Pathological Activity Research Articles

Atherosclerosis Is a Smooth Muscle Cell-Driven Tumor-Like Disease.

Atherosclerosis, a leading cause of cardiovascular disease, involves the pathological activation of various cell types, including immunocytes (eg, macrophages and T cells), smooth muscle cells (SMCs), and endothelial cells. Accumulating evidence suggests that transition of SMCs to other cell types, known as phenotypic switching, plays a central role in atherosclerosis development and complications. However, the characteristics of SMC-derived cells and the underlying mechanisms of SMC transition in disease pathogenesis remain poorly understood. Our objective is to characterize tumor cell-like behaviors of SMC-derived cells in atherosclerosis, with the ultimate goal of developing interventions targeting SMC transition for the prevention and treatment of atherosclerosis. We used SMC lineage tracing mice and human tissues and applied a range of methods, including molecular, cellular, histological, computational, human genetics, and pharmacological approaches, to investigate the features of SMC-derived cells in atherosclerosis. SMC-derived cells in mouse and human atherosclerosis exhibit multiple tumor cell-like characteristics, including genomic instability, evasion of senescence, hyperproliferation, resistance to cell death, invasiveness, and activation of comprehensive cancer-associated gene regulatory networks. Specific expression of the oncogenic mutant KrasG12D in SMCs accelerates phenotypic switching and exacerbates atherosclerosis. Furthermore, we provide proof of concept that niraparib, an anticancer drug targeting DNA damage repair, attenuates atherosclerosis progression and induces regression of lesions in advanced disease in mouse models. Our findings demonstrate that atherosclerosis is an SMC-driven tumor-like disease, advancing our understanding of its pathogenesis and opening prospects for innovative precision molecular strategies aimed at preventing and treating atherosclerotic cardiovascular disease.

FOXO1 Single-Nucleotide Polymorphisms Are Associated with Bleeding Severity and Sensitivity of Glucocorticoid Treatment of Pediatric Immune Thrombocytopenia.

Immune thrombocytopenia (ITP) is an autoimmune-mediated hemorrhagic disease. Emerging evidence indicates that FOXO1 SNPs are related to the immune dysregulation of several autoimmune diseases suggesting that FOXO1 may be involved in inflammation and pathologic activities in patients with ITP. This study aimed to evaluate whether FOXO1 gene single-nucleotide polymorphisms (SNPs) are associated with susceptibility to ITP and clinical priorities of concern include bleeding severity and sensitivity of glucocorticoid treatment. This study recruited 327 newly diagnosed ITP and 220 healthy controls. Four SNPs (rs17446593, rs17446614, rs2721068, and rs2721068) of the FOXO1 gene were detected using the Sequenom MassArray system. Bleeding severity were classified into the mild and severe groups based on the bleeding scores. ITP patients were classified as sensitive and insensitive to glucocorticoid treatment according to the practice guideline for ITP (2019 version). The frequencies of the four SNPs did not show any significant differences between the ITP and healthy control groups. Patients with AA genotype at rs17446593 (p = 0.009) and GG genotype at rs17446614 (p = 0.009) suffered more severe bleeding than patients without them. Carriers of haplotype Grs17446593Ars17446614Crs2721068Trs2755213 were protective to severe bleeding (p = 0.002). The AA genotype at rs17446593 was significantly higher in ITP patients sensitive to glucocorticoid treatment than in those insensitive to glucocorticoid treatment (p = 0.03). Haplotype Grs17446593Grs17446614Trs2721068Trs2755213 increases the risk of glucocorticoid resistance (p = 0.007). Although FOXO1 gene polymorphisms were not associated with susceptibility to ITP, the AA genotype at rs17446593 and GG genotype at rs17446614 were associated with bleeding severity. Haplotype GACT have a protective effect against severe bleeding. Patients with AA genotype at rs17446593 may tend to have good responds to glucocorticoid treatment. However, the FOXO1 gene haplotype GGTT increases the risk of glucocorticoid-resistant. Trial registration: ChiCTR1900022419.

