Acta Medica

Unravelling the maternal stress-induced orchestrations: Fndc5 gene expression dynamics across duodenum, stomach, and whole blood in offspring

Mon, 30 Sep 2024 00:00:00 +0300

Objective: Maternal stress is a known risk factor for a variety of adverse outcomes in offspring, including metabolic and behavioural abnormalities. The hormone irisin, encoded by the Fndc5 gene, is believed to mediate stress’s effects on metabolism. Two weeks of restraint stress causes stomach inflammation and increases oxidative stress in rodents. Irisin, coded by the Fndc5 gene, probably suppresses this oxidative stress. In this study, we examined the effect of early-life maternal stress on Fndc5 gene expression in the duodenum, stomach and whole-blood offspring.

Materials and Methods: This study consists of three groups: a control, an unpredictable maternal separation (MS), and an unpredictable maternal separation combined with unpredictable maternal stress (MSUS). On postnatal (PND) days 1-14, randomly three hours a day, MS and MSUS were exposed to unpredictable maternal separation. MSUS was subjected to extra unpredictable maternal stress. Mice were sacrificed on PND35. Total RNA was isolated from duodenum, stomach, and whole blood samples by Phenol-Chloroform technique, and HiScript II 1st Strand cDNA Synthesis Kit was used for cDNA synthesis. Fndc5 and Gapdh genes expression level was measured by qPCR using FastStart Universal SYBR Green Master. The data obtained were analyzed using One-Way ANOVA tests in GraphPad Prism.

Results: Fndc5 gene expression did not differ between groups in the duodenum (p>0.05), significantly increased in the MSUS group compared to the control (female p=0.0089, male p=0.0053) and MS (female p=0.0206, male p=0.026) groups in the stomach. In whole blood samples, it decreased in MS and MSUS group males (p=0.0011). In addition, a significant negative correlation (p= 0.0003) has been established between the stomach and whole blood.

Conclusion: The findings assert the role of irisin in transmitting stress-related effects on metabolism, emphasizing the therapeutic potential of targeting the Fndc5 gene in preventing and treating stress-related disorders.

Investigating the potential impact of ELF3-associated SNPs on chondrocyte inflammation

Beren Karaosmanoğlu, Büşra Aydın, Gözde İmren, Erdal Sağ, Ekim Z. Taşkıran — Mon, 30 Sep 2024 00:00:00 +0300

Objective: Chondrocyte inflammation is a critical factor in degenerative joint diseases, such as osteoarthritis (OA), significantly impairing quality of life through chronic pain and limited mobility. Genetic predisposition is recognized as a critical factor in the progression of chondrocyte inflammation and OA, with particular focus on the role of genetic variants in the expression and regulation of inflammatory mediators. This study aimed to obtain information about the potential roles of a few genes containing ELF3-associated SNPs in the pathogenesis of chondrocyte inflammation.

Materials and Methods: GVAT Database was used to select top candidate SNPs associated with ELF3, a cardinal transcription factor in chondrocyte inflammation. Inflammation was induced by IL-1β treatment in differentiated chondrocytes to analyze gene expression patterns. Transcriptome analysis was done by RNA sequencing.

Results: The most important SNPs that could potentially affect the binding affinity of ELF3 transcription factor were analyzed. As a result of the analysis, 52% of ELF3-associated SNPs were found in protein-coding regions, 40% in gene-free intergenic regions, and 8% in non-coding RNA sequences. Some of these SNPs are located in regulatory regions (enhancers). A significant increase in expression levels in the ELF3 gene was detected after IL-1β administration, indicating that IL-1β promotes the activity of this transcription factor. mRNA expressions of TLN2, BABAM2, PEPD, and NUDT5 were also increased after IL-1β stimulation.

Conclusion: The presence of ELF3-associated SNPs in the enhancer sequences of TLN2 and BABAM2 genes, in addition to the increased expression of these two genes upon IL-1β stimulation, suggested that TLN2 and BABAM2 genes may be associated with the severity of chondrocyte inflammation and OA.

