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Hepatocellular carcinoma (HCC) is a molecularly heterogeneous solid malignancy, and its fitness may be shaped by how its tumor cells evolve. However, ability to monitor tumor cell evolution is hampered by the presence of numerous passenger mutations that do not provide any biological consequences. Here we develop a strategy to determine the tumor clonality of three independent HCC cohorts of 524 patients with diverse etiologies and race/ethnicity by utilizing somatic mutations in cancer driver genes. We identify two main types of tumor evolution, i.e., linear, and non-linear models where non-linear type could be further divided into classes, which we call shallow branching and deep branching. We find that linear evolving HCC is less aggressive than other types. GTF2IRD2B mutations are enriched in HCC with linear evolution, while TP53 mutations are the most frequent genetic alterations in HCC with non-linear models. Furthermore, we observe significant B cell enrichment in linear trees compared to non-linear trees suggesting the need for further research to uncover potential variations in immune cell types within genomically determined phylogeny types. These results hint at the possibility that tumor cells and their microenvironment may collectively influence the tumor evolution process. Clonality study in HCC finds diverse evolution patterns. Linear HCC is less aggressive, with GTF2IRD2B driver mutations. Non-linear has shallow/deep branching patterns with frequent TP53 driver mutations.

Liver cancer is a heterogeneous disease characterized by extensive genetic and clonal diversity. Understanding the clonal evolution of liver tumors is crucial for developing effective treatment strategies. This dissertation aims to dissect the tumor clonality in liver cancer using computational and statistical tools, with a focus on phylogenetic analysis. Through advancements in defining and assessing phylogenetic clusters, we gain a deeper understanding of the survival disparities and clonal evolution within liver tumors, which can inform the development of tailored treatment strategies and improve patient outcomes.The thesis begins by providing an overview of sources of heterogeneity in liver cancer and data types, from Whole-Exome (WEX) and RNA sequencing (RNA-seq) read-counts by gene to derived quantities such as Copy Number Alterations (CNAs) and Single Nucleotide Variants (SNVs). Various tools for deriving copy-numbers are discussed and compared. Additionally, comparison of survival distributions is discussed.The central data analyses of the thesis concern the derivation of distinct clones and clustered phylogeny types from the basic genomic data in three independent cancer cohorts, TCGA-LIHC, TIGER-LC and NCI-MONGOLIA. The SMASH (Subclone multiplicity allocation and somatic heterogeneity) algorithm is introduced for clonality analysis, followed by a discussion on clustering analysis of nonlinear tumor evolution trees and the construction of phylogenetic trees for liver cancer cohorts. Identification of drivers of tumor evolution, and the immune cell micro-environment of tumors are also explored.In this research, we employ survival analysis tools to investigate and document survival differences between groups of subjects defined from phylogenetic clusters. Specifically, we introduce the log-rank test and its modifications for generic right-censored survival data, which we then apply to survival follow-up data for the subjects in the studied cohorts, clustered based on their genomic data. The final chapter of this thesis takes a significant step forward by extending an existing methodology for covariate-adjustment in the two-sample log-rank test to a K-sample scenario, with a specific focus on the already defined phylogeny cluster groups. This extension is not straightforward because the computation of the test statistic for K-sample and its asymptotic null distribution do not follow directly from the two-sample case. Using these extended tools, we conduct an illustrative data analysis with real data from the TIGER-LC cohort, which comprises subjects with analyzed and clustered genomic data, leading to defined phylogenetic clusters associated with two different types of liver cancer. By applying the extended methodology to this dataset, we aim to effectively assess and validate the survival curves of the defined clusters.

Some generalized integral inequalities are established for the fractional expectation and the fractional variance for continuous random variables. Special cases of integral inequalities in this paper are studied by Barnett et al. and Dahmani.