Associations of serum cystatin C concentrations with total mortality and mortality of 12 site-specific cancers.

Cystatin C (CysC), beyond its biomarker role of renal function, has been implicated in various physical and pathological activities. However, the impact of serum CysC on cancer mortality in a general population remains unknown. We aimed to examine the associations of serum CysC concentrations with total mortality and mortality of 12 site-specific cancers. We included 241,008 participants of the UK Biobank cohort with CysC measurements who had normal creatinine-based estimated glomerular filtration rates and were free of cancer and renal diseases at baseline (2006-2010). Death information was obtained from the National Health Service death records through 28 February 2021. Multivariable Cox proportional hazards models were used to compute hazard ratios (HR) per one standard deviation increase in log-transformed CysC concentrations and 95% confidence intervals (95% CI) for mortality. Over a median follow-up of 12.1 (interquartile range, 11.3-12.8) years, 5,744 cancer deaths occurred. We observed a positive association between serum CysC concentrations and total cancer mortality (HR = 1.16, 95% CI: 1.12-1.20). Specifically, participants with higher serum CysC concentrations had increased mortality due to lung cancer (HR = 1.12, 95% CI: 1.05-1.20), blood cancer (HR = 1.29, 95% CI: 1.16-1.44), brain cancer (HR = 1.19, 95% CI: 1.04-1.36), esophageal cancer (HR = 1.20, 95% CI: 1.05-1.37), breast cancer (HR = 1.18, 95% CI: 1.03-1.36), and liver cancer (HR = 1.49, 95% CI: 1.31-1.69). Our findings indicate that higher CysC concentrations are associated with increased mortality due to lung, blood, brain, esophageal, breast, and liver cancers. Future studies are necessary to clarify underlying mechanisms.

An electroencephalogram microdisplay to visualize neuronal activity on the brain surface.

Functional mapping during brain surgery is applied to define brain areas that control critical functions and cannot be removed. Currently, these procedures rely on verbal interactions between the neurosurgeon and electrophysiologist, which can be time-consuming. In addition, the electrode grids that are used to measure brain activity and to identify the boundaries of pathological versus functional brain regions have low resolution and limited conformity to the brain surface. Here, we present the development of an intracranial electroencephalogram (iEEG)-microdisplay that consists of freestanding arrays of 2048 GaN light-emitting diodes laminated on the back of micro-electrocorticography electrode grids. With a series of proof-of-concept experiments in rats and pigs, we demonstrate that these iEEG-microdisplays allowed us to perform real-time iEEG recordings and display cortical activities by spatially corresponding light patterns on the surface of the brain in the surgical field. Furthermore, iEEG-microdisplays allowed us to identify and display cortical landmarks and pathological activities from rat and pig models. Using a dual-color iEEG-microdisplay, we demonstrated coregistration of the functional cortical boundaries with one color and displayed the evolution of electrical potentials associated with epileptiform activity with another color. The iEEG-microdisplay holds promise to facilitate monitoring of pathological brain activity in clinical settings.

Purinergic Signalling Mediates Aberrant Excitability of Developing Neuronal Circuits in the Fmr1 Knockout Mouse Model.