Exploring the inhibitory potential of hormone replacement therapy drugs on glutathione transferase P1-1

Yaman Muşdal, Bengt Mannervik — Mon, 30 Sep 2024 00:00:00 +0300

Aim: Glutathione transferase P1-1 (GST P1-1) plays a crucial role in the human phase II detoxication system and is implicated in drug resistance in certain cancer cells. Analogs of drugs used in Hormone Replacement Therapy (HRT) have been reported to exhibit inhibition of various GSTs. This study aims to investigate the inhibitory potential of several HRT drugs on GST P1-1 for the possible use of counteracting drug resistance and for other therapeutic purposes.

Materials and Methods: GST P1-1 was expressed and then purified in a single step using Nickel Sepharose affinity chromatography. Synthetic drugs that are used in HRT were screened for inhibition of GST P1-1 using 1-chloro-2,4-dinitrobenzene as the substrate. The IC50 value of the most potent compound was calculated and binding location and formation of bonds to GST P1-1 were identified through docking analysis.

Results: Screening the inhibitory effect of eight synthetic estrogenic drugs reveals that estradiol valerate is the most potent inhibitor, showing 72 ± 4% inhibition of GST P1-1. This effect is followed by estradiol cypionate 53 ± 5%, mestranol 39 ± 4%, and estradiol propionate 35 ± 2%. The most potent compound estradiol valerate has an IC50 value of 30 ± 2 μM. According to docking analysis, it binds to the H-site of the enzyme where the residues Phe9, Arg14, Val36, Trp39, Ile105, Tyr109, Pro203, Asn207, and Gln210 were within 5 Å proximity of the ligand. Estradiol valerate forms Pi-alkyl interactions with Phe9 and Val36, as well as an alkyl interaction with Ile104.

Conclusion: Estradiol valerate is a modest inhibitor for hGST P1-1, however it fits in the area of H-site of the enzyme and forms bonds with critical key residues. Understanding its binding site on the enzyme is critical for designing other inhibitors targeting GSTs or possibility for the potential use as a substrate with other GSTs.

Outcomes of multidisciplinary management of pulmonary nodules in a tertiary center

Özge Öztürk Aktaş, Ahmet Uğur Demir, Ziya Toros Selçuk — Mon, 30 Sep 2024 00:00:00 +0300

Objective: A multidisciplinary approach is recommended for managing pulmonary nodules. This study aimed to examine the malignancy rates, malignancy determinants, and follow-up results of patients with pulmonary nodules whom the multidisciplinary team evaluates.

Methods: Clinical characteristics of the patients, radiological and histological characteristics of the nodules, and the follow-up outcomes were documented retrospectively. A total of 94 patients with solitary pulmonary nodules (SPNs) (n=58) and multiple pulmonary nodules (MPNs) (n=36) were included in the study.

Results: Our study showed that malignancy risk increased with irregular nodule margins (p < 0.008). Patients who had tissue sampling from suspected nodules exhibited markedly higher rates of previous malignancy than those who did not (58.5% vs. 19.5% p<0.001). For the patients with solitary pulmonary nodule (SPN), the group for whom biopsy was planned had more underlying malignancy (p=0.011) and had a bigger nodule size of 10 mm (range, 8.0-13.25 mm) vs 15.00 mm (range, 10.0-19.75 mm) (p=0.003). Among the patients who have multiple pulmonary nodules (MPN), eighty-four percent of patients in the biopsy group had underlying malignancy diagnoses, whereas this rate was 26% in the CT follow-up group (p=0.002). Adenocarcinoma was the most common SPN histology and squamous cell carcinoma for MPNs. The Multidisciplinary Thoracic Oncology Board identified malignancy in 60% of patients with SPNs and 92.3% of those with MPNs/

Conclusions: Patients evaluated in the multidisciplinary tumor board consist of a very diverse patient group. Discerning between malignant and benign conditions relies heavily on examining nodule features and assessing malignancy history.

Identification of bio-markers for insulin resistance and sensitivity through multi-omics analysis

İdil Yet — Mon, 30 Sep 2024 00:00:00 +0300

Aims: This study aims to identify multi-omics bio-markers for insulin resistance and sensitivity using machine learning approaches on a dataset integrated from several omics.

Methods: The study included 362 patients with Insulin Resistance and Insulin Sensitivity from the Integrative Personal Omics Profiling (iPOP) database. Combining the multi-omics data from the Integrative Human Microbiome Project, this study used machine learning to reveal the relationship between insulin resistance and insulin sensitivity.

