VHL tumor suppressor as a novel potential candidate biomarker in papillary thyroid carcinoma

Papillary thyroid carcinoma (PTC) is the most common type of endocrine cancer, with an increasing incidence worldwide. The treatment of PTC is currently the subject of clinical controversy, making it critically important to identify molecular markers that would help improve the risk stratification of PTC patients and optimize the therapeutic approach. The Von Hippel–Lindau (VHL) tumor suppressor gene has been implicated in tumorigenesis of various types of carcinoma and linked with their aggressive biological behavior. The role of VHL in the origin and development of PTC have only recently begun to be revealed. In this narrative review, we attempt to summarize the existing knowledge that implicates VHL in PTC pathogenesis and to outline its potential significance as a candidate molecular biomarker for the grouping of PTC patients into high and low risk groups. © 2022 Todorović and Stanojević

VHL tumor suppressor as a novel potential candidate biomarker in papillary thyroid carcinoma

Papillary thyroid carcinoma (PTC) is the most common type of endocrine cancer, with an increasing incidence worldwide. The treatment of PTC is currently the subject of clinical controversy, making it critically important to identify molecular markers that would help improve the risk stratification of PTC patients and optimize the therapeutic approach. The VHL tumor suppressor gene has been implicated in tumorigenesis of various types of carcinoma and linked with their aggressive biological behavior. The role of VHL in the origin and development of PTC has only recently begun to be revealed. In this narrative review we attempt to summarize the existing knowledge that implicates VHL in PTC pathogenesis and to outline its potential significance as a candidate molecular biomarker for the grouping of PTC patients into high and low risk groups

Umerena radioprotektivna uloga zeolita kod pacova

Background/Aim. Exposure of living organisms to γ- radiation results in the overproduction of free radicals. The aim of the study was to test if the subacute administration of micronized zeolite (MZC) accomplishes radioprotective role based on the evaluation of the status of oxidative stress (OS) in the brain and 8-hydroxyguanosine (8-OH-dG) in the plasma of the rats exposed to the single γ-ray irradiation of 2 and/or 10 Gray (Gy). Methods. Wistar rats were on a four-week normal or 5% MZC supplemented diet and af- terward exposed to the single γ-ray irradiation of 2 and 10 Gy. Groups of rats were: a) on a normal diet (the control group, and 2Gy and 10Gy groups); b) on 5% MZC supple- mented diet (the control group – MZC, MZC + 2Gy, and MZC + 10Gy groups). We measured malondialdehyde (MDA), glutathione (GSH) total, and activity of total super- oxide dismutase (tSOD) and manganese superoxide dis- mutase (MnSOD) in vulnerable brain regions (cerebellum, hippocampus, and cerebral cortex) and 8-OH-dG in plasma. Results. Lower MDA was found in the MZC+2Gy and MZC+10Gy groups compared to the 2Gy and 10Gy groups. Activity od total SOD was higher in the MZC+10Gy group than in the 10Gy one. GSH was the highest in the 10Gy group. Compared to the control group, 8-OH-dG was extremely higher in groups radiated with 10 Gy regardless of a diet, but slightly lower in the MZC+2Gy and 2Gy groups. Conclusion. Subacute MZC pretreatment accomplished partial radioprotective effect in irradiated rats compared to non-irradiated rats, based on suppressed SOD activity at 2 Gy, and reduced brain MDA when exposed to 2 Gy and 10 Gy.Uvod/Cilj. Izlaganje živih organizama gama zračenju re- zultira hiperprodukcijom slobodnih radikala. Cilj istraživanja je bio da se ispita da li subakutna ishrana dopunjena sa 5% mikronizovanog zeolita (MZC) ispoljava radiozaštitnu ulogu na osnovu statusa oksidativnog stresa (OS) u mozgu i 8- hidroksiguanozina (8-OH-dG) u plazmi pacova izloženih pojedinačnim dozama jonizujućeg zračenja od 2 i 10 Gray (Gy). Metode. Wistar pacovi su bili na četvoronedeljnoj normalnoj ishrani ili ishrani obogaćenoj sa 5% MZC, posle čega su bili izloženi pojedinačnom jonizujućem zračenju od 2 Gy, odnosno 10 Gy. Grupe pacova bile su: a) gru pa pacova na normalnoj ishrani (kontrolna grupa i grupe 2Gy i 10Gy); b) grupa pacova na ishrani obogaćenoj sa 5% MZC (kontrolna grupa – MZC i grupe MZC+2Gy i MZC+10Gy). Meren je malondialdehid (MDA), glutation (GSH) i aktivnost ukupne (tSOD) i mangan superoksid dizmutaze (MnSOD) u osetljivim strukturama mozga (cerebelum, hipokampus i cerebralni korteks), a 8-OH-dG u plazmi. Rezultati. Biomarker MDA je bio niži u MZC+2Gy i MZC+10Gy grupama, u odnosu na grupe 2Gy i 10Gy. Aktivnost ukupne SOD je bila viša u grupi MZC+10Gy, u odnosu na grupu 10Gy. Najviši nivo GSH bio je u grupi 10Gy. U pređenju sa kontrolnom grupom, 8- OH-dG je bio izuzetno viši u grupama ozračenim sa 10 Gy, bez obzira na dijetetski režim i niži u grupama MZC+2Gy i 2Gy. Zaključak. Pacovi koji su bili na režimu ishrane obogaćene sa 5% MZC bili su delimično zaštićeni od zračenja, shodno redukovanoj moždanoj aktivnosti SOD pri 2 Gy i sniženom nivou MDA pri izlaganju zračenju od 2 i 10 Gy