Neuronal hyperexcitability within developing cortical circuits is a common characteristic of several heritable neurodevelopmental disorders, including Fragile X Syndrome (FXS), intellectual disability and autism spectrum disorders (ASD). While this aberrant circuitry is typically studied from a neuron-centric perspective, glial cells secrete soluble factors that regulate both neurite extension and synaptogenesis during development. The nucleotide-mediated purinergic signalling system is particularly instrumental in facilitating these effects. We recently reported that within a FXS animal model, theFmr1 KO mouse, the purinergic signalling system is upregulated in cortical astrocytes leading to altered secretion of synaptogenic and plasticity-related proteins. In this study, we examined whether elevated astrocyte purinergic signalling also impacts neuronal morphology and connectivity of Fmr1 KO cortical neurons. Here, we found that conditioned media from primary Fmr1 KO astrocytes was sufficient to enhance neurite extension and complexity of both wildtype and Fmr1 KO neurons to a similar degree as UTP-mediated outgrowth. Significantly enhanced firing was also observed in Fmr1 KO neuron-astrocyte co-cultures grown on microelectrode arrays but was associated with large deficits in firing synchrony. The selective P2Y2 purinergic receptor antagonist AR-C 118925XX effectively normalized much of the aberrant Fmr1 KO activity, designating P2Y2 as a potential therapeutic target in FXS. These results not only demonstrate the importance of astrocyte soluble factors in the development of neural circuitry, but also show that P2Y purinergic receptors play a distinct role in pathological FXS neuronal activity.

Development of a polarity-sensitive ratiometric fluorescent probe based on the intramolecular reaction of spiro-oxazolidine and its applications for in situ visualizing the fluctuations of polarity during ER stress

Polarity is a vital element in endoplasmic reticulum (ER) microenvironment, and its variation is closely related to many physiological and pathological activities of ER, so it is necessary to trace fluctuations of polarity in ER. However, most of fluorescent probes for detecting polarity dependent on the changes of single emission, which could be affected by many factors and cause false signals. Ratiometric fluorescent probe with “built-in calibration” can effectively avoid detection errors. Here, we have designed a ratiometric fluorescent probe HM for monitoring the ER polarity based on the intramolecular reaction of spiro-oxazolidine. It forms ring open/closed isomers driven by polarity to afford ratiometric sensing. Probe HM have manifested its ratiometric responses to polarity in spectroscopic results, which could offer much more precise information for the changes of polarity in living cells with the internal built-in correction. It also showed large emission shift ( 133 nm), high selectivity and photo-stability. In biological imaging, HM could selectively accumulate in ER with high photo-stability. Importantly, HM has ability for in situ tracing the changes of ER polarity with ratiometric behavior during the ER stress process with the stimulation of tunicamycin, dithiothreitol and hypoxia, suggesting that HM is an effective molecule tool for monitoring the variations of ER polarity.

Pathological claustrum activity drives aberrant cognitive network processing in human chronic pain

Aberrant cognitive network activity and cognitive deficits are established features of chronic pain. However, the nature of cognitive network alterations associated with chronic pain and their underlying mechanisms require elucidation. Here, we report that the claustrum, a subcortical nucleus implicated in cognitive network modulation, is activated by acute painful stimulation and pain-predictive cues in healthy participants. Moreover, we discover pathological activity of the claustrum and a region near the posterior inferior frontal sulcus of the right dorsolateral prefrontal cortex (piDLPFC) in migraine patients during acute pain and cognitive task performance. Dynamic causal modeling suggests a directional influence of the claustrum on activity in this piDLPFC region, and diffusion weighted imaging verifies their structural connectivity. These findings advance understanding of claustrum function during acute pain and provide evidence of a possible circuit mechanism driving cognitive impairments in chronic pain.

Myoelectric control and virtual reality to enhance motor rehabilitation after stroke.

Effective upper-limb rehabilitation for severely impaired stroke survivors is still missing. Recent studies endorse novel motor rehabilitation approaches such as robotic exoskeletons and virtual reality systems to restore the function of the paretic limb of stroke survivors. However, the optimal way to promote the functional reorganization of the central nervous system after a stroke has yet to be uncovered. Electromyographic (EMG) signals have been employed for prosthetic control, but their application to rehabilitation has been limited. Here we propose a novel approach to promote the reorganization of pathological muscle activation patterns and enhance upper-limb motor recovery in stroke survivors by using an EMG-controlled interface to provide personalized assistance while performing movements in virtual reality (VR). We suggest that altering the visual feedback to improve motor performance in VR, thereby reducing the effect of deviations of the actual, dysfunctional muscle patterns from the functional ones, will actively engage patients in motor learning and facilitate the restoration of functional muscle patterns. An EMG-controlled VR interface may facilitate effective rehabilitation by targeting specific changes in the structure of muscle synergies and in their activations that emerged after a stroke-offering the possibility to provide rehabilitation therapies addressing specific individual impairments.

