Expression of CD105 but not of E-cadherin is associated with malignancy recurrence and disease-free interval in laryngeal cancer in men

Introduction. In this study we analyzed CD105 (endoglin) and E-cadherin expression in laryngeal squamous cell carcinoma (LSCC) to evaluate their clinicopathologic significance. Material and methods. Expression of CD105 and E-cadherin was examined immunohistochemically using paraffin-embedded archival tissues of 72 (35 glottic and 37 supraglottic) previously untreated LSCC male patients. The mean value of the positively-stained microvessels for CD105 counted in four hot spots for each case was used as the final intratumoralmicrovessel density (MVD). A staining score of E-cadherin was calculated based on the percentage of cells stained (0–100%). Results. MVD was significantly higher in patients with advanced TNM stage (P = 0.004) and younger than 65 (P = 0.008). Nodal metastases were more frequent in the cases with low E-cadherin expression (P = 0.000). Tumor recurrence was associated with advanced TNM stage (P = 0.035) and high MVD (P = 0.002). A high MVD was an independent predictor of malignancy recurrence (P = 0.021). The log-rank test showed a significant difference in the disease-free interval in patients stratified according to the MVD value (P = 0.016). Spearman’s rank correlation test did not show a significant correlation between E-cadherin and CD105 expression. Conclusions. CD105-assessed MVD and expression of E-cadherin are promising prognostic factors for the outcome of patients with LSCC. Increased expression of CD105 could help predict patients with an increased risk of developing loco-regional recurrence after surgical treatment. Decreased E-cadherin expression is a potential predictor of lymph node metastases

Prevalence and clinical implications of the HPV16 infection in oral cancer in Montenegro - Evidence to support the immunization program

Oral squamous cell carcinoma (OSCC) makes 85-95% of all malignances in the oral cavity. Increasing evidence shows that the Human Papillomaviruses (HPVs) are preferentially associated with some oropharyngeal and OSCCs, namely the genotype 16. The aim of the present study was to determine the prevalence and clinical implications of HPV16 infection in oral squamous cell carcinoma in population of Montenegro.This study included 60 patients with OSCC (localized on the lower lip, tongue or/and floor of the mouth), surgically treated at the Clinical Centre of Montenegro from 2012 to 2018. Surgically obtained formalin-fixed and paraffin-embedded specimens were used for histopathological analysis and HPV16 genome detection using standard Polymerase Chain Reaction (primers for detection of E6 gene). Each individual was further followed up for the period of three years and for different clinico-pathological characteristics, including disease free interval (DFI).The prevalence of HPV16 infection in OSCCs was 23.3% and the infection was significantly more common in female patients (P = 0.038). No significant correlation was detectable between HPV16 infection and the patients' age (P = 0.302), tumor site (P = 0.125), tumor grade (P = 0.363) and disease stage (P = 0.995). Observing the total sample the DFI was not significantly different for HPV16-positive versus HPV16-negative patients (P = 0.427), but a gender-based difference in DFI was observed, with the significantly shorter DFI (Log Rank test, P = 0.003) in HPV16 positive female patients compared to male patients (P = 0.003).The results obtained in this study provide scientific evidence for the development of national HPV vaccination program in Montenegro

