OGT and mTOR.

Assessment of lifestyle changes in combating the COVID-19 pandemic among people of Karachi, Pakistan.

Aim: COVID-19 arose as a pandemic that wreaked havoc all over the world. Study determines lifestyle changes adopted by people of Karachi in response to COVID-19 pandemic. Methods: This was the cross-sectional study and carried out at public sector hospital and 218 participants were selected through random sampling method. Results: Lifestyle changes a statistically significant difference in nutrition (p=0.000), physical activity (p=0.000), workout (p=0.000), smoking (p=0.000), sleep hours (p=0.000),and supplements (p=0.000) before and during lockdown. Face masks were utilized by 38% of individuals, gloves by 19%, and social isolation was observed by 26%. 11% of participants did not follow any protocols. Conclusion: Study found significant differences in lifestyle habits such as diet, sleep, smoking andphysical activity.

Antimicrobial properties and bonding durability of pH-responsive dentin adhesives with chlorhexidine-load mesoporous silica nanoparticles

In this study, we synthesized pH-sensitive CHX@SBA-PDA nanoparticles and characterized their structure. These nanoparticles were then incorporated into Single Bond 2 commercial dentin adhesive. Subsequently, timely and long-term antibacterial evaluation, cytotoxicity evaluation and bonding properties were conducted. The results demonstrated the successful synthesis of CHX@SBA-PDA nanoparticles. Moreover, CHX@SBA-PDA exhibited excellent pH sensitivity and maintained a high release rate of chlorhexidine (CHX) under cariogenic low pH conditions. At pH 5.0, the release rate could reach up to 71.1% after 24 h of incubation with CHX@SBA-PDA nanoparticles. Among the different adhesive formulations tested, the 2% wt adhesive displayed the strongest immediate and 30 days bacterial inhibition ability (p &amp;lt; 0.05). No significant difference was observed in immediate shear strength among the four groups (p &amp;gt; 0.05). After undergoing pH cycling, all functional adhesive groups exhibited higher shear strength compared to the control group (p &amp;lt; 0.05). Furthermore, there was no significant difference in cell proliferation activity between the experimental group and control group (p &amp;gt; 0.05). In conclusion, our functional dentin adhesive containing CHX@SBA-PDA nanoparticles demonstrated long-term antibacterial properties as well as improved bond strength characteristics, thus, offering a promising approach to enhance durability of bonded restorations.

Effects of sperm concentration on the quality of cryopreserved sperm in Yangtze sturgeon (Acipenser dabryanus)

The Yangtze sturgeon (Acipenser dabryanus) is extinct in the wild; however, artificial propagation in captivity under fully controlled conditions has been successful. Sperm cryopreservation is an effective method for germplasm conservation and aquaculture. Sperm concentration affects the quality of cryopreserved spermatozoa. Thus, in this study, we optimized the concentration (0.25 × 109, 0.5 × 109, 1.0 × 109, and 2.0 × 109 spermatozoa [spz]/mL) for Yangtze sturgeon sperm cryopreservation in a 0.5 mL plastic straw. The greatest value for the kinetic parameters was achieved when sperm were cryopreserved at 0.5 × 109 spz/mL. In comparison to other concentrations, there was a notable increase in both acrosomal and plasma membrane integrity when sperm was cryopreserved at a concentration of 0.5 × 109 spz/mL. No significant difference of superoxide dismutase and glutathione peroxidase enzyme activity was present in post-thaw sperm, except in sperm cryopreserved at a concentration of 2.0 × 109 spz/mL. Catalase activity was significantly higher in post-thaw sperm at a concentration of 0.5 × 109 spz/mL than at other concentrations. Excluding sperm cryopreserved at 2.0 × 109 spz/mL, the fertilization rate of cryopreserved sperm was not significantly different among the different concentrations. This concentration optimization improves cryopreserved sperm quality and standardizes sperm cryopreservation procedures for the Yangtze sturgeon. These findings are especially beneficial for the establishment of a sperm cryobank.