Multisensory flicker modulates widespread brain networks and reduces interictal epileptiform discharges

Modulating brain oscillations has strong therapeutic potential. Interventions that both non-invasively modulate deep brain structures and are practical for chronic daily home use are desirable for a variety of therapeutic applications. Repetitive audio-visual stimulation, or sensory flicker, is an accessible approach that modulates hippocampus in mice, but its effects in humans are poorly defined. We therefore quantified the neurophysiological effects of flicker with high spatiotemporal resolution in patients with focal epilepsy who underwent intracranial seizure monitoring. In this interventional trial (NCT04188834) with a cross-over design, subjects underwent different frequencies of flicker stimulation in the same recording session with the effect of sensory flicker exposure on local field potential (LFP) power and interictal epileptiform discharges (IEDs) as primary and secondary outcomes, respectively. Flicker focally modulated local field potentials in expected canonical sensory cortices but also in the medial temporal lobe and prefrontal cortex, likely via resonance of stimulated long-range circuits. Moreover, flicker decreased interictal epileptiform discharges, a pathological biomarker of epilepsy and degenerative diseases, most strongly in regions where potentials were flicker-modulated, especially the visual cortex and medial temporal lobe. This trial met the scientific goal and is now closed. Our findings reveal how multi-sensory stimulation may modulate cortical structures to mitigate pathological activity in humans.

Involvement of transposable elements in Alzheimer's disease pathogenesis.

Alzheimer's disease affects an average of 5 % of the population with a significant increase in prevalence with age, suggesting that the same mechanisms that underlie aging may influence this pathology. Investigation of these mechanisms is promising for effective methods of treatment and prevention of the disease. Possible participants in these mechanisms are transposons, which serve as drivers of epigenetic regulation, since they form species-specific distributions of non-coding RNA genes in genomes in evolution. Study of miRNA involvement in Alzheimer's disease pathogenesis is relevant, since the associations of protein-coding genes (APOE4, ABCA7, BIN1, CLU, CR1, PICALM, TREM2) with the disease revealed as a result of GWAS make it difficult to explain its complex pathogenesis. Specific expression changes of many genes were found in different brain parts of Alzheimer's patients, which may be due to global regulatory changes under the influence of transposons. Experimental and clinical studies have shown pathological activation of retroelements in Alzheimer's disease. Our analysis of scientific literature in accordance with MDTE DB revealed 28 miRNAs derived from transposons (17 from LINE, 5 from SINE, 4 from HERV, 2 from DNA transposons), the expression of which specifically changes in this disease (decreases in 17 and increases in 11 microRNA). Expression of 13 out of 28 miRNAs (miR-151a, -192, -211, -28, -31, -320c, -335, -340, -378a, -511, -576, -708, -885) also changes with aging and cancer development, which indicates the presence of possible common pathogenetic mechanisms. Most of these miRNAs originated from LINE retroelements, the pathological activation of which is associated with aging, carcinogenesis, and Alzheimer's disease, which supports the hypothesis that these three processes are based on the primary dysregulation of transposons that serve as drivers of epigenetic regulation of gene expression in ontogeny.

Prediction of pathological activity in Crohn’s disease based on dual-energy CT enterography