Ispitivanje neurotoksičnosti analoga fentanila kod pacova

This study aimed at evaluating the neurotoxicity of fentanyl analogs: (+/-)-cis-3-carbomethoxy fentanyl (C) and (+/-)-trans-3-carbomethoxy fentanyl (T) in rats. C and Tare less potent (2.4-3.1 and 8.4-12.3 times, respectively) than fentanyl (F) in producing both antinociception and morphine-like neurotoxic effects: loss of pinna reflex, Straub tail, impairment of motor coordination, catalepsy, loss of corneal reflex and loss of righting reflex. All of the effects tested were dose-dependent and they were abolished by pretreatment with naloxone, nonselective antagonist of opioid receptors, indicating that they are mediated via opioid receptors. Further, F, C and T exhibited similar relative potencies in producing all tested effects, indicating that similar receptors are involved in producing antinociceptive and neurotoxic effects, most probably of mu type. By using equiantinociceptive doses, C and T produced significantly shorter duration of both antinociception and neurotoxicity than F No significant differences between therapeutic indices for F, C and T were found, indicating that these compounds are equally safe and tolerable in respect to the neurotoxic effects tested. Neurotoxicity testing presented in this paper may be useful in studying the structure-activity relationship of opioid congeners.Cilj studije bio je da se ispita neurotoksičnost analoga fentanila: (±)-cis-3-karbometoksi fentanila (C) i (±)-trans-3-karbometoksi fentanil (T) kod pacova. C je oko 2,4-3,1, a T oko 8,4-12,3 puta manje potentan od fentanila u izazivanju antinocicepcije i morfinu-sličnih neurotoksičnih efekata u koje spadaju: refleks ušne školjke, Straub-ov rep, poremećaj motorne koordinacije, katalepsija, gubitak kornealnog refleksa i gubitak refleksa uspravljanja. Svi ispitivani efekti su dozno-zavisni i bivaju poništeni ako se u pretretmanu primeni nalokson, neselektivni antagonist opioidnih receptora, što ukazuje da se efekti odigravaju posredstvom opioidnih receptora. Dalje, F, C i T ispoljavaju sličnu relativnu jačinu u izazivanju ispitivanih efekata, što ukazuje da su slični receptori uključeni u mehanizam antinocicepcije i neurotoksičnih efekata, i to su najverovatnije μ receptori. Kad se primenjuju ekviantinociceptivne doze, C i T izazivaju značajno kraće i antinociceptivno i neurotoksično dejstvo od F. Nisu dokazane značajne razlike u terapijskim indeksima između F, C i T, što ukazuje da su ovi lekovi jednako bezbedni i podnošljivi kad su u pitanju ispitivani neurotoksični efekti. Ispitivanje neurotoksičnosti prikazano u ovom radu može biti korisno u proučavanju odnosa između strukture i aktivnosti hemijski srodnih opioida

