BACKGROUND Cancer of unknown primary (CUP) accounts for approximately 3% of all malignancies. Avoiding immune destruction is a major cancer characteristic and therapies aimed at immune checkpoint blockade are in use for several specific cancer types. A comprehensive survey of predictive biomarkers to immune checkpoint blockade in CUP were explored in this study. METHODS About 389 cases of CUP were analysed for mutations in 592 genes and 52 gene fusions using a massively parallel DNA sequencing platform (next-generation sequencing [NGS]). Total mutational load (TML) and microsatellite instability (MSI) were calculated from NGS data. PD-L1 expression was explored using immunohistochemistry (with 5% cutoff value). RESULTS High TML was seen in 11.8% (46/389) of tumours. MSI-high (MSI-H) was detected in 7/384 (1.8%) of tumours. Tumour PD-L1 expression was detected in 80/362 CUP (22%). A small proportion of CUP cases harboured genetic alterations of negative predictive biomarkers to immune checkpoint inhibitors (predictors to hyperprogression) including MDM2 gene amplification (2%) and loss of function JAK2 gene mutations (1%). Amplifications of CD274 (PD-L1) and PDCD1LG2 (PD-L2) genes were also rare (1.4% and 0.8%, respectively). The most frequently mutated genes were TP53 (54%), KRAS (22%), ARID1A (13%), PIK3CA (9%), CDKN2A (8%), SMARCA4 (7%) and PBRM1, STK11, APC, RB1 (5%, respectively). CONCLUSIONS Using a multiplex testing approach, 28% of CUP carried one or more predictive biomarkers (MSI-H, PD-L1 and/or TML-H) to the immune checkpoint blockade, providing a novel option for treatment in patients with CUP.

Oncoviruses are implicated in around 20% of all human cancers including both solid and non-solid malignancies. Epstein–Barr virus (EBV) and human papillomaviruses (HPVs) are the most common oncoviruses worldwide. Currently, it is well established that onco-proteins of EBV (LMP1, LMP2A, and EBNA1) and high-risk HPVs (E5 and E6/E7) play an important role in the initiation and/or progression of several human carcinomas, including cervical, oral, and breast. More significantly, it has been recently pointed out that viral onco-proteins of EBV and high-risk HPVs can be co-present and consequently cooperate to initiate and/or amplify epithelial–mesenchymal transition (EMT), which is the hallmark of cancer progression and metastasis. This could occur by β-catenin, JAK/STAT/SRC, PI3k/Akt/mTOR, and/or RAS/MEK/ERK signaling pathways, which onco-proteins of EBV and HPVs share. This review presents the most recent advances related to EBV and high-risk HPVs onco-proteins interactions and their roles in the progression of human carcinomas especially oral and breast via the initiation of EMT.

Parental health literacy plays an important role in children’s health. Experiences from pharmacy practice show that is necessary to check if parents understand instructions about use of medicines for children. This study aimed to assess pharmacotherapy literacy of parents of pre-school children and to examine association of parental pharmacotherapy literacy level with parent’s socio-demographic characteristics. The study was cross-sectional, conducted among parents of pre-school children (1–7 years of age), in kindergartens in several municipalities of Belgrade, Serbia, during regular parents meetings, from May to October 2016. Functional health literacy was measured by the Serbian version of the Short Test of Functional Health Literacy in Adults (S-TOFHLA). Parental pharmacotherapy literacy was assessed with newly constructed PTHL-SR questionnaire with good psychometric characteristics (Parental pharmacotherapy literacy questionnaire—Serbian). Overall, 813 parents participated in the study, mostly females (81.30%), between 30 to 40 years of age (70.85%) with two children (56.70%). Almost all of our study participants (99%) had adequate health literacy as assessed by S-TOFHLA. Mean score on PTHL-SR was 72.83% (standard deviation was 13.37), with better results among females than males (72% of women were in the group of highest PTHL-SR results). Our study showed that many parents (76.5%) knew the appropriate usage of non-prescription medicine for children, 57.2% parents were able to correctly calculate the dose of oral syrup for a child, and only 43.3% were able to interpret non-prescription dosage information written on the package. The majority of parents (61.3%) would make a dosage to child based on age and not on their weight. Every fifth parent with adequate functional health literacy measured by S-TOFHLA test, achieved the lowest results measured by PTHL-SR. Higher performance of the PTHL-SR was significantly correlated with education (p < 0.001), female sex (p < 0.001), married parents and those living in common-law (p < 0.001), older parents (p < 0.05) and parents who have more children (p < 0.05), and are non-smokers (p < 0.05). These results provide evidence that limitations in understanding common information about use of medicines are widespread among parents of pre-school children and encourage efforts for further investigation. PTHL-SR questionnaire may be a useful tool for identification of parents who need more instructions and assistance from healthcare providers, above all in providing better communication, written or spoken at community pharmacy settings.

