Markers Of Susceptibility Research Articles

Evaluation of serum interleukin-12 and interleukin-4 as potential biomarkers for the diagnosis of major depressive disorder

Recently, scientists have focused on pro-inflammatory cytokines and immunological dysregulation in major depressive disorder (MDD). Some research suggests pro-inflammatory cytokines' role in MDD development, whereas anti-inflammatory studies are sparse. There is no systematic investigation of Bangladeshi MDD patients' pro- and anti-inflammatory cytokines. This study examines the blood levels of IL-12 and IL-4 in Bangladeshi patients and healthy controls (HCs) to determine the diagnostic accuracy of these cytokines to identify MDD patients from those without MDD. A total of 110 people with MDD from the department of psychiatry of a teaching hospital in Dhaka and 107 HCs from Dhaka participated in this case–control study. Depression and illness severity were gauged using DSM-5 criteria and Ham-D scores. Commercially marketed ELISA kits were used in accordance with manufacturer guidelines to measure the levels of IL-12 and IL-4 in peripheral blood, allowing a comparison of the patient and control groups. In comparison to HCs, MDD patients (5333.00 ± 307.40 pg/ml) showed noticeably higher levels of IL-12 than in HCs (2331.00 ± 207.40 pg/ml). The increased levels were positively correlated with Ham-D scores (male: r = 0.351, p < 0.050; female: r = 0.389, p < 0.050), suggesting a possible relationship to disease progression. Additionally, compared to HCs (272.81 ± 23.94 pg/ml), MDD patients had significantly higher peripheral blood levels of IL-4 (876.35 ± 66.73 pg/ml) (p < 0.001). Also, there was a positive correlation between IL-4 serum levels and Ham-D scores (male: r = 0.361, p < 0.050; female: r = 0.398, p < 0.050). Therefore, we observed increased levels of these serum cytokines and their association with the severity of depression. The results of this study demonstrate the possibility of IL-12 and IL-4 blood levels as distinct markers capable of differentiating between MDD patients and HCs, possibly acting as markers of MDD susceptibility. To ascertain the diagnostic effectiveness of these two cytokines, more research is necessary.

The impact of PA/I38 substitutions and PA polymorphisms on the susceptibility of zoonotic influenza A viruses to baloxavir

Genetic reassortment of avian, swine, and human influenza A viruses (IAVs) poses potential pandemic risks. Surveillance is important for influenza pandemic preparedness, but the susceptibility of zoonotic IAVs to the cap-dependent endonuclease inhibitor baloxavir acid (BXA) has not been thoroughly researched. Although an amino acid substitution at position 38 in the polymerase acidic protein (PA/I38) in seasonal IAVs reduces BXA susceptibility, PA polymorphisms at position 38 are rarely seen in zoonotic IAVs. Here, we examined the impact of PA/I38 substitutions on the BXA susceptibility of recombinant A(H5N1) viruses. PA mutants that harbored I38T, F, and M were 48.2-, 24.0-, and 15.5-fold less susceptible, respectively, to BXA than wild-type A(H5N1) but were susceptible to the neuraminidase inhibitor oseltamivir acid and the RNA polymerase inhibitor favipiravir. PA mutants exhibited significantly impaired replicative fitness in Madin-Darby canine kidney cells at 24 h postinfection. In addition, in order to investigate new genetic markers for BXA susceptibility, we screened geographically and temporally distinct IAVs isolated worldwide from birds and pigs. The results showed that BXA exhibited antiviral activity against avian and swine viruses with similar levels to seasonal isolates. All viruses tested in the study lacked the PA/I38 substitution and were susceptible to BXA. Isolates harboring amino acid polymorphisms at positions 20, 24, and 37, which have been implicated in the binding of BXA to the PA endonuclease domain, were also susceptible to BXA. These results suggest that monitoring of the PA/I38 substitution in animal-derived influenza viruses is important for preparedness against zoonotic influenza virus outbreaks.

Is lower fetal heart rate variability a susceptibility marker to the impact of negative coparenting on infant regulatory capacity?