Results: Of 362 patients 186 were insulin resistance and 176 were insulin sensitivity. 11,585 features were used, including clinical features, RNA transcripts, gut microbiota, cytokines, proteins, and metabolomics. We found 21 features capable of distinguishing insulin resistance from insulin sensitivity using a well-known artificial neural network (ANN) method. The model had an area under the receiver operating characteristic (AUC) of 0.97 in the validation dataset and 0.89 in the test dataset. The ANN model’s performance was compared with Random Forest model. Of the 21 new findings, two metabolites (methyl-uric acid and methylxanthine) are xenobiotics, and three RNA transcripts (SERPINF1, SLC2A2, and CHL1).

Conclusion: A small number of multi-omics features identified from 11,585 potential candidates for a machine learning model can accurately predict insulin resistance and sensitivity.

Flaps of the abdominal wall

Alaz Çırak, Gökhan Sert, Galip Gencay Üstün, Hakan Uzun — Mon, 30 Sep 2024 00:00:00 +0300

Objective: The deep inferior epigastric artery perforator (DIEP) and transverse-vertical rectus abdominis myocutaneous (TRAM, VRAM) flaps are derived from the anterior abdominal wall and can be free or pedicled. This study aimed to analyze the differences in postoperative complication rates among various types of abdominal flaps and to assess the impact of chemotherapy (CT) and radiotherapy (RT) on surgical outcomes.

Materials and Methods: A retrospective study was conducted, analyzing abdominal flap operations performed between 2016 and 2023. Data on demographics, defect location, mesh use, and postoperative chemo-radiotherapy were collected. Quantitative variables were evaluated as means, minimum-maximum values, and categorical variables were assessed as percentages.

Results: A total of 37 patients underwent 38 operations. Of these, nine patients had pedicled TRAM flaps, 16 had free-TRAM flaps, 6 had free DIEP flaps, and 6 had VRAM flaps. The defect locations were predominantly for breast reconstruction (81.08%), followed by head and neck (8.1%), extremity (8.1%), and thoracic wall (2.7%). The overall donor site complication rate was 5.4%, and the flap site complication rate was 13.51%. The lowest donor site complications were observed in the free-TRAM and VRAM groups (0%), while the highest were in the DIEP group (16.66%). The lowest flap site complication rate was 0% in the free-TRAM group, and the highest was 33.33% in the VRAM group. Donor site complication rates were similar between the mesh-used (5.88%) and non-mesh-used (5%) groups. All donor site complications occurred in patients who received postoperative CT and RT.

Conclusion: Abdominal flaps were primarily utilized for breast reconstruction. The free-TRAM group exhibited the lowest donor and flap site complication rates, while the DIEP group had the highest donor site complication rates. Mesh use did not affect donor site complication rates. Postoperative administration of CT and RT was associated with increased donor site complications.

Melatonin can mitigate H2O2-induced atrophy and promote muscle fiber hypertrophy in morphological level in mouse myoblast cell line

Nazli Karimi Ahmadi, Yasemin Kartal, Murat Timur Budak — Mon, 30 Sep 2024 00:00:00 +0300

Objective: It is known that oxidative stress is the main factor in the formation of disuse muscle atrophy which is the most common type of muscle atrophy. The utilization of antioxidants as supplements, particularly the category known as mitochondrial targeting antioxidants (MTA), such as melatonin, have demonstrated significant potential as an advanced therapeutic approach. In this study, we aimed to investigate the effect of melatonin application on the cellular morphology of the C2C12 cell line.

Materials and Methods: In our experiment, we induced oxidative stress using hydrogen peroxide (H2O2) to create a model of skeletal muscle atrophy. We established four distinct groups of C2C12 cells, all exposed to the same conditions. These groups included Control (C), Melatonin (M), H2O2 (H), and Melatonin + H2O2 (MH). The aim was to examine morphological features, specifically myotube diameters, to assess atrophy.

Results: The analysis revealed significant differences in diameters among the groups (p < 0.05). The melatonin treatment group not only showed a mitigation of diameter change due to atrophy but also exhibited a significant increase in diameter.

Conclusion: The results suggest that H2O2 induces muscle atrophy, and melatonin plays a dual role in maintaining muscle health, protecting against atrophy and promoting hypertrophy, particularly at the morphological level. However, additional research is needed to figure out the details of underlying mechanisms.