Pregnancy effect on disease activity in women with multiple sclerosis treated with cladribine

IntroductionCladribine is an oral immune reconstitution therapy for relapsing multiple sclerosis (RMS). Hormonal and immune changes are responsible for the decline of disease activity in the third trimester of pregnancy and disease reactivation in the early post-partum period.We investigate the impact of pregnancy on disease activity in women with MS who conceived after cladribine treatment.MethodsWe recruited women of childbearing age with relapsing–remitting MS (RRMS) who became pregnant or not after being treated with cladribine. For both groups, demographic, clinical and radiological data were collected 1 year before and after treatment during a mean follow-up of 3.53 years. We compared disease activity over time between groups using variance analysis for repeated measures.Results48 childbearing women were included. 25 women had a pregnancy after a mean of 1.75 years from the first treatment cycle. Women with or without pregnancy did not differ in demographics or pre-cladribine disease activity. No significant differences in disease activity or EDSS worsening were found between women with or without pregnancy.DiscussionOur findings suggest that pregnancy does not appear to influence disease activity and disability in women previously treated with cladribine; further studies with larger numbers and longer follow-up are needed to confirm this finding.

Vulnerable at rest? A resting-state EEG study and psychosocial factors of young adult offspring of alcohol-dependent parents

BackgroundOffspring of parents with alcohol use disorder (AUD) are more susceptible to developing AUD, with an estimated heritability of around 50%. Vulnerability to AUD in first-degree relatives is influenced by biological factors, such as spontaneous brain activity, and high-risk psychosocial characteristics. However, existing resting-state EEG studies in AUD offspring have shown inconsistent findings regarding theta, alpha, and beta band frequencies. Additionally, research consistently demonstrates an increased risk of internalizing and externalizing disorders, self-regulation difficulties, and interpersonal issues among AUD offspring. MethodsThis study aimed to investigate the absolute power of theta, alpha, and beta frequencies in young adult offspring with a family history of AUD compared to individuals without family history. The psychosocial profiles of the offspring were also examined in relation to individuals without a family history of AUD. Furthermore, the study sought to explore the potential association between differences in frequency bands and psychosocial variables. Resting-state EEG recordings were obtained from 31 young adult healthy offspring of alcohol-dependent individuals and 43 participants with no family history of AUD (age range: 16–25 years). Participants also completed self-report questionnaires assessing anxiety and depressive symptoms, impulsivity, emotion regulation, and social involvement. ResultsThe results revealed no significant differences in spontaneous brain activity between the offspring and participants without a family history of AUD. However, in terms of psychosocial factors, the offspring exhibited significantly lower social involvement than the control group. ConclusionsThis study does not provide evidence suggesting vulnerability in offspring based on differences in spontaneous brain activity. Moreover, this investigation highlights the importance of interventions aimed at enhancing social connections in offspring. Such interventions can not only reduce the risk of developing AUD, given its strong association with increased feelings of loneliness but also improve the overall well-being of the offspring.

Non-Volatile metabolome of different cultivars of Prunus mume blossoms and screening of the antidepressant molecules targeting monoamine oxidase A