Lower fetal heart rate variability (FHRV) may be a prenatal endophenotypic susceptibility marker and increase the impact of both positive and negative coparenting on infant regulatory capacity. This study analyzed the moderator role of FHRV in the association between positive and negative coparenting and infant regulatory capacity at 3 months. The sample comprised 86 first-born infants and their mothers and fathers recruited at a public Health Service in Northern Portugal. FHRV was recorded during routine cardiotocography examination at the third trimester of gestation. Mothers and fathers reported on coparenting and infant regulatory capacity at 2 weeks and 3 months postpartum. FHRV moderated the association between mother's and father's negative coparenting at 2 weeks postpartum and infant regulatory capacity at three months. Infants with low FHRV presented higher regulatory capacity when mothers or fathers reported less negative coparenting, while lower regulatory capacity when mothers or fathers reported more negative coparenting, than infants with high FHRV. Findings suggested lower FHRV as a prenatal endophenotypic susceptibility marker that increases the impact of negative coparenting on infant regulatory capacity.

The role of cellular senescence in profibrillatory atrial remodelling associated with cardiac pathology.

Cellular senescence is a stress-related or aging response believed to contribute to many cardiac conditions; however, its role in atrial fibrillation (AF) is unknown. Age is the single most important determinant of the risk of AF. The present study was designed to (i) evaluate AF susceptibility and senescence marker expression in rat models of aging and myocardial infarction (MI), (ii) study the effect of reducing senescent-cell burden with senolytic therapy on the atrial substrate in MI rats, and (iii) assess senescence markers in human atrial tissue as a function of age and the presence of AF. AF susceptibility was studied with programmed electrical stimulation. Gene and protein expression was evaluated by immunoblot or immunofluorescence (protein) and digital polymerase chain reaction (PCR) or reverse transcriptase quantitative PCR (messenger RNA). A previously validated senolytic combination, dasatinib and quercetin, (D+Q; or corresponding vehicle) was administered from the time of sham or MI surgery through 28 days later. Experiments were performed blinded to treatment assignment. Burst pacing-induced AF was seen in 100% of aged (18-month old) rats, 87.5% of young MI rats, and 10% of young control (3-month old) rats (P ≤ 0.001 vs. each). Conduction velocity was slower in aged [both left atrium (LA) and right atrium (RA)] and young MI (LA) rats vs. young control rats (P ≤ 0.001 vs. each). Atrial fibrosis was greater in aged (LA and RA) and young MI (LA) vs. young control rats (P < 0.05 for each). Senolytic therapy reduced AF inducibility in MI rats (from 8/9 rats, 89% in MI vehicle, to 0/9 rats, 0% in MI D + Q, P < 0.001) and attenuated LA fibrosis. Double staining suggested that D + Q acts by clearing senescent myofibroblasts and endothelial cells. In human atria, senescence markers were upregulated in older (≥70 years) and long-standing AF patients vs. individuals ≤60 and sinus rhythm controls, respectively. Our results point to a potentially significant role of cellular senescence in AF pathophysiology. Modulating cell senescence might provide a basis for novel therapeutic approaches to AF.

Association of ACE1 I/D polymorphism and susceptibility to COVID-19 in Egyptian children and adolescents

BackgroundGiven the sparse data on the renin-angiotensin system (RAS) and its biological effector molecules ACE1 and ACE2 in pediatric COVID-19 cases, we investigated whether the ACE1 insertion/deletion (I/D) polymorphism could be a genetic marker for susceptibility to COVID-19 in Egyptian children and adolescents.MethodsThis was a case-control study included four hundred sixty patients diagnosed with COVID-19, and 460 well-matched healthy control children and adolescents. The I/D polymorphism (rs1799752) in the ACE1 gene was genotyped by polymerase chain reaction (PCR), meanwhile the ACE serum concentrations were assessed by ELISA.ResultsThe ACE1 D/D genotype and Deletion allele were significantly more represented in patients with COVID-19 compared to the control group (55% vs. 28%; OR = 2.4; [95% CI: 1.46–3.95]; for the DD genotype; P = 0.002) and (68% vs. 52.5%; OR: 1.93; [95% CI: 1.49–2.5] for the D allele; P = 0.032). The presence of ACE1 D/D genotype was an independent risk factor for severe COVID-19 among studied patients (adjusted OR: 2.6; [95% CI: 1.6–9.7]; P < 0.001.ConclusionsThe ACE1 insertion/deletion polymorphism may confer susceptibility to SARS-CoV-2 infection in Egyptian children and adolescents.ImpactRecent studies suggested a crucial role of renin-angiotensin system and its biological effector molecules ACE1 and ACE2 in the pathogenesis and progression of COVID-19.To our knowledge, ours is the first study to investigate the association of ACE1 I/D polymorphism and susceptibility to COVID-19 in Caucasian children and adolescents.The presence of the ACE1 D/D genotype or ACE1 Deletion allele may confer susceptibility to SARS-CoV-2 infection and being associated with higher ACE serum levels; may constitute independent risk factors for severe COVID-19.The ACE1 I/D genotyping help design further clinical trials reconsidering RAS-pathway antagonists to achieve more efficient targeted therapies.

