Effect of octreotide on oxidative stress in the erythrocyte and kidney tissue in adriamycin-induced experimental nephrotic syndrome model / Efeito do octreotide no estresse oxidativo em eritrócitos e no tecido renal no modelo de síndrome nefrótica experimental induzida por adriamicina

Abstract Introduction: Nephrotic syndrome (NS) is one of the reasons of end-stage kidney disease, and elucidating the pathogenesis and offer new treatment options is important. Oxidative stress might trigger pathogenesis systemically or isolated in the kidneys. Octreotide (OCT) has beneficial antioxidant effects. We aimed to investigate the source of oxidative stress and the effect of OCT on experimental NS model. Methods: Twenty-four non-uremic Wistar albino rats were divided into 3 groups. Control group, 2 mL saline intramuscular (im); NS group, adriamycin 5 mg/kg intravenous (iv); NS treatment group, adriamycin 5 mg/kg (iv) and OCT 200 mcg/kg (im) were administered at baseline (Day 0). At the end of 21 days, creatinine and protein levels were measured in 24-hour urine samples. Erythrocyte and renal catalase (CAT) and thiobarbituric acid reactive substance (TBARS) were measured. Renal histology was also evaluated. Results: There was no significant difference among the 3 groups in terms of CAT and TBARS in erythrocytes. Renal CAT level was lowest in NS group, and significantly lower than the control group. In treatment group, CAT level significantly increased compared with NS group. In terms of renal histology, tubular and interstitial evaluations were similar in all groups. Glomerular score was significantly higher in NS group compared with control group and it was significantly decreased in treatment group compared to NS group. Conclusions: Oxidative stress in NS might be due to the decrease in antioxidant protection mechanism in kidney. Octreotide improves antioxidant levels and histology in renal tissue and might be a treatment option.

Resumo Introdução: Síndrome nefrótica (SN) é uma das causas de doença renal em estágio terminal. É importante elucidar a patogênese e oferecer novas opções de tratamento. Estresse oxidativo pode desencadear a patogênese sistemicamente ou isoladamente nos rins. O octreotide (OCT) tem efeitos antioxidantes benéficos. Nosso objetivo foi investigar a fonte de estresse oxidativo e efeito do OCT no modelo experimental de SN. Métodos: Dividimos 24 ratos albinos Wistar não urêmicos em 3 grupos. Grupo controle, 2 mL de solução salina intramuscular (im); grupo SN, adriamicina 5 mg/kg intravenosa (iv); grupo tratamento SN, adriamicina 5 mg/kg (iv) e OCT 200 mcg/kg (im) foram administrados no início do estudo (Dia 0). Aos 21 dias, mediram-se os níveis de creatinina e proteína em amostras de urina de 24 horas. Mediu-se a catalase (CAT) eritrocitária e renal e a substância reativa ao ácido tiobarbitúrico (TBARS). Avaliou-se também histologia renal. Resultados: Não houve diferença significativa entre os três grupos em termos de CAT e TBARS em eritrócitos. O nível de CAT renal foi menor no grupo SN e significativamente menor que no grupo controle. No grupo tratamento, o nível de CAT aumentou significativamente em comparação com o grupo SN. Quanto à histologia renal, as avaliações tubular e intersticial foram semelhantes em todos os grupos. O escore glomerular foi significativamente maior no grupo SN em comparação com o grupo controle e diminuiu significativamente no grupo de tratamento em comparação com o grupo SN. Conclusões: Estresse oxidativo na SN pode ser devido à diminuição do mecanismo de proteção antioxidante nos rins. O octreotide melhora níveis de antioxidantes e histologia do tecido renal e pode ser uma opção de tratamento.

Evaluation of the effect of PET/CT Fluorodeoxyglucose inclusion on mortality and survival in operated thymoma patients.