The aim of this study was to determine the serum level of calcium (Ca), phosphorus (P) and magnesium (Mg) and hence determine the relationship and the effect of daily milk production on the mentioned essential macro elements. The metabolism and neurohumoral regulation of Ca, P and Mg are closely related, and the metabolic disorder of one of these electrolytes inevitably affects the metabolism of the other two. The study was carried out in the winter period of animal keeping and nutrition, and it included 63 Holstein-Friesian breed cows in the northern region of Bosnia and Herzegovina, aged 2-9 years in different lactation stages (1-8). The largest number of cows, eighteen of them, were in the second, third and fourth lactation stage, while nine cows were in the first lactation stage. This study was conducted on three different groups of cows corresponding to the amount of daily milk production. First was the group of lower daily milk production n=21, the second group of examined cows was the group of medium daily milk production n=23 and third was the group of higher daily milk production n=19. Ca, P and Mg were determined in blood plasma using the Beckmann spectrophotometer. By examining the obtained results and the dynamics of the tested mineral substances, we point out the different behaviour of the Ca-P relationship in correlation with the different level of daily milk produced. Although the average values ​​of both minerals are lowered with an increase in daily milk production, the analysis of single linear regression shows that there is a negative correlation between P concentration in blood plasma and the amount of daily milk produced, while for Ca it has not been established . Although the concentration of Mg in the blood plasma increases as the daily milk production increases, the analysis of single linear regression does not show a significant interconnection of these two values. Lower average values of Ca and P concentrations in the blood of cows with higher daily milk production may be associated with increased total excretion of these minerals through milk, unlike the cows which daily produced lower amounts of milk.

U ovome radu opisan je prvi nalaz hrastove mrežaste stjenice (Corythuca arcuata) na podrucju centralne Bosne, na dva lokaliteta. Kako je ovo prvi nalaz ove vrste na podrucju Bosne i Hercegovine, potrebna su dodatna istraživanja biologije i stetnosti ovog insekta. Buduci da je ovo strana i potencijalno invazivna vrsta, može se ocekivati njeno sirenje po teritoriji citave Bosne i Hercegovine.

We analyze the spectrum of the massless Dirac operator on the 3-torus $\mathbb{T}^3$. It is known that it is possible to calculate this spectrum explicitly, that it is symmetric about zero and that each eigenvalue has even multiplicity. However, for a general oriented closed Riemannian 3-manifold $(M,g)$ there is no reason for the spectrum of the massless Dirac operator to be symmetric. Using perturbation theory, we derive the asymptotic formulae for the eigenvalues $\pm 1$ and prove that by the perturbation of the Euclidean metric on the 3-torus, it is possible to obtain spectral asymmetry of the massless Dirac operator in the axisymmetric case.

in broiler’s small intestine. Investigation were carried out on isolated smooth muscle of the circular and longitudinal layer of the broilers small intestine (strip dimension 3-4 mm x 2 cm). The muscle strips were placed in an isolated organ bath. The mechanical activity of the preparations were recorded via an isotonic force transducer coupled to a pen recorder. This was done following the addition of serotonin (nonselective 5-HT agonist), 2-Me-5HT (5-HT3B agonist) and Y-25130-hydrochloride (selective 5-HT3B antagonist). The research established a presence of serotonergic 5HT3B type receptors within the smooth musculature of the small intestines of broilers (COBB 500). The 5HT3B type receptors were present in smooth muscles of duodenum, jejunum and ileum, especially in longitudinal smooth muscles since this layer reacted even to low serotonin concentration (10-6). Statistical tests of obtained results showed significant differences (p< 0.001) in responses related to muscle layers, applied concentrations and intestinal parts which were observed. In the light of these findings, we suggest that investigated substances may have considerable physiological and therapeutic implications in disturbed function of small intestine of broiler’s.

The paper aims to analyze the causal relationship between economic development and the high-technology export. Time-series annual data are collected for Turkey over the period running from 1990 to 2015. The motivation for the research was the fact that Turkey faces increasing trends in terms of economic development as well as in terms of high-technology export in the observed period. Various econometrics methods for time-series data are used in this paper to analyze the relationship between economic development and high-technology export. Initially, Johansen cointegration test is applied as well as Granger causality test. Moreover, this paper applies ARDL approach based on time-series data to explore the long-run causal linkages and short-run dynamics between the economic terms of interest. In order to test for the stability of the model, the impact of foreign direct investments is controlled. Johansen cointegration test indicates the cointegrating relationship between economic development and high-technology export. Moreover, Granger causality test reports a bidirectional relationship between economic terms of interest. In terms of ARDL model it is important to emphasize a significant positive long-run relationship that is reported between economic terms of interest in the initial model. However, the coefficient in the short-run is not reported to be significant. The extended model controls for the impact of foreign direct investments. The obtained results do not differ in sign and significance from the initial model. Therefore, the initial model can be considered stable.