Prunus mume is a traditional Chinese plant with high ornamental and medicinal values. Although there has been some research on the antidepressant effect of green calyx Mume Flos through animal tests, there is limited information on the potential antidepressant effects of different cultivars of P. mume and their relevance with intrinsic non-volatile metabolites. In this work, the non-volatile metabolites of P. mume blossom from seven cultivars were analyzed using UPLC-Q-TOF/MS, and their antidepressant activities were examined by targeting monoamine oxidase A (MAO-A). The cultivars included Gulihong (GLH), Yudie (YD), LvE (LE), Zhusha (ZS), Jiangmei (JM), Gongfen (GF) and Meirenmei (MRM). The untargeted analysis identified 148 compounds, including flavonoids, acylated sucroses, phenolic acids etc., out of 1120 compound ions. The Blireiana Prunus MRM displayed a significant difference in both metabolites and activity, compared to the other six true Prunus cultivars, with the lowest inhibitory effect on MAO-A. The correlation analysis between the spectrum and effect of the six true Prunus cultivars was conducted by partial least squares regression (PLSR) and grey correlation (GRA) and screened 45 common active compounds that are likely responsible for the antidepressant activity. A joint analysis with the 50 untargeted differential compounds resulted in 15 compounds finally, which are believed to contribute to the differences in activity between the six cultivars. All of them have a low binding energy with MAO-A in molecular docking. According to their regression coefficients, the plentiful polyacetyl coumaroylsucroses identified in blossom are believed to be the main effective substances for the inhibition activity of MAO-A instead of the flavonoids. The results also suggest that JM may be better than LE as a potential antidepressant herb. However, experiments are required for further validation.

Comparison of lifestyle, cognitive function, mental health, and quality of life between hospitalized older adults with COVID-19 and non-COVID-19 in South Korea: a cross-sectional study

BackgroundThe coronavirus disease (COVID-19) pandemic has greatly impacted older adults, resulting in many deaths. The impact of lifestyle and mental health on vulnerable groups, such as older adults, can be large and long lasting. Therefore, this study aimed to investigate the effects of COVID-19 confirmation on cognition, lifestyle, mental health, and quality of life in adults aged 55 years.MethodsThe sample consisted of 111 people in the COVID group and 189 people in the non-COVID group aged over 55 years in South Korea. An online survey was conducted between January and May 2022. Participants responded to the following assessment tools: Yonsei Lifestyle Profile, Prospective and Retrospective Memory (PRMQ), Subjective Memory Complaints Questionnaire (SMCQ), Visual Analogue Scale, Patient Health Questionnaire-9 (PHQ-9), Insomnia Severity Index (ISI), Fear of COVID-19 Scale (FCV-19 S), and the World Health Organization Quality of Life Scale abbreviated version (WHOQOL-BREF). Differences in lifestyle, cognition, depression, anxiety, and quality of life were compared between the two groups.ResultsThere were significant differences in physical activity, diet, the total score of the PRMQ, PM (a sub-score of the PRMQ), PHQ-9, Korean version of the ISI (ISI-K), and WHOQOL-BREF scores between the COVID and non-COVID groups. However, there were no significant differences in activity participation, Self-Rating Anxiety Scale (SAS), or FCV-19 S between groups.ConclusionsThe study confirms that COVID-19 negatively affects memory, physical activity, diet, quality of life, depression, and insomnia in the older adults. Therefore, this study implicated that prevention and intervention strategies required improving the memory, lifestyle, and mental health of older adults with COVID-19.Trial registrationThe study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of Yonsei university in Korea (Registration number: 1041849-202112-SB-226-03, Date of registration: 01042022).

In vitro evaluation of the binding activity of novel mouse IgG1 opsonic monoclonal antibodies to Mycobacterium tuberculosis and other selected mycobacterial species

Antimicrobial resistance alongside other challenges in tuberculosis (TB) therapeutics have stirred renewed interest in host-directed interventions, including the role of antibodies as adjunct therapeutic agents. This study assessed the binding efficacy of two novel IgG1 opsonic monoclonal antibodies (MABs; GG9 & JG7) at 5, 10, and 25 µg/mL to live cultures of Mycobacterium tuberculosis, M. avium, M. bovis, M. fortuitum, M. intracellulare, and M. smegmatis American Type Culture Collection laboratory reference strains, as well as clinical susceptible, multi-drug resistant, and extensively drug resistant M. tuberculosis strains using indirect enzyme-linked immunosorbent assays. These three MAB concentrations were selected from a range of concentrations used in previous optimization (binding and functional) assays. Both MABs bound to all mycobacterial species and sub-types tested, albeit to varying degrees. Statistically significant differences in MAB binding activity were observed when comparing the highest and lowest MAB concentrations (p < 0.05) for both MABs GG9 and JG7, irrespective of the M. tuberculosis resistance profile. Binding affinity increased with an increase in MAB concentration, and optimal binding was observed at 25 µg/mL. JG7 showed better binding activity than GG9. Both MABs also bound to five MOTT species, albeit at varied levels. This non-selective binding to different mycobacterial species suggests a potential role for GG9 and JG7 as adjunctive agents in anti-TB chemotherapy with the aim to enhance bacterial killing.