Whole exome sequencing identifies genetic markers of enterovirus susceptibility in East Asians.

Following acute enterovirus (EV) infection, outcomes vary based on factors like the immune response, viral cell entry receptor expression levels, tissue tropism, and genetic factors of both the host and virus. While most individuals exhibit mild, self-limited symptoms, others may suffer severe complications or prolonged infections that can lead to autoimmune disorders. To elucidate host responses to EV infection, we performed whole exome sequencing on blood samples from both infected and uninfected individuals. Our initial focus was on genes encoding EV entry receptors-PSGL-1, SCARB2, and ANAXA2 for EV-A71, and CD155 for poliovirus-and on host genes ACBD3 and PI4KΒ, crucial for EV replication. Although no specific genetic variants directly associated with EV infection were identified, we discovered 118 variants across 116 genes enriched in East Asian populations through multi-layered variant filtering. These variants were further analyzed for their potential impacts on organs, biological processes, and molecular pathways. Phenome-wide association studies were conducted to refine our understanding of their contributions to EV infection susceptibility. Our findings aim to develop a predictive panel based on these 118 variants, which could help susceptible individuals during EV outbreaks, guiding targeted clinical interventions and preventative strategies.

Emerging Technologies and Advanced Biomarkers for Enhanced Toxicity Prediction and Safety Pharmacology

Background: Biomarkers are important tools in toxicology that can improve risk assessment, early detection of organ injury, and monitoring of pharmacological responses. However, rigorous validation is necessary to justify use for regulatory decisionmaking. Purpose: This article reviews the current landscape surrounding established and emerging biomarkers of toxicity across multiple techniques, with a focus on assessment of merits, limitations, and validation needs. Main Body: An overview of common clinical chemistry biomarkers used for safety monitoring of liver, kidney, heart, and inflammation is first provided, highlighting their biological relevance and applications in detecting organ dysfunction. Novel protein biomarkers emerging for enhanced sensitivity of injury detection are then discussed, such as microRNAs for liver and clusterin for kidney. Metabolomic biomarker approaches to assess biofluids and mitochondrial toxicity are outlined, along with toxicogenomic markers of susceptibility like HLA alleles. Non-invasive imaging techniques including ultrasound, MRI, and PET tracers for organ function are explored as techniques that provide additional modalities for biomarker measurement. Emerging tools like organ microphysiological systems and high-throughput omics for biomarker discovery are also described. Conclusion: While great progress has been made, translation and qualification of novel biomarkers remains challenging. This review synthesizes key developments across biomarker categories, evaluates readiness for regulatory use, and outlines strategic considerations for fit-for-purpose biomarker validation to advance integration into drug development programs.

Оценка распространенности полиморфизмов в генах, кодирующих рецептор витамина D и фермент 1α-гидроксилазу, у жителей Москвы и Московской области для составления персонализированной схемы лечения препаратами витамина D