PURPOSE: In recent years, the use of fluorodeoxyglucose PET-computed tomography (PET-CT) has become widespread to evaluate the diagnosis, metabolism, stage and distant metastases of thymoma. In this study, it was aimed to investigate the connection of malignancy potential, survival and maximum standardized uptake value (SUV max ) measured by PET-CT before surgery according to the histological classification of the WHO in patients operated for thymoma. In addition, the predictive value of the Glasgow prognostic score (GPS) generated by C-reactive protein (CRP) and albumin values on recurrence and survival was investigated and its potential as a prognostic biomarker was evaluated. METHODS: Forty-five patients who underwent surgical resection for thymoma and were examined with PET-CT in the preoperative period between January 2010 and January 2022 were included in the study. The relationship between WHO histological classification, tumor size and SUV max values on PET-CT according to TNM classification of retrospectively analyzed corticoafferents were evaluated. Preoperative albumin and CRP values were used to determine GPS. RESULTS: The cutoff value for SUV max was found to be 5.65 in the patients and the overall survival rate of low-risk (<5.65) and high-risk (>5.65) patients was compared according to the SUV max threshold value (5.65) and found to be statistically significant. In addition, the power of PET/CT SUV max value to predict mortality (according to receiver operating characteristics analysis) was statistically significant ( P  = 0.048). Survival expectancy was 127.6 months in patients with mild GPS (O points), 96.7 months in patients with moderate GPS (1 point), and 25.9 months in patients with severe GPS (2 points). CONCLUSION: PET/CT SUV max values can be used to predict histological sub-type in thymoma patients, and preoperative SUV max and GPS are parameters that can provide information about survival times and mortality in thymoma patients.

Effect of octreotide on oxidative stress in the erythrocyte and kidney tissue in adriamycin-induced experimental nephrotic syndrome model.

INTRODUCTION: Nephrotic syndrome (NS) is one of the reasons of end-stage kidney disease, and elucidating the pathogenesis and offer new treatment options is important. Oxidative stress might trigger pathogenesis systemically or isolated in the kidneys. Octreotide (OCT) has beneficial antioxidant effects. We aimed to investigate the source of oxidative stress and the effect of OCT on experimental NS model. METHODS: Twenty-four non-uremic Wistar albino rats were divided into 3 groups. Control group, 2 mL saline intramuscular (im); NS group, adriamycin 5 mg/kg intravenous (iv); NS treatment group, adriamycin 5 mg/kg (iv) and OCT 200 mcg/kg (im) were administered at baseline (Day 0). At the end of 21 days, creatinine and protein levels were measured in 24-hour urine samples. Erythrocyte and renal catalase (CAT) and thiobarbituric acid reactive substance (TBARS) were measured. Renal histology was also evaluated. RESULTS: There was no significant difference among the 3 groups in terms of CAT and TBARS in erythrocytes. Renal CAT level was lowest in NS group, and significantly lower than the control group. In treatment group, CAT level significantly increased compared with NS group. In terms of renal histology, tubular and interstitial evaluations were similar in all groups. Glomerular score was significantly higher in NS group compared with control group and it was significantly decreased in treatment group compared to NS group. CONCLUSIONS: Oxidative stress in NS might be due to the decrease in antioxidant protection mechanism in kidney. Octreotide improves antioxidant levels and histology in renal tissue and might be a treatment option.

Diurnal cortisol variation during pregnancy in Turkish origin and non-migrant women in a German birth cohort study.

BACKGROUND: Immigrants from Turkey experience health disadvantages relative to non-immigrant populations in Germany that are manifest from the earliest stages of the lifespan onwards and are perpetuated across generations. Chronic stress and perturbations of stress-responsive physiological systems, including the hypothalamus-pituitary-adrenal (HPA)-axis, are believed to in part mediate this relationship. Cortisol plays an important role in the association between maternal stress during pregnancy and many pregnancy-, birth- and offspring-related outcomes. We therefore examined whether maternal migrant background is associated with diurnal cortisol variation during pregnancy. METHODS: 109 pregnant women (incl. n = 32 Turkish origin women) that participated in a multi-site prospective cohort study in Germany collected saliva samples across the day on two consecutive days around 24 and 32 weeks gestation. Hierarchical linear models were applied to quantify associations between migrant background and diurnal cortisol variation across pregnancy. RESULTS: Women of Turkish origin exhibited a significantly lower cortisol awakening response (CAR) and a flatter diurnal cortisol slope (DCS) compared to non-migrant women after adjusting for household income. These relationships between migrant status and diurnal cortisol variation were mainly driven by 2nd generation migrants. DISCUSSION: A potential HPA axis dysregulation of Turkish-origin pregnant women may contribute to the intergenerational transmission of health disadvantages in this group.