Sinteza i farmakološko ispitivanje (±)-2,3-seco-analoga fentanila

An efficient, five-step synthetic approach to various acyclic 1,3-diamines has been developed and applied to the preparation of a novel class of open-chained fentanyl analogues. The acyclic derivatives 5.1-5.5 (all new compounds) were synthesized with the aim of estimating the significance of the piperidine ring for the opioid analgesic activity of anilido-piperidines. The starting beta-keto-amide 1.1, prepared by the aminolysis of methyl acetoacetate with methyl phenethylamine, (93% yield), was successively reacted with NaH and BuLi, to form the highly reactive alpha,gamma-dienolate anion 1.1a. Regio and chemoselective gamma-alkylation of the dienolate with various primary and secondary alkyl halides furnished the beta-keto-amides 1.2-1.5 (76-91%). Reductive amination of the keto-amides 1.1-1.5 with aniline and Zn powder in acetic acid, via the enamine intermediates 2.1-2.5. afforded the beta-anilino amides 3.1-3.5 (74-85%). After reductive deoxygenation of the tertiary amide group, using in situ generated diborane, the corresponding 1,3-diamines 4.1-4.5 were obtained (87-97%). The synthesis of (+/-)-2,3-seco-fentanyls 5.1-5.5 was completed by N-acylation of the diamines 4.1-4.5 with propionyl chloride, followed by precipitation of the monooxalate salts (86-95%). The parent compound, 2,3-seco-fentanyl 5.1, was found to be a 40 times less potent narcotic analgesic than fentanyl but still 5-6 times more active than morphine in rats. while i-Pr derivative 5.3 was inactive. Apart from the pharmacological significance. the general procedure described herein may afford various functionalized, 1,3-diamines as potential complexing agents and building blocks for the synthesis of aza-crown ethers.Razvijen je efikasan postupak za dobijanje različitih acikličnih 1,3-diamina u pet faza, i primenjen u sintezi nove klase analoga fentanila otvorenog niza. Derivati 5.1–5.5 (svi su nova jedinjenja) sintetisani su sa ciljem da se proceni uticaj piperidinskog prstena na opioidnoanalgetičku aktivnost anilido-piperidina. Polazni β-keto-amid 1.1, dobijen aminolizom metilacetoacetata metilfenetilaminom (prinos 93 %), bio je sukcesivno tretiran sa NaH i BuLi, pri čemu je postao veoma reaktivni α,γ-dienolatni anjon 1.1a. Regio- i hemoselektivnim γ-alkilovanjem ovog dienolata različitim primarnim i sekundarnim alkil-halogenidima, dobijeni su β-keto-amidi 1.2–1.5 (prinos 76–91 %). Reduktivnim aminovanjem keto-amida 1.1–1.5 pomoću Zn praha i sirćetne kiseline, preko enaminskih intermedijera 2.1–2.5, postali su -anilino-amidi 3.1–3.5 (prinos 74–85 %). Posle reduktivne deoksigenacije tercijene amidne funkcije, koristeći in situ generisani diboran, odgovarajući 1,3-diamini 4.1–4.5 izolovani su u prinosima 87–97 %. Sinteza (±)-2,3-seco-fentanila 5.1–5.5 završena je N-acilovanjem diamina 4.1–4.5 propionil-hloridom, a zatim taloženjem u obliku monooksalatnih soli (prinos 86–95 %). Nađeno je da je osnovno jedinjenje, 2,3-seco fentanil 5.1, 40 puta slabiji narkotički analgetik od fentanila, ali još uvek 5–6 puta aktivniji od morfina u pacova, dok je i-Pr derivat 5.3 bio neaktivan. Osim farmakološkog značaja, opštim postupkom prikazanim u ovom radu, mogu se sintetisati različiti 1,3-diamini, uključujući i one sa funkcionalnim grupama. Ova jedinjenja mogu biti potencijalno značajna kao kompleksirajući agensi i kao intermedijeri u sintezi aza-kraun-etara

Pharmacological evaluation of 3-carbomethoxy fentanyl in mice

In many animal species, as well as in humans, high doses of fentanyl (F) produce marked neurotoxic effects, such as muscular rigidity and respiratory depression. The antinociception (hot-plate test), impairment of motor coordination (rotarod test) and acute toxicity of intraperitoneal newly synthesized analogs, (±)cis-3-carbomethoxy- fentanyl (C) and (±)trans-3-carbomethoxyfentanyl (T) were evaluated in mice. The compounds tested induced antinociception, impairment of performance on the rotarod, and lethality in a dosedependent manner. The relative order of antinociceptive potency was similar to motor impairment potency, as well as lethality: F gt C gt T. Naloxone hydrochloride (1 mg/kg; sc) abolished all the effects observed, suggesting that they are mediated via opioid receptors, most probably of μ type. There were no significant differences between the therapeutic indices of F, C and T. It is concluded, the introduction of 3-carbomethoxy group in the piperidine ring of the fentanyl skeleton reduced the potency, but did not affect tolerability and safety of the compound. © 2011 by the authors

Multiauthorship and false authorship: Why worrying about this?

Authorship and authorship abuse are in the focus of interest of all main actors in the publication game - authors, reviewers and editors of scientific journals. Along with the steady rise of the number of publications, the number of coauthors in multiauthored papers raises even more, some of them being undeserved authors. Because publication is the main way for evaluating scientists, authorship is prone to abuse, and thus the false/undeserved/gift authorship emerges. This dilutes the responsibility and damages the publication enterprise, thus initiating a constant struggle of scientific community against this type of scientific dishonesty. In this paper, several prevention and corrective measures with the aim to diminish such a dishonest behavior of authors are described