Effect of light and noise pollution on oxidative stress and proximate composition in Dreissena polymorpha

In this study, it was aimed to determine the effect of sound and light pollution on Zebra mussel (Dreissena polymorpha) by biomarker and nutritional composition. For this purpose, an experimental design was carried out in laboratory conditions where the model was exposed to live sound, light, and combined sound + light parameters for 30 min every hour over 96 h. Changes in the biomarkers superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) activities, as well as glutathione (GSH) and thiobarbituric acid (TBARS) levels, were assessed in the model organism exposed to sound, light, and sound + light pollution. The changes in protein and fat amounts were determined. When the changes in biomarkers were examined statistically compared to the control, there was no significant decrease in SOD activity (p < 0.05), a significant increase in CAT activity in sound and sound+light, but a significant decrease in light (p < 0.05), no significant difference in GPx activity (p > 0.05). It was determined that there was a significant increase in GSH and TBARS levels in all three parameters. Significant changes were also observed in the proximate composition. As a result, exposure to sound, light and sound+light pollution caused an increase in oxidative damage and decreases in protein and lipid composition were detected.

Bilateral Carotid Calcification Correlates with Regional Cerebral Glucose Metabolism: Insights from PET/CT Imaging of Patients with Cardiovascular Risk Factors

Background: Cardiovascular disease is a leading cause of illness and death globally, primarily due to atherosclerosis. This disease reduces blood flow and oxygen delivery to organs, and when it affects the carotid arteries, it can lead to cognitive impairment and dementia. In a population of 104 individuals, comprising both healthy controls and individuals at elevated risk for developing cardiovascular diseases (CVD) due to identified risk factors, we used PET imaging with 18F-fluorodeoxyglucose (FDG) to assess cerebral glucose metabolism and 18F-sodium fluoride (NaF) to detect atherosclerotic calcification. Our statistical analysis revealed significant differences in metabolic activity between healthy and at-risk individuals in specific brain regions. 18F-FDG uptake in the brain varied inversely with respect to the clinical assessment of cardiovascular risk in regions such as the cuneus (β = −0.030, SE = 0.014, p = 0.035), middle occipital gyrus (β = −0.032, SE = 0.011, p = 0.005), and posterior cingulate gyrus (β = −0.032, SE = 0.015, p = 0.044). In contrast, areas including the basis pontis (β = 0.025, SE = 0.012, p = 0.038) and the pons (β = 0.034, SE = 0.013, p = 0.008) exhibited direct correlations. Notably, carotid 18F-NaF uptake had inverse associations with 18F-FDG uptake in the cerebellum (β = −0.825, SE = 0.354, p = 0.021), medulla (β = −0.888, SE = 0.405, p = 0.029), and posterior cingulate gyrus (β = −1.253, SE = 0.567, p = 0.028), while increased carotid calcification influenced metabolic activity in the fusiform gyrus (β = 1.660, SE = 0.498, p = 0.001) and globus pallidus (β = 1.505, SE = 0.571, p = 0.009). We observed that atherosclerotic plaque accumulation, especially in the carotid arteries, has potential implications for metabolic changes in brain regions governing cognition, emotion, sensory perception, and motor activities. Our findings underscore the possible early interventions that can be used to preempt or delay cognitive deterioration linked with cardiovascular ailments.