Complication and cost analysis of transbronchial lung cryobiopsy and awake video-assisted thoracic surgery in diagnosis of interstitial lung disease.

Aim and introduction: Diagnosing of interstitial lung disease (ILD) is difficult and expensive. The standard diagnostical approaches to ILD are bronchoalveolar lavage, transbronchial lung biopsy, transbronchial lung cryobiopsy (TBLC) and surgical lung biopsy (SLB). SLB is gold standard for the confident diagnosis of ILD but because of the poor performance of the patients it's use is limited. We conducted a retrospective study to point out that TBLC plays an important role in diagnosis of ILD and has fewer complications and lower cost than awake video-assisted thoracic surgery (AVATS). Material and methods: 132 patients who underwent TBLC and AVATS with a pre-diagnosis of ILD in our hospital between 2015 and 2020 were evaluated retrospectively. Diagnosis rates, complications and costs were recorded. Results: There were no non-diagnostic materials in 44 patients in AVATS arm. Prolonged air leak was observed in 11(25.0%) of the patients, and six of them (13.6%) were discharged with Heimlich Valve (HV). Median length of stay in the hospital was 8 days, while average patient cost was $515.9 (415.2-2662.9) in the AVATS arm. Non-diagnostic material was obtained from 10 (11.3%) of 88 patients in TBLC arm. Six (6.8%) of them had pneumothorax, only one of them required a chest tube. No patient was discharged with HV (p=0.001). Median cost for each patient with a median hospital stay of 2.0 (1.0-21.0) (p<0.001) days was $171.9 (80.8-1493.3) (p<0.001). Discussion: Although TBLC is behind AVATS in terms of diagnostic accuracy, it may be an alternative diagnostic tool in the diagnosis of interstitial lung disease due to its acceptable safety profile and cost-effectiveness.

Association of maternal migrant background with inflammation during pregnancy - Results of a birth cohort study in Germany.

BACKGROUND: Health disparities in children of immigrants are prevalent from birth and are hypothesized to - in part - emerge as a biological consequence of migration's unfavorable social and psychological sequelae. The aim of this study was to examine whether maternal migrant background is associated with inflammation during pregnancy - a key pathway by which maternal states and conditions during pregnancy may influence fetal development and subsequent pregnancy, birth, and child developmental and health outcomes. MATERIAL AND METHODS: Data was available from 126 pregnant women who participated in a population based multi-site prospective birth cohort study in Bielefeld and Berlin, Germany. The study included two study visits in mid- and late pregnancy. At each visit, a composite maternal pro-inflammatory score was derived from circulating levels of plasma inflammatory markers (IL-6, CRP). Migrant background was defined by country of origin of participants and their parents' (Turkey or other) and generation status (1st or 2nd generation). We applied hierarchical linear models (HLM) in order to quantify the relationship between different migrant background variables and inflammation during pregnancy after adjustment for potential confounders (including socioeconomic status). RESULTS: Migrant background was significantly associated with inflammation during pregnancy. When compared to women without migrant background, levels of inflammation were increased in 1) pregnant women with migrant background in general (B = 0.35, SE = 0.12, p < .01); 2) 1st (B = 0.28, SE = 0.15, p < .10) and 2nd generation (B = 0.40, SE = 0.15, p < .01); 3) women with a Turkish migrant background (B = 0.28, SE = 0.14, p < .10) and women with another migrant background (B = 0.42, SE = 0.15, p < .01); and 4) 2nd generation Turkish origin women (B = 0.38, SE = 0.20, p < .10), 1st generation women with other migrant background (B = 0.44, SE = 0.26, p < .10), and 2nd generation women with other migrant background (B = 0.43, SE = 0.17, p < .05). DISCUSSION: Our findings support a role for maternal inflammation as a pathway of intergenerational transmission of migration-related health inequalities, suggest that the effect seems to persist in 2nd generation immigrants, and highlight the need for future research and targeted interventions in this context.

A Highly Potent TACC3 Inhibitor as a Novel Anticancer Drug Candidate.

