Unraveling the potential clinical utility of circulating tumor DNA detection in colorectal cancer-evaluation in a nationwide Danish cohort.

BACKGROUND: Increasingly, circulating tumor DNA (ctDNA) is proposed as a tool for minimal residual disease (MRD) assessment. Digital PCR (dPCR) offers low analysis costs and turnaround times of less than a day, making it ripe for clinical implementation. Here, we used tumor-informed dPCR for ctDNA detection in a large colorectal cancer (CRC) cohort to evaluate the potential for post-operative risk assessment and serial monitoring, and how the metastatic site may impact ctDNA detection. Additionally, we assessed how altering the ctDNA-calling algorithm could customize performance for different clinical settings. PATIENTS AND METHODS: Stage II-III CRC patients (N = 851) treated with a curative intent were recruited. Based on whole-exome sequencing on matched tumor and germline DNA, a mutational target was selected for dPCR analysis. Plasma samples (8 ml) were collected within 60 days after operation and-for a patient subset (n = 246)-every 3-4 months for up to 36 months. Single-target dPCR was used for ctDNA detection. RESULTS: Both post-operative and serial ctDNA detection were prognostic of recurrence [hazard ratio (HR) = 11.3, 95% confidence interval (CI) 7.8-16.4, P < 0.001; HR = 30.7, 95% CI 20.2-46.7, P < 0.001], with a cumulative ctDNA detection rate of 87% at the end of sample collection in recurrence patients. The ctDNA growth rate was prognostic of survival (HR = 2.6, 95% CI 1.5-4.4, P = 0.001). In recurrence patients, post-operative ctDNA detection was challenging for lung metastases (4/21 detected) and peritoneal metastases (2/10 detected). By modifying the cut-off for calling a sample ctDNA positive, we were able to adjust the sensitivity and specificity of our test for different clinical contexts. CONCLUSIONS: The presented results from 851 stage II-III CRC patients demonstrate that our personalized dPCR approach effectively detects MRD after operation and shows promise for serial ctDNA detection for recurrence surveillance. The ability to adjust sensitivity and specificity shows exciting potential to customize the ctDNA caller for specific clinical settings.

Alteration in basal redox state of young male soccer players after a six-month training programme.

Despite worldwide popularity of soccer, there are still insufficient data about the effects of training process on oxidative stress-induced damage, which may occur during chronic exercise. The present study aimed to determine the effects of a six-month training programme on basal redox status of young male soccer players. The study included 26 male soccer players, aged 12-13, who participated in a six-month training programme, and 26 age-matched non-athletes who were not implemented in the training process. Blood samples were collected (before and after six-month training programme) in order to measure the following oxidative stress markers: index of lipid peroxidation (measured as TBARS), nitrites (NO2-), superoxide anion radical (O2-), hydrogen peroxide (H2O2), superoxide dismutase (SOD), catalase (CAT) and reduced glutathione (GSH) level. After six months, the levels of TBARS and NO2- were significantly increased, while the O2- and H2O2 remained unchanged. On the other hand, SOD and CAT activity increased, while GSH decreased. A carefully prepared training programme could strengthen most components of antioxidant defence systems and, except lipid peroxidation, does not promote oxidative stress in response to regular physical activity. These findings could help in the improvement of training programmes for young athletes.

Structural characterization of self-assembled ZnO nanoparticles obtained by the sol-gel method from Zn(CH3COO)2·2H2O.

Zinc oxide nanopowders were synthesized by the sol-gel method from an ethanol solution of zinc acetate dihydrate. Detailed structural and microstructural investigations were carried out using x-ray diffraction, Raman spectroscopy, thermogravimetric and differential thermal analyses, as well as high-resolution transmission electron microscopy (TEM) and field-emission scanning electron microscopy. The intermediate compound of the reaction was layered zinc hydroxide acetate that further transforms into hexagonally shaped ZnO crystalline nanoplates (d(m) = 4 nm), which aggregate into larger spherical particles. According to the TEM analysis the ZnO nanoparticles were self-assembled into larger particles with the same orientation, i.e. aligned lattice planes of the particles. A further solvothermal treatment resulted in hexagonal, prismatic ZnO mesocrystals.

Design of a method for in vitro studies of polymer adhesion.

In this paper we describe a modified intestinal perfusion technique for investigation of bioadhesion phenomena. This technique is an in vitro method with well standardized experimental conditions which measures the intestinal intraluminal pressure and its oscillation. This also allows the vitality of the intestinal segment used in the experimental to be checked. Our results suggest that the longest adhesion occurred with polyacrylic acid, in comparison with carboxymethylcellulose sodium and the shortest with hydroxypropylcellulose.

Endothelium-dependent relaxation of rat aorta to a histamine H(3) agonist is reduced by inhibitors of nitric oxide synthase, guanylate cyclase and Na,K-ATPase.