Effects of Azadirachta indica Leaf Aqueous Extract supplemented Fish Diets on Innate Immune Response and Disease Resistance of Tilapia (Oreochromis niloticus)

Pseudomonas fluorescens is an important bacterial pathogen causing economic losses in aquaculture worldwide. The adverse effects of antibiotics raise public concerns on using them in aquaculture. The objective of this study was to examine the effectiveness of aqueous extract of Azadirachta indica leaves on nonspecific immunity and disease resistance in tilapia (Oreochromis niloticus). Fish diets supplemented with aqueous extract of A. indica at the concentrations of 0% (Diet 1), 1% (Diet 2), 1.5% (Diet 3) and 2% (Diet 4) were investigated for their effects on nonspecific immune response and disease resistance in tilapia. The fish given diet 3 and diet 4 for 3 weeks had increased levels of leukocyte phagocytic activity though higher activity was observed in diet 4 group. Diet 3 and diet 4 also enhanced plasma lysozyme activity in tilapia. The similar levels of lysozyme activity were found in the fish receiving both diets for 3 weeks. Only diet 4 had stimulatory effect on respiratory burst activity in tilapia. This effect was observed 3 weeks after feeding the fish with diet 4. Throughout the experiment, no significant differences (P &gt; 0.05) in phagocytic, lysozyme and respiratory burst activities were found between group fed with diet 1 (control) and diet 2. Following 3 weeks after feeding, fish were infected with Pseudomonas fluorescens at median lethal dose (LD50). No mortality was found in the diet 4 group while 50%, 48% and 28% of cumulative mortality were found in the fish receiving diet 1, 2 and 3 respectively. These results indicate that the aqueous extract of A. indica may elevate the nonspecific immune response and enhance disease resistance in tilapia.

The Importance of Variety and Regional Identity on the Dextrin-Reducing Enzymatic Activity of Cascade and Mosaic® Hops Grown in Washington and Oregon

This study analyzed hops from 35 fields located in two states (Washington and Oregon) repeatedly over 2 harvest years (2020 and 2021) to determine the impact that hop variety and regional identity, or “terroir,” might have on hops’ dextrin reducing enzymatic potential. Cascade and Mosaic® hops were harvested, kilned, pelletized, and analyzed for dextrin-reducing enzymatic activity using a bench-top dry-hopping assay in a high-dextrin beer. In addition, data for 25 soil, 14 management, 13 climate, and 27 chemistry variables were collected and compared to the enzyme activity results from the bench-top dry-hopping assay. There existed a highly significant difference in enzymatic activity based on hop variety (two sample t-test p-value = 1.18 × 10−14) with Cascade hops being approximately 60% higher on average than Mosaic® hops regardless of growing region or harvest year. The soil and farm management variables also showed statistically significant interactions with enzymatic activity (p-values of 7.82 × 10−9 for Cascade and < 2 × 10−16 for Mosaic®), though there was little clarity with respect to the specific “terroir” variables that might relate to hop creep. Further research is needed to better understand causal interactions between farm, soil, climate, and management practices and dry-hop-induced dextrin-reducing enzymatic activity.

Comparison of Physical and Compositional Attributes between Commercial Plant-Based and Dairy Yogurts.

A primary strategy led by the food industry to improve the sustainability of the agricultural food supply is the development of modern plant-based alternatives. The information provided via marketing and product packaging provides consumers with the expectation that these products provide a similar product experience to conventional products, yet it is not well understood whether these commercial alternative products are comparable to traditional animal-based products. To aid in developing improved plant-based products, this study aimed to compare the quality and physical attributes of commercially available plant-based and dairy yogurts. Using instrumental methods, commercially available yogurt products were analyzed for their pH, titratable acidity, color, water activity, moisture content, and rheology, which included 13 plant-based (almond, cashew, coconut, oat, soy) and 8 whole-milk dairy yogurts. The present study reveals that the plant-based and dairy yogurts had no significant differences in pH, lactic acid, water activity, or moisture content. However, there were significant differences in the color and texture properties between the plant-based and dairy yogurts. Additionally, significant differences were observed across the plant-based yogurt products in terms of their color and texture properties. This highlights the need for additional studies to determine how individual ingredients influence the physical characteristics and textural properties to direct the development of plant-based yogurts. Improving upon the physicochemical properties of plant-based yogurt may encourage more consumers to adopt a more sustainable diet.

