Comparative Functional Analysis Research Articles

Comparative Analysis of Circular RNAs Expression and Function between Aortic and Intracranial Aneurysms.

An aneurysm is an abnormal enlargement or bulging of the wall of a blood vessel. Most often, aneurysms occur in large blood vessels - the aorta (Thoracic Aortic Aneurysm (TAA) and Abdominal Aortic Aneurysm (AAA) and brain vessels (Intracranial Aneurysm (IA)). Despite the presence of significant differences in the pathogenesis of the development and progression of IA and TAA/AAA, there are also similarities. For instance, both have been shown to be strongly influenced by shear stress, inflammatory processes, and enzymatic destruction of the elastic lamellae and extracellular matrix (ECM) proteins of the vascular wall. Moreover, although IA and TAA are predominantly considered arteriopathies with different pathological mechanisms, they share risk factors with AAA, such as hypertension and smoking. However, there is a need for a more in- -depth study of the key elements that may influence the formation and progression of a particular aneurysm to find ways of therapeutic intervention or search for a diagnostic tool. Today, it is known that the disruption of gene expression is one of the main mechanisms that contribute to the development of aneurysms. At the same time, growing evidence suggests that aberrant epigenetic regulation of gene function is strongly related to the genesis of aneurysms. Although much has been studied of the known protein-coding genes, circular RNAs (circRNAs), a relatively new and rapidly evolving large family of transcripts, have recently received much scientific attention. CircRNAs regulate gene expression through the sponging of microRNAs (miRNAs) and can also be used as therapeutic targets and biomarkers. Increasing evidence has implicated circRNAs in the pathogenesis of multiple cardiovascular diseases, including the development of aneurysms. However, the mechanism of dysregulation of certain circRNAs in a particular aneurysm remains to be studied. The discovery of circRNAs has recently advanced our understanding of the latest mode of miRNAs/target genes regulation in the development and progression of IA and TAA/AAA. The aim of this study is to compare the expression profiles of circRNAs to search for similar or different effects of certain circRNAs on the formation and progression of IA and TAA/AAA.

Comparative Genomic and Functional Analysis of c-di-GMP Metabolism and Regulatory Proteins in Bacillus velezensis LQ-3.

Bacillus velezensis is a promising candidate for biocontrol applications. A common second messenger molecule, bis-(3,5)-cyclic-dimeric-guanosine monophosphate (c-di-GMP), has the ability to regulate a range of physiological functions that impact the effectiveness of biocontrol. However, the status of the c-di-GMP signaling pathway in biocontrol strain LQ-3 remains unknown. Strain LQ-3, which was isolated from wheat rhizosphere soil, has shown effective control of wheat sharp eyespot and has been identified as B. velezensis through whole-genome sequencing analyses. In this study, we investigated the intracellular c-di-GMP signaling pathway of LQ-3 and further performed a comparative genomic analysis of LQ-3 and 29 other B. velezensis strains. The results revealed the presence of four proteins containing the GGDEF domain, which is the conserved domain for c-di-GMP synthesis enzymes. Additionally, two proteins were identified with the EAL domain, which represents the conserved domain for c-di-GMP degradation enzymes. Furthermore, one protein was found to possess a PilZ domain, indicative of the conserved domain for c-di-GMP receptors in LQ-3. These proteins are called DgcK, DgcP, YybT, YdaK, PdeH, YkuI, and DgrA, respectively; they are distributed in a similar manner across the strains and belong to the signal transduction family. We selected five genes from the aforementioned seven genes for further study, excluding YybT and DgrA. They all play a role in regulating the motility, biofilm formation, and colonization of LQ-3. This study reveals the c-di-GMP signaling pathway associated with biocontrol features in B. velezensis LQ-3, providing guidance for the prevention and control of wheat sharp eyespot by LQ-3.

Comparative functional analysis reveals differential nucleotide sensitivity between human and mouse UCP1.