The use of vitamin D preparations in the treatment of several diseases is of great interest, given its multiple and diverse effects. However, despite the positive experience with cholecalciferol, there are patients in whom clinical efficacy is either absent or poorly expressed, and similar data are available in published studies. Polymorphisms in genes encoding the vitamin D receptor and the 1α-hydroxylase enzyme are a necessary addition to laboratory parameters to allow proper selection of the dose, regimen, form, and chemical structure of the vitamin D preparation. Objective. To assess the prevalence of polymorphisms in genes encoding the vitamin D receptor and the 1α-hydroxylase enzyme in residents of Moscow and the Moscow Region. Patients and methods. The study included 3000 patients living in Moscow and the Moscow Region, aged 2 to 77 years, treated with vitamin D preparations in Professor Kalinchenko Clinic between October 10, 2020, and December 23, 2023. Patients were genotyped by direct sequencing for two markers of susceptibility to vitamin D deficiency: variants in the vitamin D receptor gene (VDR, BsmI Polymorphism, rs1544410) and the 1α-hydroxylase enzyme gene (CYP27B1, g.57764205A&gt;G; rs464656536). Statistical data processing was performed using IBM SPSS Statistics 23.0 software (USA). Results. Polymorphism in the gene encoding the 1α-hydroxylase enzyme was detected in 2595 (89.5%) of 3000 patients, of which heterozygotes (A/G) in 1434 (47.8%) and homozygotes (A/A) in 1161 (38.7%). Polymorphism in the gene encoding VDR was detected in 429 (14.3%) patients, of which heterozygotes (C/T) in 1338 (44.6%) and homozygotes (C/C) in 1233 (41.1%). The combination of polymorphisms in the CYP27B1 and VDR genes was detected in 375 (12.5%) patients, the absence of polymorphisms in two genes – in 351 (11.7%). Discussion. In the presence of CYP27B1, g.57764205A &gt; G; rs4646536 in the gene encoding the 1α-hydroxylase enzyme, the intensity of calcitriol formation is reduced, which explains the lack of effect of therapy with cholecalciferol preparations. In the presence of VDR, BsmI Polymorphism, rs1544410 in the gene encoding the vitamin D receptor, the sensitivity of the receptor to hormone D is reduced, which explains the lack of clinical effects of therapy with vitamin D preparations in standard therapeutic doses. The most difficult-to-treat clinical manifestations of vitamin D deficiency were found in patients with polymorphisms in two genes encoding both VDR and 1α-hydroxylase, which amounted to 12.5% (375 people) of the total number of patients; among all patients examined, only 351 (11.7%) did not have polymorphisms in these two genes. Conclusion. Controversial literature data and clinical effects of vitamin D therapy are due to variants in the VDR and/or CYP27B1 genes. Knowledge of genetics allows individualization of the dose, form, and chemical activity of the vitamin D preparation, which is the key to success of therapy. Key words: vitamin D, calcidiol, calcitriol, vitamin D receptor, cholecalciferol, 1α-hydroxylase

Udruženost polimorfizama gena za katehol-Ometiltransferazu sa terapijskim odgovorom i komplikacijama izazvanim levodopom kod Parkinsonove bolesti - rezime sadašnjih saznanja

Catechol-O-methyltransferase (COMT) is one of the cardinal enzymes in the degradation of catecholamines and levodopa. Genetic variants of the COMT gene may affect COMT enzyme activity. The most examined COMT gene polymorphism is the nonsynonymous single nucleotide polymorphism (SNP) in exon 4 (Val108/158Met; rs4680). This highly functional polymorphism is responsible for fourfold variations in enzyme activity and Dopamine catabolism. Recent data suggested that even synonymous SNPs of the COMT gene can lead to changes in enzyme activity. Genetically determined COMT activity can affect an individual's response to levodopa therapy and carries the risk of complications from prolonged levodopa use in Parkinson's disease (PD) patients. Identifying at-risk individuals through genetic susceptibility markers could help to prevent the development of levodopa-induced complications in PD.

Genetic Risk of Rheumatoid Arthritis: A Case Control Study

Vitamin D effects are mediated by vitamin D receptors (VDRs), which are influenced by various genetic polymorphisms, including ApaI and BsmI. These polymorphisms have been linked to several diseases, including rheumatoid arthritis (RA). This study aimed to compare the frequency and association of VDR ApaI and BsmI gene polymorphisms, serum 25-hydroxy vitamin D (25-(OH)-D) levels, and calcium (Ca) levels between a RA group and a matched healthy control group. In one hundred RA patients and fifty healthy controls, the genotypes of the VDR ApaI and BsmI gene polymorphisms were analyzed using polymerase chain reaction restriction fragment length polymorphisms (PCR-RFLP). Both Serum 25-(OH)-D level and calcium level were measured in the two groups. There was no significant difference between the cases and controls regarding the VDR ApaI gene polymorphism (p = 0.89). A significant difference was observed between the cases and controls in terms of the VDR BsmI gene polymorphism (p = < 0.001). The serum levels of 25-(OH)-D and calcium were significantly lower in the RA group compared to the control group (p = 0.04 and < 0.001 respectively). Significantly higher serum vitamin D levels were associated with the aa genotype (p = 0.007). Significantly increased calcium levels were associated with the AA genotype (p = 0.02). No significant difference was found among BsmI polymorphisms regarding vitamin D and Ca levels (p = 0.25 and 0.87 respectively). Vitamin D receptor gene BsmI polymorphism but not ApaI polymorphism could be a marker of RA susceptibility. Vitamin D and Ca levels are negatively affected by RA. Vitamin D receptor gene ApaI polymorphism contributes to vitamin D and Ca levels.