TACC3, a transforming acidic coiled-coil (TACC) family member, is frequently upregulated in a broad spectrum of cancers, including breast cancer. It plays critical roles in protecting microtubule stability and centrosome integrity that is often dysregulated in cancers; therefore, making TACC3 a highly attractive therapeutic target. Here, we identified a new TACC3-targeting chemotype, BO-264, through the screening of in-house compound collection. Direct interaction between BO-264 and TACC3 was validated by using several biochemical methods, including drug affinity responsive target stability, cellular thermal shift assay, and isothermal titration calorimetry. BO-264 demonstrated superior antiproliferative activity to the two currently reported TACC3 inhibitors, especially in aggressive breast cancer subtypes, basal and HER2+, via spindle assembly checkpoint-dependent mitotic arrest, DNA damage, and apoptosis, while the cytotoxicity against normal breast cells was negligible. Furthermore, BO-264 significantly decreased centrosomal TACC3 during both mitosis and interphase. BO-264 displayed potent antiproliferative activity (∼90% have less than 1 µmol/L GI50 value) in the NCI-60 cell line panel compromising of nine different cancer types. Noteworthy, BO-264 significantly inhibited the growth of cells harboring FGFR3-TACC3 fusion, an oncogenic driver in diverse malignancies. Importantly, its oral administration significantly impaired tumor growth in immunocompromised and immunocompetent breast and colon cancer mouse models, and increased survival without any major toxicity. Finally, TACC3 expression has been identified as strong independent prognostic factor in breast cancer and strongly prognostic in several different cancers. Overall, we identified a novel and highly potent TACC3 inhibitor as a novel potential anticancer agent, inducing spindle abnormalities and mitotic cell death.

The effects of steroidal and non-steroidal anti-inflammatory drugs on tracheal wound healing in an experimental rat model.

OBJECTIVES: The effect of non-steroidal anti-inflammatory drugs (NSAID), mostly used for postoperative analgesic purposes for wound healing, is still a matter of debate. Our goal was to evaluate the effects of the most widely used NSAID and corticosteroids after surgical operations on tracheal wound healing in an experimental rat model. METHODS: Thirty-nine male Wistar albino rats were included in this study. Tracheotomy was performed in 32 rats; then they were divided into 3 groups. After the first day, the animals in group 1 were treated with an NSAID (diclofenac 10 mg/kg/day) (NSAID, n = 12) for 7 days; the animals in group 2 were treated with a corticosteroid (dexamethasone, 2 × 0.1 mg/kg/day) (steroid, n = 10) for 7 days; the animals in group 3 (control, n = 10) were not given any medications. For a fourth group (histological control, n = 7), in order to evaluate normal morphological and histological characteristics, neither surgery nor medication was used. Five rats were eliminated from the study (2 rats in the NSAID group died and 3 rats in the steroid group developed local wound infections). The drop-out rate was 12.8%. Histological characteristics, inflammation, fibrosis, necrosis, neochondrogenesis, neovascularization and epithelization were evaluated in 34 rats. Non-parametric tests were used for statistical analysis. RESULTS: Inflammation, vascularization and number of fibroblasts and chondrocytes were significantly higher in the control group than in the histological control group. There was some reduction in all parameters except vascularization in the NSAID group (P > 0.05). When the steroid group was compared to the NSAID group, inflammation (P < 0.05), vascularization and number of chondrocytes (P > 0.05) were more suppressed in the steroid group. The number of fibroblasts increased in the steroid group (P > 0.05). CONCLUSIONS: Steroids and NSAID may have negative effects on tracheal wound healing, probably by suppressing inflammation and fibroblast proliferation. NSAID was mostly used postoperatively for analgesic purposes and should be avoided.

Multilevel Impact of Prenatal Risk and Protective Factors on Stress Biology and Infant Development: Study protocol of BABIP prospective birth cohort from Turkey.