The expression of microRNA-30a-3p and estrogen receptor β in papillary thyroid cancer

Background: A number of studies point to a significant role of microRNAs (miRNAs) in papillary thyroid cancer (PTC), where specific miRNA expression profiles associate with distinct clinical and biological phenotypes of the lesion. One of the microRNAs deregulated in PTC is miR-30a-3p. Evidence suggests that estrogen receptor β (ERβ), also found to be deregulated in PTCs, may directly regulate microRNA-30a-3p biogenesis and expression. Considering the possibility that ERβ might influence PTC cell behavior via miRNAs, in particular, miR-30a-3p, we have investigated their expression and correlation in PTCs with different clinico-pathological characteristics. Patients and Methods: Quantitative PCR was used to determine the relative miR-30a-3p and ERβ expression levels in 37 pairs of PTCs and matched non-tumor thyroid tissues. Results: The expression levels of miR-30a and ERβ were significantly altered in tumors compared with non-tumor tissues. A negative correlation between miR-30 and ERβ was detected in tumors with pT4 category (P=0.038, r = - 0.738) and capsular invasion (only in women) (P=0.041. r= -0.552) compared to positive correlations (or trends) found in tumors with lower pT categories (pT1+pT2) (P=0.061, r=0.463) and tumors with no capsular invasion (P=0.019, r=0.618). Similar trend was found in tumors with classic papillary pattern in the group of women (P=0.09, r= - 0.432) while in women with histovariants other than classic there was a trend towards positive correlation (P=0.066, r=0.486). Conclusion: The results suggest that in some PTCs, ERβ might negatively regulate miR-30a expression, and the opposite roles they may play are associated with more aggressive tumor features.5th Congress of the Serbian Association for Cancer Research with International Participation SDIR-5, Virtual event, December 3, Belgrade, 2021

Interleukin-6, a potential plasma biomarker for diagnosis and prognosis of thyroid neoplasms