Early life stress predicts trajectories of emotional problems and hippocampal volume in adolescence.

Exposure to early life stress (ELS) has been consistently associated with adverse emotional and neural consequences in youth. The development of brain structures such as the hippocampus, which plays a significant role in stress and emotion regulation, may be particularly salient in the development of psychopathology. Prior work has documented smaller hippocampal volume (HCV) in relation to both ELS exposure and risk for psychopathology. We used longitudinal k-means clustering to identify simultaneous trajectories of HCV and emotional problems in 155 youth across three assessments conducted approximately two years apart (mean baseline age = 11.33years, 57% female). We also examined depressive symptoms and resilience approximately two years after the third timepoint. We identified three clusters of participants: a cluster with high HCV and low emotional problems; a cluster with low HCV and high emotional problems; and a cluster with low HCV and low emotional problems. Importantly, severity of ELS was associated with greater likelihood of belonging to the low HCV/high symptom cluster than to the low HCV/low symptom cluster. Further, low HCV/high symptom participants had more depressive symptoms and lower resilience scores than did participants in the low HCV/low symptom, but not than in the high HCV/low symptom cluster. Our findings suggest that smaller HCV indexes biological sensitivity to stress. This adds to our understanding of the ways in which ELS can affect hippocampal and emotional development in young people and points to hippocampal volume as a marker of susceptibility to context.

Clinical significance of BTLA gene expression and rs1982809 polymorphism in pan-cancer

The association between the B and T lymphocyte attenuator (BTLA) gene rs1982809 polymorphism and cancer susceptibility has been reported, but these findings are inconsistent. In addition to clarifying the relationship between the rs1982809 polymorphism and cancer susceptibility, the current study also explored the clinical significance of BTLA gene expression. The GSCA tool and Stata software were used to explore the association between BTLA gene expression and tumor stage, immune infiltration, survival prognosis, and drug sensitivity for pan-cancer, and the association of BTLA gene rs1982809 polymorphism with cancer susceptibility, respectively. BTLA gene expression was associated not only with the pathologic stages of thyroid carcinoma, skin cutaneous melanoma, and kidney renal clear cell carcinoma, but also with immune infiltration in 33 types of cancers. In addition, BTLA gene expression was linked to survival prognosis in 8 types of cancers and the sensitivity of 255 drugs such as 5-Fluorouracil, docetaxel, and methotrexate. A meta-analysis of 7 relevant studies with 4002 cancer patients and 5278 healthy controls showed that the BTLA gene rs1982809 polymorphism was unrelated to cancer susceptibility under all genetic models. However, a country-based stratification analysis suggested that the rs1982809 polymorphism could reduce cancer susceptibility in Polish and Tunisian populations. In conclusion, BTLA is expected to serve as a prognostic marker and therapeutic target for certain cancers, and the rs1982809 polymorphism is expected to serve as a cancer susceptibility marker in Polish and Tunisian populations.

CSF AβX‐34 ‐ a new biomarker for amyloid‐related small vessel pathology in early Alzheimer’s Disease