PurposeTo explore the feasibility of predicting the pathological activity of Crohn’s disease (CD) based on dual-energy CT enterography (DECTE).MethodsThe clinical, endoscopic, imaging and pathological data of 55 patients with CD scanned by DECTE were retrospectively analyzed; the pathological results were used as a reference standard to classify the diseased bowel segments into active and inactive phases. The normalized iodine concentration (NIC), energy-spectrum curve slope K, dual energy index (DEI), fat fraction (FF) of the arterial phases and venous phases were compared. To assess the parameters’ predictive ability, receiver-operating characteristic curves were used. The Delong test was used to compare the differences between the diagnostic efficiency of each parameter.ResultsA total of 84 intestinal segments were included in the study, including 54 active intestinal segments and 30 inactive intestinal segments. The NIC, energy-spectrum curve slope K and DEI were significantly different between active and inactive bowel segments in the arterial and venous phases (P < 0.05), while FF were not significantly different (P > 0.05). The largest area under the curve (AUC) of NIC, energy-spectrum curve slope K and DEI were higher in arterial phase than in venous phase. For identifying the intestinal activity of CD, the maximum AUC of NIC in arterial phase was 0.908, with a sensitivity of 0.833 and a specificity of 0.800, and the DEI in arterial phase had the highest sensitivity (0.944).ConclusionThe NIC, energy-spectrum curve slope K and DEI can effectively distinguish the active and inactive phases of the intestinal segments of CD patients and provide good assistance for determining further treatment.Graphical abstract

Assessment of the FRET-based Teen sensor to monitor ERK activation changes preceding morphological defects in a RASopathy zebrafish model and phenotypic rescue by MEK inhibitor

BackgroundRASopathies are genetic syndromes affecting development and having variable cancer predisposition. These disorders are clinically related and are caused by germline mutations affecting key players and regulators of the RAS-MAPK signaling pathway generally leading to an upregulated ERK activity. Gain-of-function (GOF) mutations in PTPN11, encoding SHP2, a cytosolic protein tyrosine phosphatase positively controlling RAS function, underlie approximately 50% of Noonan syndromes (NS), the most common RASopathy. A different class of these activating mutations occurs as somatic events in childhood leukemias.MethodHere, we evaluated the application of a FRET-based zebrafish ERK reporter, Teen, and used quantitative FRET protocols to monitor non-physiological RASopathy-associated changes in ERK activation. In a multi-level experimental workflow, we tested the suitability of the Teen reporter to detect pan-embryo ERK activity correlates of morphometric alterations driven by the NS-causing Shp2D61G allele.ResultsSpectral unmixing- and acceptor photobleaching (AB)-FRET analyses captured pathological ERK activity preceding the manifestation of quantifiable body axes defects, a morphological pillar used to test the strength of SHP2 GoF mutations. Last, the work shows that by multi-modal FRET analysis, we can quantitatively trace back the modulation of ERK phosphorylation obtained by low-dose MEK inhibitor treatment to early development, before the onset of morphological defects.ConclusionThis work proves the usefulness of FRET imaging protocols on both live and fixed Teen ERK reporter fish to readily monitor and quantify pharmacologically- and genetically-induced ERK activity modulations in early embryos, representing a useful tool in pre-clinical applications targeting RAS-MAPK signaling.

Integration of single-cell transcriptome and chromatin accessibility and its application on tumor investigation

Abstract The advent of single-cell sequencing techniques has not only revolutionized the investigation of biological processes but also significantly contributed to unraveling cellular heterogeneity at unprecedented levels. Among the various methods, single-cell transcriptome sequencing stands out as the best established, and has been employed in exploring many physiological and pathological activities. The recently developed single-cell epigenetic sequencing techniques, especially chromatin accessibility sequencing, have further deepened our understanding of gene regulatory networks. In this review, we summarize the recent breakthroughs in single-cell transcriptome and chromatin accessibility sequencing methodologies. Additionally, we describe current bioinformatic strategies to integrate data obtained through these single-cell sequencing methods and highlight the application of this analysis strategy on a deeper understanding of tumorigenesis and tumor progression. Finally, we also discuss the challenges and anticipated developments in this field.