Abstract 4972: Bioinformatic analysis of an annotated genomic database is clinically useful in a private cancer center

Abstract Background: Sequencing of patient solid tumor tissue is not a common service provided by community cancer centers. Our community cancer center has collected and sequenced over 5,000 tumor tissue samples from patients with various types of cancer. Since April 2019, we have conducted whole-exome and whole-transcriptome sequencing and stored this data in an internal genomics database. To analyze large patient cohorts, we must first optimize bioinformatic workflows on a smaller scale, which can then be applied to studies of larger populations. Previous studies have shown BRAF mutations are associated with an increased activation of the mitogen-activated protein kinase (MAPK) pathway. We analyzed transcriptomes of a cohort of 30 patients with thyroid cancer, 15 with V600E BRAF mutations and 15 wild-type for BRAF, for MAPK Pathway Activation Scores (MPAS). MPAS serves as a transcriptomic measure of the activation state of the MAPK pathway and has been shown to be a reliable prognostic biomarker of MAPK activity. Method: We conducted a retrospective analysis of data from FFPE tumor samples sent to a commercial CLIA-certified laboratory from April 2019 to October 2023. Samples were profiled by whole exome, whole transcriptome sequencing and immunohistochemistry (IHC). Whole transcriptome sequencing (WTS) was executed using Illumina NovaSeq along with the Agilent SureSelect Human All Exon V7 bait panel. Resulting data were reported in transcripts per million (TPM) using the Salmon expression pipeline. MPAS was calculated using the expression profile of 10 MAPK-associated genes. Results: There was no significant difference in BRAF expression levels or MAPK activation between patients with BRAF mutant and BRAF wild-type thyroid cancer (median MPAS scores: -0.09 vs. 0.11, p=0.9). This analysis workflow will be repeated with a larger patient population of patients with melanoma in the future; however, the consistency of expression between the groups, the rank-order, and the low variability per group suggest that expression changes related to this BRAF mutation may occur upstream or via differential regulation of an indirect pathway. Rank-order statistics and percentiles become more precise as data per tumor type grows. Conclusions: Our community cancer center began building an internal genomics database including whole-exome and whole-transcriptome sequencing since 2019. This resource facilitates analysis of patient samples for tumor mutational burden, gene fusions, transcriptomic data, and other important characteristics which could reveal patterns or trends that inform cancer diagnosis and prognosis of other patients. Analysis of expression data for patients with advanced solid tumors who have mutations in genes of interest could inform on potential targeted treatments in the future. This study represents a single example of the potential of our internal clinically annotated genomics database. Citation Format: Carlos E. Zuazo, Sourat Darabi, David R. Braxton, Phillip Stafford, Michael J. Demeure. Bioinformatic analysis of an annotated genomic database is clinically useful in a private cancer center [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 4972.

Abstract 7061: Targeting metabolic vulnerabilities in ARID1A/B dual-deficient dedifferentiated endometrial carcinoma