AbstractBackgroundBrain small vessel disease (SVD) increases Alzheimer’s disease (AD) risk. Impaired amyloid β (Aβ) clearance is linked to amyloid plaque formation and cerebral amyloid angiopathy (CAA). Aβ1‐40 is deposited in vessel walls, and Aβ with a C‐terminal 34' cut‐point is produced by perivascular cells. Evidence for SVD‐AD interactions in early AD is elusive, but incipient CAA putatively increases susceptibility for amyloid‐related imaging abnormalities (ARIA) in AD patients.Here we compare the SVD MRI marker “peak width of skeletonized mean diffusivity” (PSMD) to cerebrospinal fluid (CSF) Aβ species and the neurodegeneration marker Neurofilament light chain (Nfl), assessing links between SVD and AD pathologies and Aβ species as potential markers for incipient CAA.MethodCross‐sectional data from the Dementia Disease Initiation (DDI) cohort were available, comprising (n = 112) cognitively normal (CN) and (n = 115) cases with mild cognitive impairment (MCI) (n = 227). CSF markers for AD A/T/N‐staging identified 134 cases with negative markers (A‐/T‐/N‐), 21 with amyloid positive markers (A+/T‐/N‐) and 72 with amyloid and tau‐positive markers (A+/T or N+) (see table 1 for sample descriptives). Multiple linear regression models were used with PSMD by lobe as the dependent variable, and NfL, Aβ1‐40 (MesoScale), Aβx‐34 (Bioventix, Pre Diagnostic) (separately) and interactions with A/T/N group as independent variables. Variables were log‐transformed and standardized.ResultHigher Nfl was related to higher PSMD independently of the Aβ species in all lobes. Although Nfl correlated with Aβ1‐40 (figure 1), no multicollinearity was observed in the model. In A+, lower Aβ markers were related to higher PSMD in all lobes, but particularly for the temporal lobe (figure 2). Aβx‐34 showed more robust relationships with PSMD in both A+ groups particularly in the temporal lobes (A+/T‐/N‐ b = .62, p = &lt;.001, A+/T or N+ b = .52, p&lt;.001) than Aβ1‐40. (A+/T‐/N‐ b = .66, p = &lt;.01, A+/T or N+ b = .33, p&lt;.001). Neither t‐ nor p‐tau measures were associated with PSMD (not shown).ConclusionNfl independently related to PSMD, possibly reflecting amyloid‐independent neurodegeneration. CSF Aβx‐34 was in particular tightly linked to increased temporal lobe PSMD even in A+/T‐/N‐, pointing to early AD‐related SVD. This supports further evaluation of Aβx‐34 as a marker for CAA and susceptibility marker for ARIA.

Comparative assessment of heat and cold stress-induced changes in clinical parameters in Boer goats

This study was carried out on heat- and cold-adapted boar goats kept in their natural habitat to examine the physiological parameters and their seasonal fluctuations in relation to the adaptation to heat stress in boar goats. The study was conducted in two distinct stages that corresponded with the winter and summer seasons. Under the experiment, twelve experimental boar goats of both sexes were chosen at randomly. The goats were 1.5 to 2 years old and weighed between 16 to 22 kg. The temperature-humidity index (THI) was calculated by recording the daily temperature of the surrounding air and relative humidity using a digital hygrometer and thermometer that were placed in the animal shed. In this study, Heart rate (HR), respiration rate (RR), and rectal temperature (RT) were combined to determine physiological markers for thermal stress susceptibility. The temperature-humidity index (THI) was calculated by observing the daily ambient temperature and relative humidity. The THI value of summer and winter season were 31.67 and 15.34, respectively. The findings of this study revealed that the levels of physiological responses, such as rectal temperature, respiration rate, and heart rate, were significantly (p 0.05) differed throughout seasons (summer and winter) and recording periods. It has been discovered that THI, a sensitive indicator of both heat and cold stress, is more affected by ambient temperature in boar goats than relative humidity. Therefore, in Boar goats, heat and cold stress is related to certain physiological effects.

Analyzing Proportion and Susceptibility Markers of Sarcopenia In Korean Younger Female

Analyzing Proportion and Susceptibility Markers of Sarcopenia In Korean Younger Female

Mutation analysis of the TERT gene in ovarian cancer patients of the Turkish population by next generation sequencing method.