Mitochondrial uncoupling protein 1 (UCP1) is a unique protein of brown adipose tissue. Upon activation by free fatty acids, UCP1 facilitates a thermogenic net proton flux across the mitochondrial inner membrane. Non-complexed purine nucleotides inhibit this fatty acid-induced activity of UCP1. The most available data have been generated from rodent model systems. In light of its role as a putative pharmacological target for treating metabolic disease, in-depth analyses of human UCP1 activity, regulation, and structural features are essential. In the present study, we established a doxycycline-regulated cell model with inducible human or murine UCP1 expression and conducted functional studies using respirometry comparing wild-type and mutant variants of human UCP1. We demonstrate that human and mouse UCP1 exhibit similar specific fatty acid-induced activity but a different inhibitory potential of purine nucleotides. Mutagenesis of non-conserved residues in human UCP1 revealed structural components in α-helix 56 and α-helix 6 crucial for uncoupling function. Comparative studies of human UCP1 with other orthologs can provide new insights into the structure-function relationship for this mitochondrial carrier and will be instrumental in searching for new activators.

An Embedded Neural Network Approach for Reinforcing Deep Learning: Advancing Hand Gesture Recognition

Deep neural networks (DNNs) can face limitations during training for recognition, motivating this study to improve recognition capabilities by optimizing deep learning features for hand gesture image recognition. We propose a novel approach that enhances features from well-trained DNNs using an improved radial basis function (RBF) neural network, targeting recognition within individual gesture categories. We achieve this by clustering images with a self-organizing map (SOM) network to identify optimal centers for RBF training. Our enhanced SOM, employing the Hassanat distance metric, outperforms the traditional K-Means method across a comparative analysis of various distance functions and the expanded number of cluster centers, accurately identifying hand gestures in images. Our training pipeline learns from hand gesture videos and static images, addressing the growing need for machines to interact with gestures. Despite challenges posed by gesture videos, such as sensitivity to hand pose sequences within a single gesture category and overlapping hand poses due to the high similarities and repetitions, our pipeline achieved significant enhancement without requiring time-related training data. We also improve the recognition of static hand pose images within the same category. Our work advances DNNs by integrating deep learning features and incorporating SOM for RBF training.

Comparative analysis of addiction severity and renal functions in patients with synthetic cannabinoid use disorder versus cannabis use disorder

BackgroundThe use of synthetic cannabinoids (SC) has become a concerning public health issue due to their potential adverse effects on both physical and mental health. Understanding the effect of cannabis and synthetic cannabinoids use on kidney functions and creatinine phosphokinase-total (CPK) levels is essential for targeted intervention and patient care.MethodsThis cross-sectional study aimed to assess addiction severity using the Addiction Severity Index (ASI) and kidney functions in 45 patients with SC use disorder and compare them to 45 patients with cannabis use disorder (CUD). Participants were recruited from the addiction outpatient clinics and inpatient ward of the addiction psychiatry unit at “Kasr Al Aini Hospital,” Cairo University.ResultsThere was a statistically significant difference between the 2 groups regarding the Addiction Severity Index domains, where patients with SC use disorder had higher scores in all domains of the ASI.Regarding kidney functions and CPK-total levels, there was a significant difference in the serum CPK-total level (p < 0.05) between the 2 groups; however, there was no significant difference regarding the other kidney function tests (serum creatinine, urea, blood urea nitrogen, and estimated glomerular filtration rate).As for the correlative analysis, there was a significant correlation between some domains of the ASI and the kidney function tests in both patient groups.ConclusionOur results strongly suggest that SC may have a more hazardous and detrimental impact on individuals, encompassing various aspects of addiction severity such as physical health, psychological well-being, social functioning, and overall quality of life. Our findings also highlight the potential risk of elevated CPK-total levels in patients with SC use disorder; therefore, regular monitoring of kidney function in patients with synthetic cannabinoid use disorder is crucial for guiding appropriate treatment interventions and mitigating adverse health outcomes.

Comparative Functional and Performance Analysis of Apache Cordova and Android UI Development Tools

Comparative Functional and Performance Analysis of Apache Cordova and Android UI Development Tools

Comparative Analysis of Tool Functionality in Descriptive Statistics of Language R

The article provides methods and procedures of getting numerical statistical characteristics of qualitative and quantitative features by means of language R in the process of preliminary data analysis. The most expedient, in view of simplicity of use and information value of result, specification of functions of language descriptive statistics was shown. The author studied comparative advantages of tools of descriptive statistics of the language with the open software code R in comparison with similar units Python and Ms Excel. A conclusion was drawn about the convenience and appeal of using language R for estimating descriptive statistics for beginners, who have not got specific knowledge in programming. For example, it was shown that in order to get min 12 characteristics of descriptive data statistics grouped by categories only one command will be enough. As for estimating one statistical characteristic for segment of data produced by several grouping features, again only one command is necessary. Findings of the research can be useful for investigators of different fields, both beginners and experts, who work with methods of statistical data processing in academic and practical spheres.