The possible involvement of different effector systems (nitric oxide synthase, guanylate cyclase, beta-adrenergic and muscarinic cholinergic receptors, cyclooxygenase and lipoxygenase, and Na(+),K(+)-ATPase) was evaluated in a histamine H(3) receptor agonist-induced ((R)alpha-methylhistamine, (R)alpha-MeHA) endothelium-dependent rat aorta relaxation assay. (R)alpha-MeHA (0.1 nM - 0.01 mM) relaxed endothelium-dependent rat aorta, with a pD(2) value of 8.22 +/- 0.06, compared with a pD(2) value of 7.98 +/- 0.02 caused by histamine (50% and 70% relaxation, respectively). The effect of (R)alpha-MeHA (0.1 nM - 0.01 mM) was competitively antagonized by thioperamide (1, 10 and 30 nM) (pA(2) = 9.21 +/- 0.40; slope = 1.03 +/- 0.35) but it was unaffected by pyrilamine (100 nM), cimetidine (1 muM), atropine (10 muM), propranolol (1 muM), indomethacin (10 muM) or nordthydroguaiaretic acid (0.1 mM). Inhibitors of nitric oxide synthase, L-N(G)-monomethylarginine (L-NMMA, 10 muM) and N(G)-nitro-L-arginine methylester (L-NOARG, 10 muM) inhibited the relaxation effect of (R)alpha-MeHA, by approximately 52% and 70%, respectively). This inhibitory effect of L-NMMA was partially reversed by L-arginine (10 muM). Methylene blue (10 muM) and ouabain (10 muM) inhibited relaxation (R)alpha-MeHA-induced by approximately 50% and 90%, respectively. The products of cyclooxygenase and lipoxygenase are not involved in (R)alpha-MeHA-induced endothelium-dependent rat aorta relaxation nor are the muscarinic cholinergic and beta-adrenergic receptors. The results also suggest the involvement of NO synthase, guanylate cyclase and Na(+),K(+)-ATPase in (R)alpha-MeHA-induced endothelium-dependent rat aorta relaxation.

[The effect of parathormone on arterial blood pressure in patients on hemodialysis]. / Uticaj parathormona na arterijski pritisak krvi kod bolesnika na hemodijalizi.

We evaluated the effect of PTH on blood pressure in haemodialysed patients. The correlation was found between systolic, diastolic pressure and PTH. The results have shown that PTH might have the influence on regulation of arterial blood pressure in these patients.

[Voice frequencies in patients treated with chronic hemodialysis]. / Osnovna frekvencija glasa bolesnika lecenih ponavljanim hemodializama.

Stress effects on respiration and muscle tension are most likely to affect phonation and articulation; the acoustic parameters reflecting vocal indicators of stress are fundamental frequency, duration and intensity. The aim of this study was to explore the link between some psychosomatic states of patients on dialysis and physical parameters of the vowel "e". Fundamental frequency, intensity and duration of the vowel "e" produced before, during and after dialysis were investigated. The results showed that in the period before dialysis the fundamental frequency was greater, duration was longer and intensity was unchanged. This investigation showed that the changes of the parameters of voice were induced with the changes of psychophysiological states of the patients on dialysis. These patients were in the state of chronicle stress, but the period before the treatment was associated with special, anticipatory stress that induced greater fundamental frequency and longer duration of the pronunciation of the vowel "e".

The influence of prostacyclin (PGI2) on contractile properties of isolated right ventricle of rat heart.

The mechanism of the positive inotropic effect of prostacyclin (PGI2) (2.6 x 10(-6) mol/l) on the isolated right ventricle of rat heart was studied. Our results show that the positive inotropic effect of prostacyclin is produced indirectly through beta adrenoceptors and slow Ca2+ channels, because blockade of slow Ca2+ channels with verapamil (10(-6) mol/l) and beta adrenoceptors with propranolol (10(-6) mol/l) abolishes this effect. Alpha adrenoceptors do not mediate the action of PGI2.

[Mortality in malignant hemopathies in Yugoslavia]. / Smrtnost od malignih hemopatija u Jugoslaviji.

The authors have analysed the mortality of malignant haemopathies in Yugoslavia from 1978 to 1987. The standardized rate of mortality among all malignant haemopathies was from 6.5 to 7.2%000. These rates were higher in males (7.8-8.8%000), than in the females (4.8-5.9%000). The mortality of this group of malignant tumors shows a decreasing tendency, which is more evident in females than in males. Since Hodgkin's disease and lymphoid leukemia participate with about 50% in the structure of mortality from all malignant hemopathies, and for that reason, mortality from these two diseases is especially analysed. The standardized rate of mortality from Hodgkin's disease was between 1.7-2.5%000 (males 2.1-3.2%000; females 1.3-2.0%000). Mortality from this malignant haemopathy has a tendency of decreasing, which is approximately of the same intensity in both sexes. Mortality from lymphoid leukemia in the period between 1978 and 1987 was from 0.7 to 1.2%000 (males 0.9-1.7%000; females 0.5-1.0%000). The mortality trend from lymphoid leukemia shows a similar slight decrease in males and females.

[Retinoblastoma]. / Retinoblastom.

Basic elements of retinoblastoma were evaluated in a sample of 14 patients. The analysis of the sex distribution has revealed that a greater number of male children was affected by the disease (p = 0.64). The average age ranged from 2 months to 3.5 years. Usually the first visible symptom is a white pupillary reflex, while the first clinical findings show that there is a tumorous formation in the fundus. A significant correlation between the age of the patient and the length of his survival was found by Fisher's test, as well as between the laboratory findings of tumor cells in the optical nerve incision and the length of survival.