Ovarian cancer (OC) ranks seventh among malignant tumors worldwide. As one of the most common gynecological malignancies, ovarian cancer has the second-highest mortality rate, after cervical and uterine cancer. Next-Generation Sequencing (NGS) technology has enhanced multi-gene panel analysis and its clinical utility for identifying cancer-causing gene mutations. This study aimed to determine the presence of significant and nonsense mutations in telomerase reverse transcriptase (TERT), alpha-thalassemia/mental retardation, X-linked (ATRX), O-6-methylguanine-DNA methyltransferase (MGMT), and isocitrate dehydrogenase 1 and 2 (IDH1/IDH2) genes using the Next-Generation Sequencing (NGS) method. A cohort of 33 patients diagnosed with ovarian cancer was included in this investigation, and peripheral blood samples were collected from all participants. Significant and nonsense mutations in TERT, ATRX, MGMT, IDH1, and IDH2 genes were detected using the Next-Generation Sequencing method. Bioinformatics analysis was conducted using the QIAGEN Clinical Insight system. Twenty-four patients exhibited seven different TERT mutations, occurring in both exonic and intronic regions. One patient displayed a c.699-3delC deletion in the intronic region of the IDH1 gene, and the c.532G > A (p.V178I) mutation observed in three patients was assessed as potentially harmful. Additionally, novel mutations c.881A > G and c.995A > G were observed in the ATRX gene. The heterozygous novel mutation identified in the ATRX gene was confirmed through Sanger sequencing. These mutations were not previously associated with ovarian cancer and are considered novel candidate markers for ovarian cancer susceptibility. Confirmation of these results through larger cohort studies or functional investigations will contribute to a better understanding of the molecular mechanisms underlying ovarian cancer.

Analysis of the Polymorphisms and Expression Levels of the BCL2, BAX and c-MYC Genes in Patients with Ovarian Cancer.

Ovarian cancer (OC) is one of the biggest problems in gynecological oncology and is one of the most lethal cancers in women worldwide. Most patients with OC are diagnosed at an advanced stage; therefore, there is an urgent need to find new biomarkers for this disease. Gene expression profiling is proving to be a very effective tool for exploring new molecular markers for OC patients, although the relationship between such markers and patient survival and clinical outcomes is still elusive. Moreover, polymorphisms in genes encoding both apoptosis-associated proteins and oncoproteins may serve as key markers of cancer susceptibility. The aim of our study was to analyze the polymorphisms and expressions of the BCL2, BAX and c-MYC genes in a group of 198 women, including 98 with OC. The polymorphisms and mRNA expressions of the BCL2, BAX and c-MYC genes were analyzed using real-time PCR. The analysis of the BAX (rs4645878; G>A) and c-MYC (rs4645943; C>T) polymorphisms showed no association with ovarian cancer risk. The BCL2 polymorphism (rs2279115; C>A) showed a significant difference in the frequency of genotypes between the studied groups (CC: 23.47% vs. 16.00%, AA: 25.51% vs. 37.00%; p = 0.046; OR = 1.61). Furthermore, the expression levels of the BCL2 and c-MYC genes showed a decrease at the transcript level for OC patients compared to the control group (BCL2: 17.46% ± 3.26 vs. 100% ± 8.32; p < 0.05; c-MYC: 37.56% ± 8.16 vs. 100% ± 9.12; p < 0.05). No significant changes in the mRNA level were observed for the BAX gene (104.36% ± 9.26 vs. 100% ± 9.44; p > 0.05). A similar relationship was demonstrated in the case of the protein expressions of the studied genes. These findings suggest that the CC genotype and C allele of the BCL2 polymorphism could be genetic risk factors for OC development. A gene expression analysis indicated that BCL2 and c-MYC are associated with OC risk.

From Recognition to Remedy: The Significance of Biomarkers in Neurodegenerative Disease Pathology.

With the inexorable aging of the global populace, neurodegenerative diseases (NDs) like Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS) pose escalating challenges, which are underscored by their socioeconomic repercussions. A pivotal aspect in addressing these challenges lies in the elucidation and application of biomarkers for timely diagnosis, vigilant monitoring, and effective treatment modalities. This review delineates the quintessence of biomarkers in the realm of NDs, elucidating various classifications and their indispensable roles. Particularly, the quest for novel biomarkers in AD, transcending traditional markers in PD, and the frontier of biomarker research in ALS are scrutinized. Emergent susceptibility and trait markers herald a new era of personalized medicine, promising enhanced treatment initiation especially in cases of SOD1-ALS. The discourse extends to diagnostic and state markers, revolutionizing early detection and monitoring, alongside progression markers that unveil the trajectory of NDs, propelling forward the potential for tailored interventions. The synergy between burgeoning technologies and innovative techniques like -omics, histologic assessments, and imaging is spotlighted, underscoring their pivotal roles in biomarker discovery. Reflecting on the progress hitherto, the review underscores the exigent need for multidisciplinary collaborations to surmount the challenges ahead, accelerate biomarker discovery, and herald a new epoch of understanding and managing NDs. Through a panoramic lens, this article endeavors to provide a comprehensive insight into the burgeoning field of biomarkers in NDs, spotlighting the promise they hold in transforming the diagnostic landscape, enhancing disease management, and illuminating the pathway toward efficacious therapeutic interventions.