Malignant pleural effusions: Are we better than the past?

Oğuz Karcıoğlu, Fatih Tekin, Ebru Öztürk, Sevgen Önder, Ziya Toros Selçuk — Mon, 30 Sep 2024 00:00:00 +0300

Objective: Malignant pleural effusion (MPE) is indicative of advanced-stage disease and a poor prognosis in almost all cancer types. Lung and breast cancers are the predominant malignancies causing MPE, collectively representing over 60% of the total. In recent years, cancer has become a type of chronic disease, with advancements in diagnostic tools and treatment strategies. Our objective was to assess the evolution of primary diagnoses, survival rates, and associated variables among individuals with MPE in recent years.

Materials and Methods: A retrospective search was conducted on the demographics, comorbidities, primary cancer sites, diagnostic interventions, and laboratory results of patients diagnosed with MPE between January 1, 2005, and July 30, 2018.

Results: Of the 663 patients who have MPE, the female/male ratio was 373/290. The mean age was 59.2 ± 14.0 at the time of diagnosis. The most common cancers were lung cancer (30.9%), breast cancer (23.3%), and gastrointestinal system cancers (16.62%). It was observed that the rate of MPE due to lung cancer increased gradually over the years. Initially, breast cancer constituted the most prevalent diagnosis in 28.2% of cases, whereas lung cancer rose to the top as the most prevalent in the second and third five-year periods (28.9% and 37.4%, respectively). Overall, the median survival time was 2.07 months. Kaplan-Meier analysis also revealed that survival times did not change significantly over fourteen years.

Conclusion: Advances in diagnostic methods and treatment modalities have altered the most common primary cancer causing MPE in recent years but have not contributed to survival time.

Comparison of the safety profile of tofacitinib and etanercept in rheumatoid arthritis patients aged 60 years and over: The real-life data from the HUR-BIO registry

Mon, 30 Sep 2024 00:00:00 +0300

Objective: To investigate the safety profile of tofacitinib in rheumatoid arthritis (RA) patients aged 60 and over and to compare these findings with etanercept.

Materials and methods: HUR-BIO (Hacettepe University Rheumatology Biologic Registry) is a single-center registry for biological and targeted synthetic DMARDs since 2005. We included RA patients aged ≥ 60 years who were prescribed tofacitinib or etanercept as their first bDMARD or tsDMARD and had at least one control visit. MACE (major adverse cardiovascular event), VTE (venous thromboembolism), malignancy, herpes zoster, and infections requiring hospitalization were recorded for the safety profile. Incidence rate (IR) and incidence rate ratios (IRR) per 1000 patient years were calculated for all safety data.

Results: This study consisted of 123 RA patients (tofacitinib n=70, etanercept n=53). In the overall population, the mean age was 67.9 ± 6.2 years and the median follow-up period was 2.1 years. Among the traditional cardiovascular risk factors, smoking history and hyperlipidemia were more common in the tofacitinib group. The IRR per 1000 patients years for MACE, herpes zoster, and infections requiring hospitalization was similar between the groups. All three patients who diagnosed with DVT or PE were in the tofacitinib group, and the significance level of the increase in IR was close to the statistical threshold (p=0.057). There was only one patient who developed non-melanoma skin cancer, and that patient was in the tofacitinib group.

Conclusion: The incidence of MACE, herpes zoster, and infections requiring hospitalization was comparable between tofacitinib and etanercept. However, the occurrence of VTE exclusively in the tofacitinib group suggests that this issue needs careful evaluation for these patients.

Pelger-Huët Anomaly (PHA) Case Report

Hamza Sümter — Mon, 30 Sep 2024 00:00:00 +0300

Pelger-Huët anomaly is a rare benign hematological disorder. It was first described in the 1920s. It is inherited in an autosomal dominant manner. Nuclear hypolobulation, which can also be seen in other leukocytes, especially neutrophils, is a characteristic feature. This morphological change does not cause a defect in the immune system. It should be differentiated clinically from pseudo-Pelger-Huët anomaly (PPHA). In this study, Pelger-Huët anomaly is presented which is noticed in the peripheral smear of a 22-year-old female patient who came to the hematology outpatient clinic due to her sibling having Hodgkin’s lymphoma. The family members of the case were also evaluated in this respect.