Lymphocytic infiltration as a prognostic factor in papillary thyroid carcinoma

Introduction/Objective. We examine the prognostic significance and association between lymphocytic infiltration and papillary thyroid carcinoma. This manuscript aims to establish whether the presence of lymphocytic infiltration in the classical type of papillary thyroid carcinoma is a favorable prognostic factor for survival. Methods. This is a retrospective study of patients treated for papillary thyroid carcinoma at the Clinical Centre of Montenegro over a period of seven years (2010–2017). A total of 105 patients aged 12 to 84 years were included in the study, of which 74% showed concomitant histological evidence of lymphocytic infiltration. The patients were divided into two groups – one with lymphocytic infiltration and the other without it. Anti-CD3 and anti-CD20 antibodies were used to identify T and B lymphocytes. The prognostic outcome was assessed using the Kaplan–Meier survival plots. Results. The cohort with lymphocytic infiltration revealed a lower frequency of extrathyroidal invasion (p < 0.0001), nodal metastases (p < 0.0001), and the absence of distant metastases, compared with those without lymphocytic infiltration. Chronic lymphocytic thyroiditis is a favorable prognostic factor for survival in our examined group (p < 0.0001). Conclusion. The present study shows that immune reaction involving lymphocytic infiltration plays a role in extrathyroidal tumor growth and development of nodal and distant metastases in patients with papillary thyroid cancer. The presence of lymphocytic infiltration is a favorable factor for survival in the classical form of papillary thyroid carcinoma

Synthesis of "in situ" reinforced silicon nitride composites

The objective of this work was to investigate the effect of two different sintering additives (CeO2 and Y2O3 + Al2O3), sintering time and amount of beta-Si3N4 seeds on the densification. mechanical properties and microstructure of self-reinforced Si3N4 based composites obtained by pressureless sintering. Preparation of beta-Si3N4 seeds, also obtained by a pressureless sintering procedure. is described. Samples without seeds were prepared for comparison. The results imply that self-reinforced silicon nitride based composites with densities close to the theoretical values and with fracture toughness of 9.3 MPa m(1/2) can be obtained using a presureless sintering procedure

Synthesis of in situ reinforced silicon nitride composites

The objective of this work was to investigate the effect of two different sintering additives (CeO2 and Y2O3 + Al2O3), sintering time and amount of b-Si3N4 seeds on the densification, mechanical properties and microstructure of self-reinforced Si3N4 based composites obtained by pressureless sintering. Preparation of b-Si3N4 seeds, also obtained by a pressureless sintering procedure, is described. Samples without seeds were prepared for comparison. The results imply that self-reinforced silicon nitride based composites with densities close to the theoretical values and with fracture toughness of 9.3 MPa m1/2 can be obtained using a presureless sintering procedure

Modeling the ligand specific μ- and δ-opioid receptor conformations

An automated docking procedure was applied to study the binding of a series of mu- and delta-selective ligands to ligand-specific mu- and delta-opioid receptor models. Short-time molecular dynamic simulations were used to obtain ligand-specific mu- and delta-opioid receptors from arbitrarily chosen models of the active form of these receptors. The quality of receptor model depended on the molecular volume of the ligand in the receptor-ligand complex used in the molecular dynamic simulations. Within a series of ligands of similar size (volume), the results of ligand docking to the obtained ligand-specific receptor conformation were in agreement with point mutation studies. The correlation of the calculated and the experimentally determined binding energies was improved in relation to the initial receptor conformation.Računska metoda automatizovanog dokiranja primenjena je na vezivanje serije liganada, specifičnih za µ- i δ-receptore, za modele ovih receptora. Kratkotrajna molekulsko dinamička simulacija je korišćena za dobijanje konformacija ovih receptora koje su specifične za pojedine ligande, polazeći od slučajno izabranog modela aktiviranog receptora. Kvalitet ovako dobijenog modela receptora zavisi od molekulske zapremine liganda u ligand-receptor kompleksu korišćenog u molekulsko-dinamičkoj simulaciji. Za seriju liganda slične zapremine rezultati dokiranja su u skladu sa eksperimentalnim rezltatima mutacija aminokiselina u receptoru. Korelacija izračunatih i merenih energija vezivanja je poboljšana u odnosu na rezultate dobijene sa polaznom konformacijom receptora