Comparative Genomic and Functional Analyses for Insights into Pantoea agglomerans Strains Adaptability in Diverse Ecological Niches.

Pantoea agglomerans inhabit diverse ecological niches, ranging from epiphytes and endophytes in plants, body of animals, and occasionally in the human system. This multifaceted bacterium contributes substantially to plant growth promotion, stress resilience, and biocontrol but can also act as a pathogen to its host. The genetic determinants underlying these diverse functions remain largely unfathomed and to uncover this phenomenon,nineteenstrains ofPantoea agglomeranswere selected and analyzed. Genome-to-Genome Distance Calculator (GGDC) which uses the Genome Blast Distance Phylogeny (GBDP) technique to calculate digital DDH values.Phylogenetic analysis via Genome-to-Genome distance, Average Nucleotide Identity, and Amino Acid Identity calculation revealed that all strains belonged to the genusPantoea. However, strain 33.1 had a lower value than the threshold for the same species delineation. Bacterial Pan Genome Analysis (BPGA) Pipeline and MinPath analysis revealed genetic traits associated with environmental resilience, such as oxidative stress, UV radiation, temperature extremes, and metabolism of distinct host-specific carbohydrates. Protein-protein interactome analysis illustrated osmotic stress proteins closely linked with core proteins, while heavy metal tolerance, nitrogen metabolism, and Type III and VI secretion systems proteins generally associated with pathogenicity formed a separate network, indicating strain-specific characteristics. These findings shed new light on the intricate genetic architecture ofPantoea agglomerans, revealing its adaptability to inhabit diverse niches and thrive in varied environments.

Functional and Structural Characterization of Clinical-Stage Janus Kinase 2 Inhibitors Identifies Determinants for Drug Selectivity.

Janus kinase 2 (JAK2) plays a critical role in orchestrating hematopoiesis, and its deregulation leads to various blood disorders, most importantly myeloproliferative neoplasms (MPNs). Ruxolitinib, fedratinib, momelotinib, and pacritinib are FDA-/EMA-approved JAK inhibitors effective in relieving symptoms in MPN patients but show variable clinical profiles due to poor JAK selectivity. The development of next-generation JAK2 inhibitors is hampered by the lack of comparative functional analysis and knowledge of the molecular basis of their selectivity. Here, we provide mechanistic profiling of the four approved and six clinical-stage JAK2 inhibitors and connect selectivity data with high-resolution structural and thermodynamic analyses. All of the JAK inhibitors potently inhibited JAK2 activity. Inhibitors differed in their JAK isoform selectivity and potency for erythropoietin signaling, but their general cytokine inhibition signatures in blood cells were comparable. Structural data indicate that high potency and moderate JAK2 selectivity can be obtained by targeting the front pocket of the adenosine 5'-triphosphate-binding site.

Comparative analysis of pulmonary function in school-going adolescents: Examining the impact of depression and anxiety

Objectives: Given the rising concern over depression and anxiety among adolescents, this study aims to investigate their potential impact on respiratory health by comparing pulmonary function test (PFT) parameters between healthy adolescents and those with either depression or anxiety or those exhibiting symptoms of both depression and anxiety. Materials and Methods: In this cross-sectional study, a random sample of school-going adolescents aged 13–18 years from various schools in Sikkim, both males and females, were selected. Depression and anxiety were assessed using the Revised Children’s Anxiety and Depression Scale-25, and pulmonary function was measured using a computerised spirometer-Spirolab III. The recorded variables included forced vital capacity (FVC), forced expiratory volume in 1st second (FEV1), FEV1/FVC ratio, peak expiratory flow rate (PEFR) and forced expiratory flow at 25–75% (FEF 25–75%). Results: Significant differences emerged in FVC (P = 0.034), PEFR (P = 0.013) and FEF 25–75% (P = 0.023) between healthy and depressed adolescents aged 13–18 years. Similarly, a significant difference was observed in PEFR (P = 0.022) and FEF 25–75% (P = 0.002) between healthy adolescents and those with symptoms of both depression and anxiety. These differences were more pronounced among students in higher grades. Furthermore, significant differences in PEFR (P = 0.015) and FEF 25–75% (P ≤ 0.001) were found while comparing healthy males and males with symptoms of both depression and anxiety. However, no such disparities were seen in girls. There was no significant difference in any of the parameters when compared between the healthy group and those with anxiety. Conclusion: Depressed adolescents exhibited significantly reduced FVC, PEFR and FEF 25–75% compared to their healthy counterparts, despite being otherwise healthy. This negative association was more pronounced in the higher age group. However, anxious adolescents did not show any significant difference in PFT compared to healthy peers.