1139 Retrospective Review of Stereotactic Electroencephalogram Recordings in Temporal Lobectomy Patients Demonstrates the Predictive Value of Interictal Cross-frequency Correlations

INTRODUCTION: Positive correlations between low and high frequency spectra in invasive electroencephalogram (EEG) have been implicated in pathological brain activity interictally and have been used for ictal detection in both focal and network models. METHODS: We retrospectively analyzed interictal signals from 22 patients who underwent SEEG at our institution between 12/2/14 to 12/8/20. We then analyzed significant HG/Beta cross-frequency correlations using similar processing to our previous publication. These signals were then separated based on temporal and extra-temporal locations. We further evaluated any statistical differences between the seizure free (SF) and non-seizure free (NSF) groups, and mesial (M) versus mesial temporal-plus (M+) onset location. RESULTS: 1) Clinical recordings from SEEG electrodes can detect cross-frequency correlations between HG/Beta using our previous methodology. 2) Positive correlations are significantly increased in temporal versus other sampled areas. 3) Positive correlations are more predictive of seizure onset during asleep recordings. 4) NSF patients show a significantly higher proportion of positive electrodes in the resected temporal lobe than SF patients. 5) SF patients have a greater proportion of significant contacts in the mesial versus the lateral temporal lobe than NSF patients. 6) Significant HG/Beta correlations in the mesial versus lateral temporal lobe predict seizure freedom better than ictal SEEG localization of seizure onset to M or M+ locations. CONCLUSIONS: We present preliminary data that local HG/Beta correlations may be predictive for epilepsy focus and surgical outcome and may have utility as adjunct methods to conventional SEEG analysis. Further studies are needed to determine strategies for prospective studies and clinical use.

Роль ангиогенного фактора в развитии эндометриальной дисфункции у женщин репродуктивного возраста с аномальными маточными кровотечениями и ожирением

The steady increase in the number of patients with abnormal uterine bleeding (AUB) has a negative impact on a woman's reproductive health. Obesity is defined as one of the risk factors for AUB and its role in the development of AUB-M and AUB-O has been studied to date. However, our earlier analysis of the results of histological examination of endometrial biopsies showed that in obese women with AUB, the desquamation phase (AUB-E) is significantly more common in the endometrium than in normal-weight women. One of the possible pathogenetic mechanisms may be abnormal endometrial vascularization due to systemic proinflammatory status and local tissue hypoxia. Aim. To identify the features of the expression of endothelial markers CD34+ and eNOS in endometrial biopsies of patients with AUB and obesity and their role in the pathogenesis of endometrial dysfunction. Materials and methods. A prospective randomized cohort study included 40 patients of reproductive age with AUB-E. Depending on the presence of obesity, women were stratified into 2 groups: 20 patients with AUB-E and obesity (group 1) and 20 normal-weight patients with AUB-E (group 2). 10 healthy women of reproductive age were included as a control group. All patients underwent endometrial biopsy followed by histological examination according to the standard procedure. At the second stage, an immunohistochemical study of CD34+ and eNOS angiogenesis markers was performed using monoclonal mouse antibodies in standard dilution. The IBM SPSS Statistics v.26 program (IBM Corporation, USA) was used for statistical data analysis. Results. CD34+ expression in patients with AUB and obesity was significantly higher than in normal-weight patients with AUB and healthy women (2,5±0,2, respectively; 95% CI 2,1–2,8 vs. 1,8±0,2; 95% CI 1,5–2,2 and 0,5±0,1; 95% CI 0,4–0,6; p1-2=0,03; p1-3&lt;0,001; p2-3&lt;0,001), as well as eNOS expression (respectively 8,7±0,6; 95% CI 7,3–10,0 vs. 4,0±0,5; 95% CI 3–5 and 1,3±0,2; 95% CI 0,9–1,7; p1-2&lt;0,001; p1-3&lt;0,001; p2-3&lt;0,001). Conclusion. Patients with AUB-E and obesity are characterized by increased expression of CD34+ and eNOS in endometrial tissue, which indicates pathological activation of neoangigenesis. Perhaps one of the mechanisms of pathogenesis is the formation of a proinflammatory profile against the background of obesity, which contributes to the pathological hypervascularization of the endometrium. Effective weight loss measures can probably reduce the incidence and recurrence of AUB-E.