Background: Thyroid neoplasms include benign tumors – thyroid adenoma (TA), and malignant tumors of various histological types: papillary thyroid carcinoma (PTC) – the most common and usually indolent, anaplasƟ c thyroid carcinoma (ATC) – the most aggressive, and several other types such as follicular, medullary and poorly diff erenƟ ated. Despite the progress in understanding the epidemiology and geneƟ c landscape of thyroid tumors, the diagnosis, prognosis and treatment approach require further improvement. Interleukin-6 (IL-6) is a pro-infl ammatory cytokine with a central role in the regulaƟ on of immune and infl ammatory responses including autoimmune thyroid diseases. Studies have revealed a potenƟ al impact of IL-6 in the development, progression and control of thyroid cancer. The aim of this study was to provide novel aspects for the preoperaƟ ve diff erenƟ al diagnosis and/or prognosis of thyroid cancer. To achieve this, we assessed the circulaƟ ng levels of IL-6 in paƟ ents with benign and malignant thyroid tumors of various histotypes, compared them with healthy volunteers, and correlated the results with clinicopathological parameters. PaƟ ents and Methods: The study included 43 paƟ ents with benign or malignant thyroid tumors, surgically treated at the Center for Endocrine Surgery, Clinical Center of Serbia. IL-6 protein levels were determined in plasma samples by quanƟ taƟ ve ELISA. Parametric and nonparametric staƟ sƟ cal tests were used for data analysis. Results: IL-6 concentraƟ ons in paƟ ents with either TA or carcinoma (PTC, ATC) were signifi cantly higher compared to the healthy volunteers (Mann Whitney test). The highest concentraƟ ons were detected in ATC paƟ ents (Median±SD 15.97±0.71 pg/mL), being signifi cantly higher compared to TA and PTC (2.14±1.34 pg/mL and 1.96±2.12 pg/mL, respecƟ vely). In PTC microcarcinoma, IL-6 was higher compared to controls, but there was no signifi cant diff erence compared to other PTC or TA (Mann Whitney test). The correlaƟ on analysis with clinicopathological parameters in PTC paƟ ents revealed a trend towards the associaƟ on of increased IL-6 plasma levels with the presence of nodal and distant metastases. No other signifi cant associaƟ ons were found. Conclusion: PaƟ ents with thyroid adenoma or carcinoma have increased plasma IL-6 levels that are in proporƟ on with the aggressiveness of the thyroid tumor, suggesƟ ng that IL-6 might be a candidate biomarker for diagnosis and prognosis of thyroid neoplasms.The first number of Oncology Insights includes Proceedings book of The Sixth Congress of the Serbian Association for Cancer Research with international participation (Oct 2-4, 2023, Belgrade