Abstract 14862: Electrophysiological Predictors of Susceptible Atrial Substrate for the Onset and Recurrence of Atrial Fibrillation

Introduction: Atrial electro-anatomical substrate is essential for pathogenesis of atrial fibrillation (AF). Electrophysiological markers of AF susceptibility, however, are not well characterized. Identifying markers of atrial substrate has significant clinical implications in early detection and intervention for AF or stratifying patients at higher risk of AF recurrence following ablation. Hypothesis: We hypothesized that conduction indices on surface electrocardiogram (ECG) and intracardiac electrogram (EGM) may predict susceptibility and/or AF recurrence following ablation. Methods: We studied all consecutive patients who underwent electrophysiological study and catheter ablation for AF or atrioventricular nodal reentrant tachycardia (AVNRT) from 2013 to 2018. Atrial conduction indices were measured on ECG and EGM during the electrophysiology study. We evaluated correlations between both AF and AF recurrence with conduction indices, and associations between AF recurrence and conduction indices were evaluated with univariate logistic regression analyses and machine learning. Results: The study population included 387 patients with AF (mean age 63 years, 31% female) and compared to patients with AVNRT (n=94) who were considered as a control group. AF was associated with significant prolongation of all measured surface ECG and EGM parameters (p&lt;0.05). During a mean follow up of 5±2 years, recurrence of AF (48%) after successful ablation occurred in patient with longer P wave duration, left atrial (LA) conduction duration, proximal to distal coronary sinus (pCS-dCS) interval, and P-dCS interval (p&lt;0.05). Prolonged P wave duration, LA duration, pCS-dCS interval, and QRS duration were predictors of AF recurrence. Machine learning modeling determined that pCS-dCS interval, QRS duration, and LA duration (lead V1 and II) were the most impactful conduction indices for AF recurrence. Conclusions: Atrial conduction indices are markers of susceptible substrate for the onset and the recurrence of AF after successful ablation. LA conduction parameters can be used for risk stratification to facilitate early detection and management of AF.

Inferring the Functional Effect of Gene-body H3K79me2 Signals in Normal Samples on Gene Expression Changes: A Potential Susceptibility Marker in Chronic Myelogenous Leukemia

Background: Current identification of chronic myelogenous leukemia markers tends to mine diagnostic or prognostic biomarkers, ignoring susceptibility markers in normal samples. Objective: We aim to identify possible susceptibility markers for preventing chronic myelogenous leukemia. Methods: Functional links of H3K79me2 patterns and gene expression changes were inferred by correlation analyses. DNase-seq read distribution, transcription factor motifs, and their binding data were acquired via ceasBW and HOMER. Normalized transcription factor binding signals were submitted to a random forest algorithm to predict susceptibility gene expression changes. Three strategies were performed to validate the influence of low H3K79me2 signals on gene expression changes. Results: The gene-body H3K79me2 signals in normal samples were negatively related to gene expression changes during leukemogenesis (ρ=-0.92), regardless of gene lengths and expression levels. Characterization revealed that genes with lower H3K79me2 signals in normal samples have more open environments. Transcription factors GATA3, GATA4, TEAD1, TEAD3, TEAD4, and TRPS1 may induce the upregulation of up-susceptibility genes (ρ=0.95), and ASCL2, IRF4, IRF3, E2A, OCT4, and ZEB2 may mediate the downregulation of down-susceptibility genes (ρ=0.97). Enrichment analysis implied that the screened susceptibility genes were involved in leukemia-related pathways, and about 50% of leukemia stem cell differentially expressed genes were included in these genes. Besides, all hub genes extracted from susceptibility genes were well documented in different leukemia subtypes. Finally, the effect of H3K79me2 signals on gene expression changes were validated in a mouse model and three cell models. Conclusion: Low gene-body H3K79me2 signals in normal samples may serve as susceptibility markers for chronic myelogenous leukemia.