Abstract Background: Dedifferentiated endometrial carcinoma (DDEC) is an aggressive endometrial carcinoma defined histologically by undifferentiated carcinoma juxtaposed against stage 1 or 2 endometrial adenocarcinoma. DDEC responds poorly to conventional platinum/taxane-based chemotherapy, particularly in the case of extrauterine spread. This highlights a need to develop novel therapies for individuals with DDEC. Genetically, a third of DDEC cases have co-inactivating mutations of ARID1A and ARID1B. These genes encode core subunits of the sucrose/switch non-fermentable (SWI/SNF) complex that regulate transcription. Furthermore, dual loss of ARID1A/B is believed to play a role in driving DDEC tumor development. We hypothesize that ARID1A/B dual-deficiency in DDEC generates unique genetic deficiencies that allow for the development of novel therapies for this cancer. We approached this hypothesis by first conducting a preliminary analysis of the Cancer Dependency Map (DepMap), which has identified vulnerabilities in mitochondrial functioning in ARID1A/B dual-deficient DDECs. As such, we aimed to understand the role of mitochondrial oxidative phosphorylation (OXPHOS) and redox homeostasis in ARID1A/B dual-deficient DDEC to create new treatment options. Methods: A panel of ARID1A/B dual-deficient and proficient endometrial cancer cell lines were treated with OXPHOS inhibitor IACS-010759 and reactive oxidative species (ROS)-inducing agent elesclomol to identify shifts in drug response between the two groups. To account for genomic differences between the cell lines, we also treated an ARID1B knock-out isogeneic cell line with the drugs. Additionally, changes in metabolism in the endometrial cancer cell lines were measured using Seahorse metabolic flux assays to determine if ARID1A/B dual-deficient cell lines have an increased dependency on OXPHOS for cell growth. Results: While the Seahorse assays revealed no significant difference in OXPHOS and glycolysis activities between the two groups, drug sensitivity assays demonstrated that ARID1A/B dual-deficient cancers are more sensitive to OXPHOS inhibition and increased ROS production than the proficient cell lines. Depletion of ARID1B in an ARID1A deficient cell line sensitizes the cells to both drugs. Furthermore, IACS-010759 significantly suppressed the growth of ARID1A/B-deficient DDEC xenograft tumor growth. Conclusion: ARID1A/B-dual deficient cancer cells rely on mitochondria function for survival. The underlying mechanisms are currently under investigation. Citation Format: Rebecca Ho, Eunice Li, Chae Young Shin, Shary Chen, David Huntsman, Yemin Wang. Targeting metabolic vulnerabilities in ARID1A/B dual-deficient dedifferentiated endometrial carcinoma [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 7061.

Genetic contribution to microglial activation in schizophrenia.

Several lines of evidence indicate the involvement of neuroinflammatory processes in the pathophysiology of schizophrenia (SCZ). Microglia are brain resident immune cells responding toward invading pathogens and injury-related products, and additionally, have a critical role in improving neurogenesis and synaptic functions. Aberrant activation of microglia in SCZ is one of the leading hypotheses for disease pathogenesis, but due to the lack of proper human cell models, the role of microglia in SCZ is not well studied. We used monozygotic twins discordant for SCZ and healthy individuals to generate human induced pluripotent stem cell-derived microglia to assess the transcriptional and functional differences in microglia between healthy controls, affected twins and unaffected twins. The microglia from affected twins had increased expression of several common inflammation-related genes compared to healthy individuals. Microglia from affected twins had also reduced response to interleukin 1 beta (IL1β) treatment, but no significant differences in migration or phagocytotic activity. Ingenuity Pathway Analysis (IPA) showed abnormalities related to extracellular matrix signaling. RNA sequencing predicted downregulation of extracellular matrix structure constituent Gene Ontology (GO) terms and hepatic fibrosis pathway activation that were shared by microglia of both affected and unaffected twins, but the upregulation of major histocompatibility complex (MHC) class II receptors was observed only in affected twin microglia. Also, the microglia of affected twins had heterogeneous response to clozapine, minocycline, and sulforaphane treatments. Overall, despite the increased expression of inflammatory genes, we observed no clear functional signs of hyperactivation in microglia from patients with SCZ. We conclude that microglia of the patients with SCZ have gene expression aberrations related to inflammation response and extracellular matrix without contributing to increased microglial activation.