Mastering the ways of indicating transport when mastering Russian as a native and as a foreign language

The subject of the article's research is the peculiarities of prepositional-case constructions with the meaning of vehicle in children's monolingual speech, in the speech of Chinese students studying Russian as a foreign language and in the speech of heritage Russian speakers with different dominant languages. The study examines case constructions with the meaning of movement. The specificity of mastering grammatical construction in the course of mastering Russian as a native language, as one of the native languages, and as a foreign language is analyzed. The research material was experimental data collected in a children's classroom and in an adult foreign audience, as well as information from the “Russian Academic Corps /RLC” (Corpus of the Linguistic Laboratory for Corpus Technologies of the National Research University Higher School of Economics, containing information about the development of Russian as a foreign language and native speakers of Russian with different dominant languages). The research methodology included: longitudinal observation of the speech of monolingual children, psycholinguistic experiment in a foreign audience, corpus research method; comparative research, semantic and functional analysis. The scientific novelty of the proposed work lies in the fact that for the first time a comparative analysis of data is presented that describes the ways of mastering the case construction with the meaning of indicating transport by Russian-speaking children, Chinese students and heritage native speakers of the Russian language. Typical differences and errors in the choice of construction are considered, the strategy of simplification in the speech of foreign students is described, and the ways of grammatical interference are analyzed. Analysis of errors made by Russian-speaking children and adult foreigners allows us to draw conclusions about the specifics of mastering Russian case meanings. Errors in choosing a case ending with a correctly chosen preposition are often observed in the speech of foreign students and heritage speakers, but do not appear in children's speech. Thus, in the Russian language there is a wide variety of ways to indicate a vehicle. Choosing the correct construction when indicating transport represents a specific difficulty in the course of mastering Russian as a foreign language and requires special attention.

Comparative executive function analysis: Cochlear implants and normal hearing in 7- to 11-year-old children from Iran

Objective This study compares executive functioning in deaf children with cochlear implants and those with normal hearing. Individuals who lacked auditory stimulation during their early years might experience cognitive challenges that extend beyond just speech and language abilities. Methods The executive functioning abilities of a group of 32 children who were born deaf and received cochlear implants before the age of 7 were contrasted with those of 30 children with normal hearing. Both sets of children underwent assessments using the Tower of London, BRIEF, and Stroop tests. Results The average score on the Tower of London task reveals that children who received cochlear implants (4.03 ± 2.53) achieved lower scores than typically hearing children (8.37 ± 2.79). This group also exhibited higher errors in the Stroop test and slightly longer response times Additionally, in terms of emotional control assessed by the BRIEF, a higher score was recorded. Notably, significant differences between the two groups were identified for organizing materials (t(62) = −4.204, p = 0.00). The tests measuring phonemic fluency, categorical fluency, and working memory also revealed significant differences. Conclusions The significant differences in data between both groups suggest the influence of cochlear implantation on cognitive functions. This emphasizes the importance of a holistic approach to supporting the overall development of these children.

Splice variants of CK1α and CK1α-like: Comparative analysis of subcellular localization, kinase activity, and function in the Wnt signaling pathway