Sezonska dinamika prisustva culicoides spp u Srbiji u periodu 2015-2016. godine

Genus Culicoides spp. includes small insects 0.5-2 mm in length, usually grey or black and at first glance very similar to mosquitoes. They are strictly hematophagous, feeding by attacking hosts outdoors and indoors (although they are less susceptible to the stationing like Aedes mosquitoes do). The sting is very painful at the injection site and often followed by hypersensibilisation with the consequent formation of allergic dermatitis. In addition, the insects carry and transmit a multitude of diseases, often of a zoonotic character, and therefore are of great epidemiological importance. In our country, continuous monitoring of Culicolides spp. has been carried out and seasonal dynamics of their appearance in the period 2015-2016 is presented in this article. During October 2015, the presence of Culicolides spp. was confirmed in 10.00% of samples; in November, their presence was not established, whereas in December, 2.35% of samples proved positive for the presence of Culicolides spp. During 2016, from January to March, no Culicolides spp. were found in any of the examined samples. During April, their prevalence was 9.63%, in May - 6.74%, in June - 3.70%, in July - 15.78%, in August - 18.07%, in September - 27.27%, and in October - 45.65%. In Serbia, the dominant Culicoides spp. species are Obsoletus complex and Pulicaris complex established in 57.21% and 33.37% of samples, respectively. Other species are present in lesser extent. In Obsoletus complex, the dominant species was Culicoides obsoletus/scoticus. The percentage of Culicoides obsoletus /scoticus males in samples was 25.52%. Non-pigmented (young) females were present in 66.06% of samples; females who took blood in 7.55% and 0.87% were gravid females. In Pulicaris complex, the dominant species was Culicoides pulicaris. Males of Culicoides pulicaris were found in 19.23% of samples, non-pigmented (young) females in 70.96%, females who took blood in 9.08% while 0.73% were gravid females.Rod Culicoides spp. su mali insekti veličine 0,5-2 mm, većinom sivkaste ili crne boje i na prvi pogled veoma slični komarcima. Oni su striktne hematofage. Ubod je veoma bolan, a mesta uboda su često hipersenzibilisana uz posledično nastajanje alergijskih dermatitisa. Uz to oni prenose mnoštvo oboljenja često zoonotskog karaktera tako da su od izuzetnog epidemiološkog značaja. U našoj zemlji se vrši stalni monitoring Culicolides-a i ovde dajemo prikaz sezonske dinamike njihovog pojavljivanja u periodu 2015-2016.godine. Tokom 2015. godine u oktobru je njihovo prisustvo ustanovljeno u 10.,00% uzoraka, u novembru ih nije bilo, a tokom decembra su bili prisutni u 2,35%. Tokom 2016. godine tokom januara, februara i marta nisu nađeni ni u jednom prispelom uzorku. Tokom aprila meseca njihova prevalencija je iznosila 9,63%, u maju je bila 6,74%, u junu 3,70%, u julu 15,78%, u avgustu 18,07%, u septembru 27,27% i u oktobru 45,65%. U Srbiji su dominantne vrste Culicoides spp. iz Obsoletus kompleksa i ustanovljeni su u 57,21%. Culicoides spp. iz Pulicaris kompleksa ustanovljeni su 33,37% dok su ostale vrste manje zastupljene. Kod Culicoides spp. iz Obsoletus kompleksa dominantna vrsta je bila Culicoides obsoletus/scoticus. Mužjaci su nađeni u 25,52%, nepigmentisane (mlade) ženke u 66,06%, ženke koje su uzele krv u 7,55%, a 0,87% su bile gravidne ženke. Kod Culicoides spp. iz Pulicaris kompleksa dominantna vrsta je bila Culicoides pulicaris. Mužjaci su nađeni u 19,23%, nepigmentisane (mlade) ženke u 70,96%, ženke koje su uzele krv u 9,08%, a 0,73% su bile gravidne ženke

Altered expression of microRNA-30a-3p in papillary thyroid cancer and its association with clinicopathological characteristics

A growing number of studies suggest a tumor suppressive role and potential prognostic significance of miR- 30a-3p in different types of cancer. However, relatively few studies have focused on this microRNA in neoplastic thyroid lesions, including papillary thyroid cancer (PTC). The aim of our study was to shed more light on the potential involvement and clinical relevance of miR-30a-3p in this type of cancer. We examined the expression levels of this microRNA in 42 pairs of PTCs and matched non-tumor thyroid tissues using quantitative RT-PCR. We analyzed their association with clinical and histopathological parameters. The results revealed that miR-30a-3p was significantly downregulated in the majority of PTC tissues compared to corresponding non-tumor tissues. Moreover, decreased expression of miR-30a-3p was associated with advanced clinical stage, presence of multiple tumor foci and capsular invasion, suggesting a role in aggressive disease. Although the role of this microRNA and its prognostic utility remain to be elucidated, the presented data suggest that downregulated expression of miR-30a-3p indicates poorer prognosis in PTC patients, warranting further investigations

Validation of diagnostic and prognostic potential of PINK1, DLGAP5 and BUB1B expression patterns in adrenocortical tumors