PurposeGranulocyte colony stimulating factor (GCSF; also known as filgrastim) is a growth factor used to induce production of granulocytes. As the first locally developed and approved biosimilar medicine of Turkey, Fraven® being a biosimilar of filgrastim has been ab initio manufactured from cell to finished product at two different production facilities. Comprehensive structural, biological and functional characterization studies were performed to compare Fraven® from two different production sites and its reference product Neupogen® sourced from Turkey.MethodsPrimary and higher-order protein structures were analyzed by high performance liquid chromatography electrospray ionization-time of flight mass spectrometry, circular dichroism, and two-dimensional nuclear magnetic resonance spectroscopy. Isoelectric focusing, SDS-Page, size exclusion chromatography, and related proteins analyses were used to compare impurities. In order to assess functional similarity, surface plasmon resonance (SPR) was used. In vitro cell proliferation assay was also performed to show dose related drug response in NFS-60 cell line.ResultsPrimary, secondary and tertiary structures of biosimilar Fraven® manufactured at both sites were found to be highly similar to the reference Neupogen®. Product related substances and impurities were also highly similar to the reference. Comparability of GCSF receptor binding affinities of each product was shown using the KD values of SPR analysis. In vitro cell proliferation similarity was also evaluated and proven by PLA.ConclusionBased on the similarity assessment, despite being manufactured at two different production sites, biosimilar Fraven® is highly similar to the reference product Turkey originated Neupogen®.

Among the various instruments used in literature, the Big Three Perfectionism Scale (BTPS) is designed to meet the need for a comprehensive and current tool for the measurement of perfectionism and the assessment of personal tendencies. The present study adapts and examines the psychometric properties of the Turkish versions of both the BTPS-45 and BTPS-16, based on the responses of 427 Turkish community adults who were recruited for the purpose. All of the respondents were assessed with the two popular perfectionism scales, and for dark personality features and psychological problems, while 109 re-completed the BTPS-45 and BTPS-16 scales for the evaluation of test-retest reliability 2 weeks later. The results of the confirmatory factor analysis conducted to test the various models with different factor structures showed that the models comprising the three main and 10 sub-dimensions of the BTPS-45 and three main dimensions of the BTPS-16 showed the best fit. The significant relationships found between the BTPS factors, the scores recorded from the other perfectionism scale, the dark triad and the psychopathology symptoms all supported the validity of both the BTPS-45 and the BTPS-16. The findings further indicated that the structures of these forms had acceptable internal consistency and demonstrated satisfactory test-retest reliability. The reliability and validity of the Turkish versions of the long and short forms of the BTPS were thus established, supporting their use in further empirical studies and psychological interventions.

Abstract Disclosure: H. Kelestimur: None. F. Tan: None. M. Ozdede: None. Z. Oz: None. I. Serhatlioglu: None. E. Kacar: None. Purpose: Sexual dysfunction is a common clinical condition due to different causes including the use of selective serotonin reuptake inhibitors (SSRIs). Paroxetine is known to cause sexual dysfunction including erectile dysfunction in men. Asprosin, released from white adipose tissue cells, is a glucogenic adipokine that modulates hepatic glucose release by causing rapid release of glucose into the circulation during fasting. It is known that asprosine crosses the blood-brain barrier and activates orexigenic AgRP and is also involved in the mobilization of sperm for fertilization through the olfactory receptor OLFR734. The fact that reproductive organs such as testes, like the brain, need free glucose at all times suggests that asprosin may also have an important role in reproductive functions. Based on this idea, we aimed to reveal the effects of asprosin in rats with paroxetine-induced sexual dysfunction. Materials and Methods: In the present study, 60 male Sprague Dawley rats were used as control, sham control, paroxetine, asprosin and paroxetine+asprosin groups (n=12). Paroxetine was administered via oral gavage, while asprosine infusion was administered via intracerebroventricular cannula. The sexual behavioral experiments were performed in the male rats. Results: As a result of our study, it was observed that asprosine infusion promoted erection in behavioral experiments and increased sexual motivation by facilitating ejaculation. In histologic examinations, paroxetine group rats showed edema and vascular congestion in the interstitial area and separation of the basement membranes of the seminiferous tubules, while paroxetine+asprosine group rats showed significant improvements (p<0.05). While there was no difference in epididymis weight between the groups, paroxetine treatment decreased sperm concentration compared to the control group (p<0.05) and asprosine increased sperm concentration and total motility compared to the control and paroxetine groups (p<0.01). In our investigations on serum hormone levels, asprosine decreased prolactin level (p<0.05) and increased oxytocin level (p<0.01). Conclusion: These results demonstrate that asprosin may be a therapeutic modality or improving SSRI-associated sexual dysfunction in men through increased expression of sexual motivation and copulatory behaviors. . Acknowledgement: This study was supported by TUBITAK (Project No: 220S744) Presentation: Saturday, July 12, 2025