Members of the casein kinase 1 (CK1) family are important regulators of multiple signaling pathways. CK1α is a well-known negative regulator of the Wnt/β-catenin pathway, which promotes the degradation of β-catenin via its phosphorylation of Ser45. In contrast, the closest paralog of CK1α, CK1α-like, is a poorly characterized kinase of unknown function. In this study, we show that the deletion of CK1α, but not CK1α-like, resulted in a strong activation of the Wnt/β-catenin pathway. Wnt-3a treatment further enhanced the activation, which suggests there are at least two modes, a CK1α-dependent and Wnt-dependent, of β-catenin regulation. Rescue experiments showed that only two out of ten naturally occurring splice CK1α/α-like variants were able to rescue the augmented Wnt/β-catenin signaling caused by CK1α deficiency in cells. Importantly, the ability to phosphorylate β-catenin on Ser45 in the invitro kinase assay was required but not sufficient for such rescue. Our compound CK1α and GSK3α/β KO models suggest that the additional nonredundant function of CK1α in the Wnt pathway beyond Ser45-β-catenin phosphorylation includes Axin phosphorylation. Finally, we established NanoBRET assays for the three most common CK1α splice variants as well as CK1α-like. Target engagement data revealed comparable potency of known CK1α inhibitors for all CK1α variants but not for CK1α-like. In summary, our work brings important novel insights into the biology of CK1α, including evidence for the lack of redundancy with other CK1 kinases in the negative regulation of the Wnt/β-catenin pathway at the level of β-catenin and Axin.

Comparative metagenomic analysis of microbial community compositions and functions in cage aquaculture and its nearby non-aquaculture environments.

In the context of burgeoning global aquaculture, its environmental repercussions, particularly in marine ecosystems, have gained significant attentions. Cage aquaculture, a prominent method, has been observed to significantly influence marine environments by discharging substantial amounts of organic materials and pollutants. It is also one of the important reasons for water eutrophication. This study investigated the impacts of cage aquaculture on microbial diversity and functional potential using metagenomics. Specifically, a comparison was made of the physicochemical indicators and microbial diversity between three grouper aquaculture cage nets in Lingshui Xincun Port and three nearby non-aquaculture area surface waters. We found that compared to non-aquaculture areas, the eutrophication indicators in aquaculture environments significantly increased, and the abundances of Vibrio and Pseudoalteromonas in aquaculture environments significantly rose. Additionally, microbial functional genes related to carbon, nitrogen, and sulfur metabolisms were also found to be significantly affected by aquaculture activities. The correlation analysis between microbial populations and environmental factors revealed that the abundances of most microbial taxa showed positive correlations with dissolved inorganic nitrogen, soluble reactive phosphorus, NH4+, and negative correlations with dissolved oxygen. Overall, this study elucidated the significant impacts of aquaculture-induced eutrophication on the diversity and functions of planktonic bacterial communities.

Comparative analysis of left ventricle function and deformation imaging in short and long axis plane in cardiac magnetic resonance imaging.

Advancements in cardiac imaging have revolutionized our understanding of ventricular contraction. While ejection fraction (EF) is still the gold standard parameter to assess left ventricle (LV) function, strain imaging (SI) has provided valuable insights into ventricular mechanics. The lack of an integrative method including SI parameters in a single, validated formula may limit its use. Our aim was to compare different methods for evaluating global circumferential strain (GCS) and their relationship with global longitudinal strain (GLS) and EF in CMR and how the different evaluations fit in the theoretical relationship between EF and global strain. Retrospective monocenter study. Inclusion of every patient who underwent a CMR during a 15 months period with various clinical indication (congenital heart defect, myocarditis, cardiomyopathy). A minimum of three LV long-axis planes and a stack of short-axis slices covering the LV using classical steady-state free precession cine sequences. A single assessment of GLS on long axis (LAX) slices and a double assessment of GCS and EF with both short axis (SAX) and LAX slices were made by a single experienced CMR investigator. GCS-SAX and GCS-LAX were correlated (r = 0.77, P < 0.001) without being interchangeable with a high reproducibility for GCS, GLS and EF. EF calculated from LAX images showed an overestimation compared to EF derived from SAX images of 7%. The correlation between calculated EF and theoretical EF derived from SI was high (r = 0.88 with EF-SAX, 0.95 with EF-LAX). This study highlights the need to integrate strain imaging techniques into clinical by incorporating strain parameters into EF calculations, because it gives a deeper understanding of cardiac mechanics.

Comparative transcriptome and functional analyses provide insights into the key factors regulating shoot regeneration in highbush blueberry.