Pathological mechanisms of cold and mechanical stress in modulating cancer progression.

Environmental temperature and cellular mechanical force are the inherent factors that participate in various biological processes and regulate cancer progress, which have been hot topics worldwide. They occupy a dominant part in the cancer tissues through different approaches. However, extensive investigation regarding pathological mechanisms in the carcinogenic field. After research, we found cold stress via two means to manipulate tumors: neuroscience and mechanically sensitive ion channels (MICHs) such as TRP families to regulate the physiological and pathological activities. Excessive cold stimulation mediated neuroscience acting on every cancer stage through the hypothalamus-pituitary-adrenocorticoid (HPA) to reach the target organs. Comparatively speaking, mechanical force via Piezo of MICHs controls cancer development. The progression of cancer depends on the internal activation of proto-oncogenes and the external tumorigenic factors; the above two means eventually lead to genetic disorders at the molecular level. This review summarizes the interaction of bidirectional communication between them and the tumor. It covers the main processes from cytoplasm to nucleus related to metastasis cascade and tumor immune escape.

Abstract 7115: Mutational signatures in PDXs for improved understanding of drug response and companion biomarkers identification

Abstract Genomic DNA editing is a continuous process that occurs during the entire cell life span. The type and frequency of these modifications can be related to the physiological or pathological activity of intrinsic mechanisms such as DNA surveillance and repair or to extrinsic events that may induce an alteration of DNA sequence by exposure to agents that directly or indirectly induce accumulations of DNA alterations. In the past few years, large-scale analyses have revealed mutational signatures across human cancer types. These signatures can be used as markers of defective internal processes, such as DNA repair deficiency, or external exposures, such as carcinogens, like tobacco, or genotoxic therapies such as radiation and chemotherapy. Our TumorGraft platform, a collection of 1500 patient-derived xenograft generated from more than 50 different types of cancer, is one of the most comprehensive preclinical oncology platforms worldwide, and aims to recapitulate the variety of the patient population and tumor biology complexity. This platform is currently used to evaluate the efficacy of new drugs, and all our models are very well characterized at the molecular level, including whole transcriptome, proteomics and phospho-proteomics, quantification, and genomic variation calls. This allows accurate selection of models with the molecular characteristics of the target patient population, as well as to identify biomarkers predictive of treatment efficacy. This could eventually lead to the development of companion biomarkers in the clinical setting to improve the identification of patients that will benefit from the treatment and those that should be spared. To maximize the chances of identifying relevant molecular traits associated with tumor response, we have been utilizing the Pharmaco-Pheno-Multiomic (PPMO) integration workflow, a machine learning approach which combines phenotypic and therapeutic response profiles with multiple omics datatypes to generate complex biomarker profiles. To provide additional insights on the molecular characteristics of our tumors, we decided to perform the mutational signatures profiling of our models by using whole exome sequencing data. The results obtained were crossed with patient’s clinical history and showed good correlation between the mutational signatures identified and the treatments received by the patient, in particular for exposure to platinum salts. The addition of PDXs mutational signatures strongly improves our knowledge on these models and confers an important parameter for model selection. Moreover, the integration of mutational signature profiles in the PPMO workflow would make a significant contribution for companion biomarkers identification. Citation Format: Haia Khoury, Stefano Cairo, Mara Gilardi, Michael Ritchie, Gilad Silberberg. Mutational signatures in PDXs for improved understanding of drug response and companion biomarkers identification [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 7115.