Abstract 1762: Characterization of somatic copy number deletion of chromosome 22q in papillary thyroid carcinoma

Abstract Deletion in the long arm of chromosome 22 (22qDEL) is the most prevalent somatic copy number alteration (SCNA) observed in papillary thyroid carcinoma (PTC). Despite its recurrence, the specific characteristics and role of 22qDEL in PTC have not been fully studied. We conducted a pooled analysis of 22qDEL by integrating patient and clinical information and molecular profiles from 1,094 primary PTC tumors across four major published PTC genomic studies: The Cancer Genome Atlas (TCGA) PTC profile study, the National Cancer Institute (NCI) post-Chornobyl PTC study, the Memorial Sloan Kettering Cancer Center Integrated Mutation Profiling of Actionable Cancer Targets (MSKCC-IMPACT) PTC cases, and the Seoul National University (SNU) thyroid cancer profile study. The majority of PTC with 22qDEL demonstrated arm-level loss of heterozygosity (86%). Even in PTC cases with partial 22qDEL, we observed a loss across 70% of chromosome 22, encompassing regions 22q12 and 22q13, which harbors known cancer genes (NF2 and CHEK2). More than 90% of 22qDEL co-occurred with established oncogenic drivers of PTC, though a full assessment of PTC drivers was not available for all cases. 22qDEL occurred more frequently with RAS point mutations (50.4%) than other drivers (9.3%). A higher fraction of 22qDEL was clonal in RAS-driven PTCs (78.3%), suggesting 22qDEL occurs early in RAS-driven tumor development. We did not observe any association between 22qDEL and established PTC risk factors such as age, sex, and radiation, nor with clinical features including tumor size, multifocality, and metastasis (p-values&amp;gt;0.22). RNA sequencing gene expression analysis based on 22qDEL status revealed downregulation of most genes residing on chromosome 22q and significant differential expression activity of immune-related genes, further implicating a role of immune dysregulation in PTC. Our study suggests that 22qDEL may not act as a primary driver of PTC but plays an important role as a co-factor of RAS point mutations, which could further drive PTC development. Citation Format: Olivia W. Lee, Danielle Karyadi, Stephen Hartley, Weyin Zhou, Mitchell Machiela, Mykola Tronko, Tetiana Bogdanova, Liudmyla Zurnadzhy, Lindsay Morton, Stephen Chanock. Characterization of somatic copy number deletion of chromosome 22q in papillary thyroid carcinoma [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 1762.

In Vitro Low-Bortezomib Doses Induce Apoptosis and Independently Decrease the Activities of Glutathione S-Transferase and Glutathione Peroxidase in Multiple Myeloma, Taking into Account the GSTT1 and GSTM1 Gene Variants.

Multiple myeloma (MM) is a malignancy derived from plasma cells. Bortezomib affects the concentration of reduced glutathione (GSH) and the activity of glutathione enzymes. The aim of our study was to analyze deletion (null/present) variants of GSTT1 and GSTM1 genes and their association with the levels of glutathione and its enzymes in bortezomib-treated cell cultures derived from MM patients. This study included 180 individuals (80 MM patients and 100 healthy blood donors) who were genotyped via multiplex PCR (for the GSTT1/GSTM1 genes). Under in vitro conditions, MM bone marrow cells were treated with bortezomib (1-4 nM) to determine apoptosis (via fluorescence microscopy), GSH concentration, and activity of glutathione enzymes (via ELISA). Bortezomib increased the number of apoptotic cells and decreased the activity of S-glutathione transferase (GST) and glutathione peroxidase (GPx). We found significant differences in GST activity between 1 nM (GSTT1-null vs. GSTT1-present), 2 nM (GSTT1-null vs. GSTT1-present), and 4 nM (GSTM1-null vs. GSTM1-present) bortezomib: 0.07 vs. 0.12, p = 0.02; 0.06 vs. 0.10, p = 0.02; and 0.03 vs. 0.08, p = 0.01, respectively. Bortezomib affects the activities of GST and GPx. GST activity was associated with GSTT1 and GSTM1 variants but only at some bortezomib doses.