Prenatal environment has long-lasting effects on offspring development and health. Research on prenatal stress identified various mechanisms of these effects, from changes in epigenetic and gene expression profiles to Maternal-Placental-Fetal (MPF) stress biology. There is also evidence for the role of additional risk and protective factors influencing the impact of prenatal stress on maternal and infant outcomes. Considering these findings, we present the study protocol of BABIP, a prospective birth cohort from Turkey. The aim of the project is to investigate the effect of prenatal stress on MPF stress biology (i.e. neuroendocrine, immune and metabolic systems), differential DNA methylation and gene expression patterns, and infant birth and developmental outcomes. We are recruiting 150 pregnant women and their babies for a longitudinal project with 4 time points: 20-24 (T1) and 30-34 (T2) weeks of pregnancy, and 1-month (T3) and 4-months (T4) after giving birth. Maternal early and prenatal environment (prenatal stress, early life stress, psychosocial resources, and health-related behaviors) are assessed during pregnancy with MPF stress biology, DNA methylation and gene expression measures. Infant birth outcomes, DNA methylation and development are assessed postpartum. BABIP is the first prospective birth cohort from Turkey with extensive measures on prenatal environment and health. Through investigating the multilevel impact of prenatal stress and related risk and protective factors during and after pregnancy, BABIP will contribute to our understanding of the mechanisms by which prenatal environment influences infant development and health. Being the first such cohort from Turkey, it may also allow identification of prenatal risk and protective factors specific to the context and population in Turkey.

Biomineralization of Calcium Phosphate Crystals Controlled by Protein-Protein Interactions.

Hydroxyapatite (HAP) is the major biomineral of bone. Despite the large number of studies addressing HAP formation, a fundamental understanding of the critical roles of HAP-forming proteins in vitro is needed. Effects of two HAP-interacting proteins, osteocalcin (OCN) and osteopontin (OPN), on HAP formation was investigated via in vitro biomineralization experiments, and their outcomes on the crystal structure of calcium phosphate (CaP) was revealed. Our data suggest that OCN concentration is negatively correlated with crystal formation rate and crystal size, yet the presence of OCN leads to a more ordered HAP crystal formation. On the other hand, OPN protein promotes faster formation of CaP crystals potentially working as a growth site for mineral formation, and it decreases the Ca:P ratio. This effect results in a shift from HAP-type minerals to less ordered crystals. The crystal size, shape, and Ca:P ratio can be tuned to design improved mammalian hard tissue environment-mimicking matrices by taking advantage of the OCN and OPN proteins on crystal formation. We believe our current findings will lead to innovative approaches for bone biomineralization in regenerative medicine.

Sublobar resections in early-stage non-small cell lung cancer.

BACKGROUND: This study aims to evaluate the outcomes of sublobar resections in patients with early-stage non-small cell lung cancer and to investigate the factors affecting survival. METHODS: Medical files of a total of 63 patients (52 males, 11 females; mean age 64 years; range, 39 to 81 years) who underwent sublobar resection for suspected or known early-stage non-small cell lung cancer between January 2001 and August 2013 were retrospectively reviewed. Data including demographic characteristics of the patients, comorbid conditions, smoking status, surgical margin, visceral pleura invasion, distance from surgical margin to tumor, tumor size, pathological N status, cell type, tumor localization, and recurrences were recorded. RESULTS: Survival was significantly longer in the patients with negative surgical margin for tumor (R0) than in those with positive margin (R1) (94.1 months vs. 32.2 months, p<0.01). Survival was also significantly longer in the patients without lymphatic invasion (p<0.01). CONCLUSION: In early-stage lung tumors, sublobar resection can be performed, if complete resection is performed. Lymphatic invasion is a negative prognostic factor for survival following sublobar resection.

A simple modification to the luminometric methylation assay to control for the effects of DNA fragmentation.

Variations in DNA methylation have been implicated in a number of disorders. Changes in global DNA methylation levels have long been associated with various types of cancer. One of the recently described methods for determining global DNA methylation levels is the LUminometric Methylation Assay (LUMA), which utilizes methylation sensitive and insensitive restriction endonucleases and pyrosequencing technology for quantification. Here we provide evidence suggesting that the global methylation level reported by LUMA is affected by the integrity of the DNA being analyzed. The less intact the DNA, the lower the global methylation levels reported by LUMA. In order to overcome this problem, we propose the use of undigested DNA alongside digested samples. Finally, we demonstrate that this results in a more accurate assessment of global DNA methylation levels.

Influence of life stress, 5-HTTLPR genotype, and SLC6A4 methylation on gene expression and stress response in healthy Caucasian males.