Adrenocortical tumors (ACTs) are heterogeneous neoplasms with incompletely understood pathogenesis. Correct differential diagnosis between adrenocortical adenoma (ACA) and localized adrenocortical carcinoma (ACC), as well as improved prognostic stratification of ACC patients, are of great clinical importance. Alterations in gene expression patterns have been found in adrenocortical neoplasms compared to normal tissue. In addition to having a role in tumorigenesis, distinct gene expression signatures may help to distinguish different ACT types. The combined expression patterns of PINK1, DLGAP5 and BUB1B have been suggested as malignancy and outcome predictors in previous studies. In order to validate their diagnostic/prognostic potential, we investigated the expression levels of these three genes and their association with clinico-pathological parameters in a cohort of 47 ACC and 15 ACA patients from Serbia. In addition, we analyzed the association of their expression levels with survival data in an independent ACC cohort of 79 patients from The Cancer Genome Atlas (TCGA) database. The results showed that high expression levels of BUB1B and DLGAP5, and low expression levels of PINK1 significantly associated with ACC. Moreover, combined expression of both DLGAP5 and BUB1B with PINK1 were significantly higher in localized ACC compared with ACA. The results from the TCGA cohort showed that expression alterations of these genes were strong predictors of disease-free and overall survival in ACC patients. These results are consistent with the previously reported results and confirm that the expression patterns of PINK1, DLGAP5 and BUB1B might have value as molecular predictors of malignancy and/or survival in ACC patients.The 21st ENS@T and 1st COST-HARMONIS@TION meeting; September 28-30, Warsaw, Poland, 2022

Synergistic effect of 17-allylamino-17-demethoxygeldanamycin with dehydroxymethylepoxyquinomicin on the human anaplastic thyroid carcinoma cell line KTC2

The use of targeted inhibitors has shown promise as an effective approach in cancer therapy. However, targeted therapies based only on one drug, such as 17-allylamino-17-demethoxygeldanamycin (17-AAG), have limited success, partly because cancer cells engage alternate pathways for survival and proliferation. In the present study, we evaluated whether dehydroxymethylepoxyquinomicin (DHMEQ), a nuclear factor ?B (NF-?B) inhibitor, can enhance the antitumor activities of 17-AAG, a 90 kDa heat shock protein (Hsp90) inhibitor, in the anaplastic thyroid cancer cell line KTC2. We examined the effect of combined drug treatment vs single drug treatment on cell survival. Isobologram analysis was performed to distinguish the additive vs synergistic effects of the drug combination. Western blotting was performed to investigate apoptosis markers: caspase 3, poly(ADP-ribose) polymerase-one (PARP-1), B-cell lymphoma-extra large (Bcl-XL), X-linked inhibitor of apoptosis (XIAP) and cellular inhibitor of apoptosis 2 (cIAP-2). Compared to monotherapy, the combined treatment enhanced growth-inhibitory effects in a synergistic manner and strongly potentiated apoptosis. These results demonstrate the first in vitro evidence that a combination of Hsp90 and NF-?B inhibitors is a more effective modality for inhibiting cell proliferation and survival in anaplastic thyroid carcinoma cells than either agent alone, warranting further investigations

Methylation status of p16INK4a tumor-suppressor gene in adrenocortical carcinoma: preliminary study

Adrenocortical carcinoma (ACC) is a rare cancer with poor prognosis. Identifying novel molecular parameters with prognostic value is of great clinical importance for a personalized therapeutic approach. Epigenetic changes have been proven to play an important role in cancer pathogenesis. Hypermethylation of the promoter region of p16INK4a gene has been shown to be a significant event in a number of cancer types. Several studies suggested that it might have a prognostic impact in ACC as well, however the data are relatively ambiguous. According to the dataset from The Cancer Genome Atlas (TCGA) database, in cohort of 79 ACC patients, the analysis of the p16INK4a gene methylation showed that higher methylation was associated with shorter progression-free and overall survival. We evaluate the methylation status of p16INK4a in a preliminary cohort of 30 ACC patients by using the methylation-specific polymerase chain reaction (MSP) and aberrant methylation of p16INK4a was present in 66.7% (20/30) of cases. Our results indicate that epigenetic alteration of this gene is common event in ACC and may be important for pathogenesis of this tumor type. Although, we did not observed significant association between p16INK4a methylation status and clinico-pathological characteristics (age and gender, tumor size and weight, regional lymph node and distant metastasis), we will evaluate methylation status of this gene in another 30 ACC cases and compare it with methylation profile of adrenocortical adenoma patients, since inactivation of p16INK4a gene by promoter hypermethylation has been frequently reported as an early event in premalignant lesions in many tumor types.The 21st ENS@T and 1st COST-HARMONIS@TION meeting; September 28-30, Warsaw, Poland, 2022