Establishing an efficient plant regeneration system is a crucial prerequisite for genetic engineering technology in plants. However, the regeneration rate exhibits considerable variability among genotypes, and the key factors underlying shoot regeneration capacity remain largely elusive. Blueberry leaf explants cultured on a medium rich in cytokinins exhibit direct shoot organogenesis without prominent callus formation, which holds promise for expediting genetic transformation while minimizing somatic mutations during culture. The objective of this study is to unravel the molecular and genetic determinants that govern cultivar-specific shoot regeneration potential in highbush blueberry (Vaccinium corymbosum L.). We conducted comparative transcriptome analysis using two highbush blueberry genotypes: 'Blue Muffin' ('BM') displaying a high regeneration rate (>80%) and 'O'Neal' ('ON') exhibiting a low regeneration rate (<10%). The findings revealed differential expression of numerous auxin-related genes; notably, 'BM' exhibited higher expression of auxin signaling genes compared to 'ON'. Among blueberry orthologs of transcription factors involved in meristem formation in Arabidopsis, expression of VcENHANCER OF SHOOT REGENERATION (VcESR), VcWUSCHEL (VcWUS), and VcCUP-SHAPED COTYLEDON 2.1 were significantly higher in 'BM' relative to 'ON'. Exogenous application of auxin promoted regeneration, as well as VcESR and VcWUS expression, whereas inhibition of auxin biosynthesis yielded the opposite effects. Overexpression of VcESR in 'BM' promoted shoot regeneration under phytohormone-free conditions by activating the expression of cytokinin- and auxin-related genes. These findings provide new insights into the molecular mechanisms underlying blueberry regeneration and have practical implications for enhancing plant regeneration and transformation techniques.

Assessment of Anxiety and Depression in the Perioperative Period in Women of Reproductive Age During Regional Anesthesia

Introduction Perioperative cognitive impairment occurs in both pregnant and non-pregnant women. Prediction, early detection and effective treatment of these disorders are important for the well-being of women and their offspring.Aim of study To evaluate the effect of anesthesia and surgery on the level of anxiety, depression, short-term memory, and concentration in pregnant and nonpregnant women.Material and methods The observational prospective study included 120 patients who were divided into two equal groups — pregnant (n=60) and nonpregnant (n=60) women. A comparative analysis of testing psychosomatic reactions and cognitive functions using the MoCa test, Benton and Wechsler tests, selfassessment questionnaire, Hospital Anxiety and Depression Scale (HADS) was carried out. The relative risk and odds ratio of developing anxiety and depression were calculated.Results Anxiety indicators in pregnant women before surgery reached subclinical values of 7.5 (8.4; 6.6), and in non-pregnant women – the norm: 6.5 (7.3; 5.7) (p&lt;0.001); Results of depression in pregnant women after surgery were 7.3 (8.5; 6.1), in non-pregnant women — the norm: 6.3 (7; 5.5) (p&lt;0.001). The odds of developing short-term memory impairment in pregnant women before surgery was 3.1 times higher than in non-pregnant women, odds ratio 3.1 (95% CI [1.3–7.4]). In the pregnant group, short-term memory scores before surgery were 5 (5.8; 4.2), and after surgery they decreased to 3.8 (4.7; 2.9) (p&lt;0.001). There was a decrease in concentration of attention in pregnant women: before surgery 6.2 (6.8; 5.6), and after surgery — 5 (5.8; 4.2) (p&lt;0.001). The relative risk (RR) of developing depression in pregnant women after surgery was 6.1 times RR=6.1 (95% CI 2.4; 15.8), sensitivity Se (%)=0.9, specificity Sp (%)=0.5. The relative risk (RR) of developing short-term memory impairment after surgery was 1.1 times RR=1.1 (95% CI 1; 1.2), sensitivity Se (%)=0.5, specificity Sp (%)=0, 8. The relative risk (RR) of developing problems with concentration after surgery was 8.3 times RR=8.3 (95% CI 3.9; 18.3), sensitivity Se (%)=0.8, specificity Sp (%)=0.7.Conclusions The Results obtained allow us to conclude that before surgery, pregnant women experience a subclinical version of anxiety, against the background of which the chances of developing problems with short-term memory and concentration increase. After surgery, pregnant women experience a subclinical version of depression, along with it there is also impairment of intelligence, short-term memory and concentration. The initial impairment of memory and attention requires the selection of anesthesia in a group of pregnant women.

