Running Title: PARP inhibition promotes Taxol resistance via Akt activationThe nonstandard abbreviations used are: PARP, Poly (ADP-ribose) polymerase; PAR, poly (ADP-ribose); PI-3K, phosphatidylinositol-3-kinase; Akt/PKB, protein kinase B; MTT + , 3-[4, 5-dimethylthiazol-2-yl]-2, 5-diphenyl-tetrazolium bromide. When activation of the PI-3-kinase-Akt pathway was prevented by LY-294002 or Akt Inhibitor IV, the cytoprotective effect of PARP inhibition was significantly diminished showing that the activation of PI-3-kinase-Akt cascade had significantly contributed to the cytostatic resistance.Our study demonstrates that drug-induced drug resistance can be responsible for the reduced efficacy of antitumor treatment. Although inhibition of PARP-1 can promote cell death in tumor cells by the inhibition of DNA repair, PARP-inhibition promoted activation of the PI-3-kinaseAkt pathway can counteract this facilitating effect, and can cause cytostatic resistance. We suggest augmenting PARP inhibition by the inhibition of the PI-3-kinase-Akt pathway for antitumor therapy.
Health-related quality of life (HRQoL) is an important outcome in oncology care although an underexplored area in bladder cancer (BC). Our aims were to assess HRQoL of patients with BC, analyse relationships between diverse HRQoL measures and validate the Hungarian version of the Bladder Cancer Index (BCI) questionnaire. A cross-sectional survey was performed among patients with BC (N = 151). Validated Hungarian versions of the FACT-Bl, SF-36 and EQ-5D were applied and SF-6D was derived. Psychometric analysis of the Hungarian BCI was performed. Pearson correlations between the five measures were analysed. Deterioration in SF-36 Physical Functioning was detected among patients aged 45-64 years. The EQ-5D score did not differ significantly from the age-matched population norm. Correlations between the FACT-Bl, EQ-5D and SF-6D utility measures were strong (r > 0.6). Cronbach alpha coefficients of the Hungarian BCI ranged from 0.75 to 0.97 and factor analysis confirmed that data fit to the six predefined subdomains. Test-retest correlations (reliability, N = 50) ranged from 0.67 to 0.87 and interscale correlations between urinary, bowel and sexual BCI domains were weak or moderate (r = 0.29 to 0.49). Convergent validity revealed a stronger correlation with FACT-Bl (r = 0.126 to 0.719) than with generic health state scores (r = 0.096 to 0.584). Results of divergent validity of the Hungarian BCI by treatment groups by Kruskal Wallis test were promising although limited by low sample sizes in cystectomy subgroups. Generic health state measures have limited capacity to capture HRQoL impact of BC. Validity tests yielded favourable results for the Hungarian BCI. Mapping studies to estimate utility scores from FACT-Bl are encouraged but less recommendable with the BCI.
Previous studies on the degenerative animal model of multiple sclerosis suggested that the copper-chelator cuprizone might directly suppress T-cell functions. Peripheral T-cell function in the cuprizone model has already been explored; therefore, in the present study, we investigated, for the first time, how cuprizone feeding affects the thymus, the organ of T-cell maturation and selection. We found that even one week of cuprizone treatment induced significant thymic atrophy, affecting the cortex over the medulla. Fluorescent microscopy and flow-cytometric analyses of thymi from cuprizone- and vehicle-treated mice indicated that eradication of the cluster of the differentiation-4 (CD4)-CD8 double-positive T-cell subset was behind the substantial cell loss. This result was confirmed with CD3-CD4-CD8 triple-staining experiments. Ultrastructurally, we observed degraded as well as enlarged mitochondria, myelin-bodies, large lipid droplets, and large lysosomes in the thymi of cuprizone-treated mice. Some of these features were similar to those in physiological and steroid-induced accelerated aging. According to our results, apoptosis was mainly of mitochondrial origin mediated by both caspase-3- and apoptosis inducing factor-mediated mechanisms. Additionally, mitogen activated protein kinase activation and increased pro-apoptotic B cell lymphoma-2 family protein expression were the major underlying processes. Our results do not indicate a functional relationship between cuprizone-induced thymus involution and the absence of inflammatory responses or the selective demyelination observed in the cuprizone model. On the other hand, due to the reversible nature of cuprizone’s deleterious effects, the cuprizone model could be valuable in studying thymus regeneration as well as remyelination processes.
According to some estimates, at least 70% of feedstuffs and finished feeds are contaminated with one or more mycotoxins and, due to its significant prevalence, both animals and humans are highly likely to be exposed to these toxins. In addition to health risks, they also cause economic issues. From a healthcare point of view, zearalenone (ZEA) and its derivatives have been shown to exert many negative effects. Specifically, ZEA has hepatotoxicity, immunotoxicity, genotoxicity, carcinogenicity, intestinal toxicity, reproductive toxicity and endocrine disruption effects. Of these effects, male reproductive deterioration and processes that lead to this have been reviewed in this study. Papers are reviewed that demonstrate estrogenic effects of ZEA due to its analogy to estradiol and how these effects may influence male reproductive cells such as spermatozoa, Sertoli cells and Leydig cells. Data that employ epigenetic effects of ZEA are also discussed. We discuss literature data demonstrating that reactive oxygen species formation in ZEA-exposed cells plays a crucial role in diminished spermatogenesis; reduced sperm motility, viability and mitochondrial membrane potential; altered intracellular antioxidant enzyme activities; and increased rates of apoptosis and DNA fragmentation; thereby resulting in reduced pregnancy.
IntroductionMetoidioplasty is a variant of phalloplasty for transmen that includes the creation of the neophallus from a hormonally enlarged clitoris, urethral lengthening and scrotoplasty. The procedure results in male appearance of genitalia, voiding in standing position and preserved sexual arousal, but without possibility for penetrative intercourse. We evaluated outcomes of metoidioplasty at our center, based on latest surgical refinements.MethodsDuring the period of 14 years (from February 2006 to April 2020), 813 transmen with mean age of 24.4 years and mean body mass index of 24.6, underwent one stage metoidioplasty. Hysterectomy was simultaneously performed in 156, and mastectomy in 58 cases. Hysterectomy, mastectomy and metoidioplasty were done as a one-stage procedure in 46 transmen. Patients are divided in 5 groups, depending on the type of urethroplasty. Postoperative questionnaires were used to evaluate cosmetic and functional outcomes, as well as patients’ satisfaction.ResultsFollow-up ranged from 16 to 180 months (mean 94 months). Mean surgery time was 170 minutes and mean hospital stay was 3 days. Length of the neophallus ranged from 4.8 cm to 10.2 cm (mean 5.6 cm). Urethroplasty was complication-free in 89.5% of cases, and ranged between 81% to 90.3% in different groups. Urethral fistula and stricture occured in 8.85% and 1.70% of cases, respectively. Other complications included testicular implant rejection in 2%, testicular displacement in 3.20% and vaginal remnant in 9.60% of cases. From 655 patients who answered the questionnaire, 79% were totally satisfied and 20% mainly satisfied with the result of surgery. All patients reported voiding in standing position and good sexual arousal of the neophallus, without possibility for penetrative intercourse due to small size of the neophallus.ConclusionMetoidioplasty has good cosmetic and functional outcomes, with low complication rate and high level of patients’ satisfaction. In transmen who request total phalloplasty after metoidioplasty, all available phalloplasty techniques are feasable.
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