Identification of cellular senescence-associated genes as new biomarkers for predicting the prognosis and immunotherapy response of non-small cell lung cancer and construction of a prognostic model

BackgroundGlobally, lung carcinoma remains the leading cause of death, with its associated morbidity and mortality rates remaining elevated. Despite the slow advancement of treatment, the outlook remains bleak. Cellular senescence represents a halt in the cell cycle, encompassing a range of physiological and pathological activities, along with diverse phenotypic alterations, including variations in secretory phenotype, macromolecular harm, and metabolic disturbances. Research has revealed its vital function in the formation and growth of tumors. This study aimed to examine cellular senescence-related mRNAs linked to the outlook of non-small cell lung cancer (NSCLC) and to formulate a predictive risk framework for NSCLC. MethodsWe acquired the NSCLC expression data from The Cancer Genome Atlas (TCGA) to examine mRNAs linked to cellular senescence. Both single-variable and multiple-variable cox proportion risk assessments were utilized to determine the traits of cellular senescence-related mRNAs linked to NSCLC prognosis. Subsequently, the prognostic model for cellular senescence-related mRNAs was integrated with clinical-pathological characteristics to create a prognostic nomogram. Furthermore, the study delved into the risk-oriented predictive model, examining immune infiltration and responses to immunotherapy among both high and low-risk categories. ResultsUtilizing both univariate and multivariate Cox proportion risk assessments, a risk model comprising 12 mRNAs associated with cellular aging was ultimately developed: IGFBP1, TLR3, WT1, ID1, PTTG1, ERRFI1, HEPACAM, MAP2K3, RAD21, NANOG, PRKCD, SOX5. Univariate analysis and multivariate analysis illustrated that the risk score served as a standalone indicator for prognosis, and the hazard ratio (HR) of the risk score were 1.182 (1.139–1.226) (p < 0.001) and 1.162 (1.119 − 1.206) (p < 0.001), respectively. Individual prognoses were forecasted using nomogram, c-index, and principal component analysis (PCA). Furthermore, the risk-oriented model revealed notable statistical variances in immune infiltration and response to immunotherapy among the high and low risk categories. ConclusionsThis study shows that mRNAs related to cell senescence associated with prognosis are reliable predictors of NSCLC immunotherapy reaction and prognosis.

Naujųjų anti-CD20 monokloninių antikūnų vaidmuo gydant itin aktyvią recidyvuojančiąją remituojančiąją išsėtinę sklerozę: ofatumumabo klinikinis efektyvumas ir saugumas

Multiple sclerosis is the most common chronic demyelinating neurodegenerative central nervous system disease among young adults. Considering its extent in a relatively young population, multiple sclerosis determines a significant socioeconomic burden to the society due to the cost of disease modifying treatment and a lower working capacity of patients and their caregivers. It is important to control neuroinflammation in the central nervous system caused by the pathologic activity of immune cells by considering a high efficacy treatment early in the disease course in order to prevent accumulation of neurological damage and to improve long term outcomes. According to the newest clinical studies, anti-CD20 therapies have proven their effectiveness and safety in active relapsing multiple sclerosis treatment: since 2018, ocrelizumab, and, since 2023, ofatumumab have both been available as treatment options in Lithuania. Because of its high potency and safety, as well as the specific mechanism of action, ofatumumab is effective in lower doses, and, after initial training at a health care facility, it can be self-administered through subcutaneous injection. This article reviews the efficacy, safety data and treatment indications of the latest available anti-CD20 monoclonal antibodies.

Analysis of the relationship of various pathologies with the degree of multifractality of electrical activity of the brain

The review is devoted to the analysis of the relationship between dynamic changes in patterns of electrical activity of the brain during the occurrence of mental disorders in the form of paranoid schizophrenia and depression and in patterns of brain activity in cardiovascular pathology associated with permanent atrial fibrillation, as well as indicators of multifractality of the studied patterns. To assess these indicators of electroencephalographic patterns, we describe a method of multifractal analysis based on the search for maxima of wavelet coefficient modules, and to isolate the fractal component of the signal in the power spectrum we describe a method of autospectral analysis with irregular resampling. It has been shown that the main differences between the multifractal properties of the electrical activity of the brain in health and in pathology are the different widths of the multifractality spectrum and its location, associated with different types of sequential pattern values. In this regard, the multifractality indicators can serve as informative markers of neuronal disorders and can be included in a set of tests for studying various pathologies.