Abstract 4186: Development of an orthotopic A549 lung carcinoma model in CD34+ humanized NCG mice and response to treatment with paclitaxel and pembrolizumab

Abstract Translational in vivo models are needed to expedite the discovery of new treatments for lung cancer. One such approach is the use of humanized mouse models that enable immunotherapies targeting human immune cells to be evaluated for efficacy and tolerability. We developed an orthotopic lung carcinoma model in humanized mice (HuCD34 NCG), utilizing serial bioluminescence imaging to evaluate the activity of paclitaxel and pembrolizumab as single and combination agents. Paclitaxel, which disrupts microtuble function, and pembrolizumab, a PD-1-targeting immunotherapy, are both approved for the treatment of certain types of lung cancer. Paclitaxel kills cancer cells directly, and may also promote anti-tumor responses through enhanced presentation of tumor antigens and activation of T cells. Immunodeficient NCG mice were humanized with cord blood-derived hCD34+ stem cells from 3 donors. High levels of human cell engraftment, with expected frequencies of hCD45+ cells and other immune subsets, was observed by 14 weeks post-injection. Luciferase expressing A549 cells were implanted orthotopically into the pulmonary space of the left lobe of the lung, and animals were subsequently flux sorted into treatment groups. Tumor burden, measured by luciferase expression, increased progressively in untreated animals, and moribundity was often associated with clinical indications of respiratory distress. Treatment with paclitaxel significantly decreased the tumor burden and extended survival. In contrast, pembrolizumab did not control tumor growth or extend survival. There was no synergistic effect with the combination therapy, in fact, the addition of pembrolizumab was associated with a modest increase in tumor burden and disease progression. Comparative analysis of immune cell composition, function and persistence in lung and other tissues provided insights into the distinct pharmacodynamic responses associated with the different treatment regimens. This model establishes a robust in vivo platform to identify novel therapies for the treatment of lung cancer. Citation Format: Anya Avrutskaya, Elizabeth Rainbolt, Bincy John, Cara Clouse, Murray Stackhouse, Christopher Currie, Sydney Scatigno, Steven Bronson, Jenny Rowe, Chassidy Hall, David P. Harris. Development of an orthotopic A549 lung carcinoma model in CD34+ humanized NCG mice and response to treatment with paclitaxel and pembrolizumab [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 4186.

Prognostic gene landscapes and therapeutic insights in sepsis-induced coagulopathy

BackgroundSepsis is a common and critical condition encountered in clinical practice that can lead to multi-organ dysfunction. Sepsis-induced coagulopathy (SIC) significantly affects patient outcomes. However, the precise mechanisms remain unclear, making the identification of effective prognostic and therapeutic targets imperative. MethodsThe analysis of transcriptome data from the whole blood of sepsis patients, facilitated the identification of key genes implicated in coagulation. Then we developed a prognostic model and a nomogram to predict patient survival. Consensus clustering classified sepsis patients into three subgroups for comparative analysis of immune function and immune cell infiltration. Single-cell sequencing elucidated alterations in intercellular communication between platelets and immune cells in sepsis, as well as the role of the coagulation-related gene FYN. Real-time quantitative PCR determined the mRNA levels of critical coagulation genes in septic rats' blood. Finally, administration of a FYN agonist to septic rats was observed for its effects on coagulation functions and survival. ResultsThis study identified four pivotal genes—CFD, FYN, ITGAM, and VSIG4—as significant predictors of survival in patients with sepsis. Among them, CFD, FYN, and ITGAM were underexpressed, while VSIG4 was upregulated in patients with sepsis. Moreover, a nomogram that incorporates the coagulation-related genes (CoRGs) risk score with clinical features of patients accurately predicted survival probabilities. Subgroup analysis of CoRGs expression delineated three molecular sepsis subtypes, each with distinct prognoses and immune profiles. Single-cell sequencing shed light on heightened communication between platelets and monocytes, T cells, and plasmacytoid dendritic cells, alongside reduced interactions with neutrophils in sepsis. The collagen signaling pathway was found to be essential in this dynamic. FYN may affect platelet function by modulating factors such as ELF1, PTCRA, and RASGRP2. The administration of the FYN agonist can effectively improve coagulation dysfunction and survival in septic rats. ConclusionsThe research identifies CoRGs as crucial prognostic markers for sepsis, highlighting the FYN gene's central role in coagulation disorders associated with the condition and suggesting novel therapeutic intervention strategies.

Comparative Analysis of CNN Architectures and Loss Functions on Age Estimation of Archaeological Artifacts

Comparative Analysis of CNN Architectures and Loss Functions on Age Estimation of Archaeological Artifacts