In this study, the antibacterial activity of environmentally friendly synthesized 2D copper oxide nanoleaves (Cu 2 O NLs) on ceramic glazes and photocatalytic activity against methylene blue (MB) dye was investigated. The SPR band of biogenic Cu 2 O NLs was observed between 200–300 nm. Transmission electron microscopy (TEM) analysis revealed that the Cu 2 O NLs were in a nanoleaves structure and had a particle size of 42.04 nm. In order to determine the antibacterial activity of the synthesized Cu 2 O NLs in ceramic structures, NLs were added to the transparent glaze recipe used in tableware. The antibacterial properties of the test mixture were then examined against the gram ( +) and gram (-) bacteria. In addition, the photodegradation rate of Cu 2 O NLs against MB dye was found to be 68% after 90 min. Experimental results of Cu 2 O NLs synthesized with environmentally friendly have shown that they can have potential applications in the ceramic industry and water treatment systems.

The main drawback of hypoallergenic formulas for cow’s milk protein allergy (CMPA) is their low palatability. This study aims to examine the decisions made by mothers of infants diagnosed with CMPA and physicians regarding the taste of extensively hydrolyzed formulas (eHFs), amino acid-based formulas (AAFs), and rice-based formulas. This single-blind, multicenter study was conducted in nine pediatric allergy centers across Türkiye and included 181 pediatricians and 137 mothers of children with CMPA. Seven substitution formulas without added sweeteners or additional flavorings available on the market were tested: Two AAFs (Neocate-Numil®, Alfamino-Nestlé®), one AAF with synbiotics (Pregomin Syneo-Numil®), one AAF specifically designed to meet the nutritional and lifestyle needs of children over 1 year of age (Neocate Junior-Numil®), one synbiotic eHF (Aptamil Pepti Syneo-Numil®), and two rice protein-based formulas (Evolvia RP1-Montero® and Evolvia RP2-Montero®). A sensory evaluation was conducted using a single-blind protocol, following the methodology previously applied in the CONTEST-1 study. Neocate Junior-Numil® was the most preferred product in terms of taste, smell, and appearance, as rated by both mothers and physicians. It was the most preferred formula by both mothers (49.6%) and physicians (62.4%) in terms of taste. Aptamil Pepti Syneo-Numil® ranked second (32.8% for mothers, 42.0% for physicians), followed by Evolvia RP2-Montero® (23.4%) for mothers and Alfamino-Nestle® (22.1%) for physicians. The fact that both mothers and physicians most frequently preferred Neocate Junior-Numil® suggests that sensory characteristics of formulas used in CMPA management—such as taste, smell, and appearance—may play a decisive role in treatment adherence. This finding highlights the importance of considering not only nutritional adequacy but also acceptability when selecting a formula.