BACKGROUND: Previous research reported that individual differences in the stress response were moderated by an interaction between individuals' life stress experience and the serotonin transporter-linked polymorphic region (5-HTTLPR), a common polymorphism located in the promoter region of the serotonin transporter gene (SLC6A4). Furthermore, this work suggested that individual differences in SLC6A4 DNA methylation could be one underlying mechanism by which stressful life events might regulate gene expression. The aim of this study was to understand the relation between early and recent life stress experiences, 5-HTTLPR genotype, and SLC6A4 methylation. In addition, we aimed to address how these factors influence gene expression and cortisol response to an acute psychosocial stressor, operationalized as the Trier Social Stress Test (TSST). In a sample of 105 Caucasian males, we collected early and recent life stress measures and blood samples to determine 5-HTTLPR genotype and SLC6A4 methylation. Furthermore, 71 of these participants provided blood and saliva samples before and after the TSST to measure changes in SLC6A4 and NR3C1 gene expression and cortisol response. RESULTS: Compared to S-group individuals, LL individuals responded with increased SLC6A4 mRNA levels to the TSST (t(66) = 3.71, P < .001) and also showed increased global methylation as a function of ELS (r (32) = .45, P = .008) and chronic stress (r (32) = .44, P = .010). Compared to LL individuals, S-group individuals showed reduced SLC6A4 mRNA levels (r (41) = -.31, P = .042) and increased F3 methylation (r (67) = .30, P = .015) as a function of ELS; as well as increased F1 methylation as a function of chronic stress and recent depressive symptoms (r = .41, P < .01), which correlated positively with NR3C1 expression (r (42) = .31, P = .040). CONCLUSIONS: Both early and recent life stress alter DNA methylation as a function of 5-HTTLPR genotype. Some of these changes are also reflected in gene expression and cortisol response, differentially affecting individuals' stress response in a manner that may confer susceptibility or resilience for psychopathology upon experiencing stressful life events.

Bilateral chylhotorax after falling from height.

Chylothorax is accumulation of chyle in the pleural cavity due to disruption of the thoracic duct. The causes can be classified as neoplastic, traumatic (iatrogenic or noniatrogenic), congenital, sporadic, spontaneous, and miscellaneous. A 22-year-old man with no feature in his history and family history was referred to emergency department with the case of falling from height. Abdominal computed tomogram (CT) revealed laceration of liver, grade 5 splenic laceration, fracture of the left acetabulum, and dislocation of the left hip. He was optimized for emergency splenectomy and close left hip reduction. On the 2nd day of the operation, bilateral chylotorax revealed. The treatment depends on its etiology, the amount of drainage, and the clinical picture. Treatment can be classified into 3 categories treatment of the underlying condition, conservative management (such as bed rest, nil by mouth or low fat medium chain triglycerides by mouth and total parenteral nutrition), and surgical management by ligation or clipping of the thoracic duct with open thoracotomy or video-assisted thoracoscopic surgery. The main purpose of surgical treatment is to stop the chylous leak.

Is Acrylate Co-monomer (Glubran-2) Useful in the Prevention of Prolonged Air Leaks After Pulmonary Lobectomy?

Many synthetic materials are being used in order to reduce the frequency of prolonged air leak (PAL) in thoracic surgical practice. This study presents our experience with the topical application of acrylate co-monomer (Glubran-2) as a synthetic tissue adhesive in an attempt to decrease troublesome postoperative air leaks in patients undergoing resection for non-small cell lung carcinoma. Of the 112 patients who had undergone resection for lung carcinoma, 69 patients having lobectomy or bilobectomy were included in this study. The application group (group A) consisted of 33 patients where a synthetic tissue adhesive (Glubran-2) was used and compared with the control group (group C, n = 36) retrospectively. There was no difference between the groups regarding demographic details and operative variables. Both groups were compared in view to PAL, chest tube duration, in-hospital stay and hospital costs. There was no significant difference between group A (n = 11, 33 %) and group C (n = 6, 17 %) for the development of PAL (P = 0.11). Hospital stay was 16.1 ± 6.7 days in group A and 15.3 ± 5.8 days in group C (P = 0.66). The surgical cost was significantly higher in group A (€806 ± 127) than the group C (€624 ± 94) (P < 0.001). There was no significant difference between the groups regarding overall hospital costs (P = 0.41). In this study, the use of Glubran-2 following lung resection for non-small cell lung carcinoma did not decrease the incidence of PAL. Neither did it have a favorable effect concerning in-hospital stay nor did it decrease overall hospital costs while increasing surgical costs as expected.