Abstract Disclosure: H. Kelestimur: None. Z. Oz: None. M. Ozdede: None. &. Serhatlioglu: None. E. Kacar: None. B. Yilmaz: None. Purpose: Asprosin, a novel glucogenic adipokine produced by the fibrillin 1 (FBN1) gene, is integral to the body's energy regulation processes. Generated and released by white adipose tissue during fasting, asprosin affects the hypothalamic-pituitary-gonadal (HPG) axis, impacting reproduction. While its effects on metabolic parameters are well established, the understanding of its impact on reproductive health and functionality is still emerging. This study investigates the effects of exogenous asprosin administration on the reproductive capabilities of male and female rats. Materials and Methods: Forty-eight Sprague-Dawley rats, 21 days old and weighing 35±2 grams, were divided into control and asprosin-treated groups (n = 12 per group, for both genders). This approach allowed direct comparison between treated and untreated groups. From postnatal day 21, treatment groups received daily intraperitoneal injections of asprosin (500 ng/kg) for ten weeks (male) and eight weeks (female), while control groups received only saline (1 ml/kg). The study examined various reproductive parameters, including those related to pubertal maturation and sexual behavior, and conducted hormonal analyses on blood samples collected at the experiment's conclusion. Results: Asprosin administration did not alter puberty onset or weight in either gender. However, asprosin-treated rats showed significantly earlier sperm formation in males and earlier estrus in females compared to controls. In male sexual behavior, asprosin reduced intromission latency and increased ejaculation frequency. While interaction with females remained unchanged, asprosin notably increased time near males and male preference ratio. The rate of male investigation preference and the activity index (frequency of passing through the test device's center) also significantly increased in the asprosin-treated group. Conclusion: These findings suggest that asprosin may stimulate the reproductive system in both male and female rats. They highlight the potential role of asprosin in reproductive biology and underscore the need for further research to fully understand the mechanisms by which asprosin influences reproduction. Such studies could significantly advance our knowledge in endocrine regulation. Acknowledgement: This study was supported by TUBITAK (Project No: 220S744). Presentation: 6/1/2024

Disclosure: H. Kelestimur: None. Z. Oz: None. M. Ozdede: None. I. Serhatlioglu: None. N. Kaya Tektemur: None. E. Kacar: None. Purpose: Asprosin is a novel glucogenic and orexigenic hormone produced by the fibrillin 1 (FBN1) gene that is secreted by white adipose tissue during fasting. Fibrillins (FBNs) are structural and signalling proteins found mainly in the ovarian stroma, tunica albuginea and theca layers. The aim of this study was to determine the effects of asprosin on ovarian tissue in the female rats. Materials and methods: Twenty-four female Sprague-Dawley rats were randomly divided into 2 groups (n=12) as control and asprosin. Asprosin and control groups were given intraperitoneal saline at doses of 500 ng/kg and 1 ml/kg, respectively, at 14.00 every day for eight weeks. After the application, decapitation was performed, and the rapidly removed ovarian tissues were placed in a 10% formaldehyde solution for fixation. Formalin-fixed ovaries were dehydrated in a graded alcohol series and graded ethanol, respectively After that, all tissues were embedded in paraffin wax. The ovaries were cut into 5-µm sections and stained with hematoxylin and eosin (H&E) and also Masson trichrome staining. Ovarian follicular reserve and fibrosis were evaluated by light microscopy. The follicles were histologically classified as primordial, primary, secondary, and Graaf and all follicular structures were counted in each section. The fibrosis was evaluated with Masson’s trichrome staining and scored from 0 to 3 semi-quantitatively (0 = no fibrosis, 1 = low fibrosis, 2 = intermediate fibrosis, 3 = severe fibrosis). Results: In the asprosin group, unlike the control group, occasional congestion was observed in the vessels located in the ovarian medulla. Apart from this, no histopathological changes were found. An increase in fibrosis was detected in the ovarian sections of the asprosin group when compared to the control group (p = 0,035). In the light microscopic evaluation of the ovarian sections of the rats in the asprosin group, the primary and secondary follicle numbers were significantly higher than those in the control group (p = 0,008 and p = 0,047 respectively). However, the difference between the control and asprosin groups in terms of the primordial follicle, Graafian follicle and corpus luteum numbers were not statistically significant. Conclusion: Our results have shown that chronic asprosin administration causes an increase in the number of primary and secondary follicles, suggesting that changes in ovarian steroidogenesis and folliculogenesis depending on the application may lead to positive effects on female fertility. Keywords: Asprosin, adipokine, ovarian follicle. Acknowledgement: This study was supported by TUBITAK (Project: 220S744). Presentation: Friday, June 16, 2023