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•Ovarian cancer; the highest mortality rate among all gynecologic cancers.•Platinum-resistant ovarian cancer is invariably a fatal disease.•Currently no validated molecular predictive ...biomarkers for platinum resistance.•Enhanced expressions of ATP7A/7B; poor outcome in platinum-based chemotherapy.•ATP7A/7B; warrant further evaluation as predictive markers of platinum resistance.
Ovarian cancer has the highest mortality rate among all gynecologic cancers, with most patients presenting with advanced stage tumors. About a third of patients do not respond to primary platinum-based chemotherapy treatment, and over time up to 80 % of others develop chemoresistance, rendering recurrent disease incurable. Moreover, according to latest EMSO-ESGO (European Society for Medical Oncology – European Society for Gynecological Oncology) consensus conference manuscript on ovarian cancer, there are currently no validated molecular predictive biomarkers for platinum resistance. Recent studies suggest that the copper efflux transporters ATP7A and ATP7B play an important role in platinum resistance. In addition, by exploring their role in mediating resistance, new pathways of platinum resistance emerge, such as lysosomal storage disorders, which might be explored in the future as a new target to circumvent platinum resistance. This review outlines a challenging clinical hurdle in ovarian cancer therapy due to platinum resistance, links between the essential trace element copper and cytotoxic platinum-based medicines, and enigmatic mechanisms of ATP7A and ATP7B mediating platinum resistance. It then presents clinical studies showing a significant association of ATP7A and ATP7B with response to cisplatin/carboplatin and prognosis. Based on the results of in vitro assays, disease-relevant animal models, and clinical studies to date, it may be concluded that APT7A and ATP7B deserve further development as predictive markers of platinum resistance in ovarian cancer. Both transporters could play a particularly important role in early estimation of therapy response to identify platinum-resistant tumors and to adjust the treatment of ovarian cancer patients accordingly.
Platinum-resistant high-grade serous carcinoma (HGSC) is an incurable disease, so biomarkers that could help with timely treatment adjustments and personalized approach are extensively being sought. ...Tumor-derived extracellular vesicles (EVs) that can be isolated from ascites and blood of HGSC patients are such promising biomarkers. Epithelial cell adhesion molecule (EpCAM) expression is upregulated in most epithelium-derived tumors; however, studies on prognostic value of EpCAM overexpression in ovarian carcinoma have shown contradictory results. The aim of our study was to evaluate the potential of total and EpCAM-positive EVs as prognostic and predictive biomarkers for advanced HGSC. Flow cytometry was used to determine the concentration of total and EpCAM-positive EVs in paired pretreatment ascites and plasma samples of 37 patients with advanced HGSC who underwent different first-line therapy. We found that higher EpCAM-positive EVs concentration in ascites is associated with shorter progression-free survival (PFS) regardless of treatment strategy. We also found a strong correlation of EpCAM-positive EVs concentration between ascites and plasma. Our findings indicate that EpCAM-positive EVs in ascites of patients with advanced HGSC have the potential to serve as prognostic biomarkers for predicting early recurrence and thereby likelihood of more aggressive tumor biology and development of chemoresistance.
L. contains more than 100 phytocannabinoids that can interact with cannabinoid receptors CB
and CB
. None of the cannabinoid receptor ligands is entirely CB
- or CB
-specific. The effects of ...cannabinoids therefore differ not just because of different potency at cannabinoid receptors but also because they can interact with other non-CB
and non-CB
targets, such as TRPV1, GPR55, and GPR119. The most studied phytocannabinoid is Δ
-tetrahydrocannabinol (THC). THC is a partial agonist at both cannabinoid receptors, but its psychotomimetic effect is produced primarily via activation of the CB
receptor, which is strongly expressed in the central nervous system, with the noteworthy exception of the brain stem. Although acute cognitive and other effects of THC are well known, the risk of irreversible neuropsychological effects of THC needs further research to elucidate the association. Unlike THC, phytocannabinoid cannabidiol (CBD) does not appear to have psychotomimetic effects but may interact with some of the effects of THC if taken concomitantly. CBD administered orally has recently undergone well-controlled clinical trials to assess its safety in the treatment of paediatric epilepsy syndromes. Their findings point to increased transaminase levels as a safety issue that calls for postmarketing surveillance for liver toxicity. The aim of this review is to summarise what is known about acute and chronic toxicological effects of both compounds and address the gaps in knowledge about the safety of exogenous cannabinoids that are still open.
The retrofitting of cultural heritage buildings for energy efficiency often requires the internal thermal insulation of external walls. Most of the in situ studies of capillary active interior ...insulation were performed in mild oceanic climate regions, and they showed an excellent performance. However, as a large part of Central–Eastern Europe belongs to a continental climate with cold winters and long periods of temperatures below the freezing temperature, the applicability of the capillary active interior insulation in cold climate was studied. The hydrothermal behaviour of the three walls was determined—each consists of one of three different interior insulations—and the original wall is made of historic regular solid bricks. Two interior thermal insulations were capillary active (aerated cellular concrete, calcium silicate) and one vapour-tight (glass foam). A hot box–cold box experiment and a steady-state model were used to demonstrate an increase in the original wall mass due to the water condensation only when the capillary active interior insulation is used. The combination of the water condensation and the low sub-zero temperature may lead to a risk of freeze–thaw damage to the original wall. The numerical simulation of the water vapour condensation for the considered walls for the Slovenian town Bled with sub-zero average winter temperatures was performed to obtain the whole temperature and moisture profile. It showed good agreement between an experimentally and numerically obtained amount of water condensation. The capillary active interior insulation proved to be unsuitable for improving the thermal insulation of buildings in cold continental climate, and only a vapour-tight system can be recommended.
In parallel to medical treatment of ovarian cancer, methods for the early detection of cancer tumors are being sought. In this contribution, the use of non-invasive static (SLS) and dynamic light ...scattering (DLS) for the characterization of extracellular nanoparticles (ENPs) in body fluids of advanced serous ovarian cancer (OC) and benign gynecological pathology (BP) patients is demonstrated and critically evaluated. Samples of plasma and ascites (OC patients) or plasma, peritoneal fluid, and peritoneal washing (BP patients) were analyzed. The hydrodynamic radius (
) and the radius of gyration (
) of ENPs were calculated from the angular dependency of LS intensity for two ENP subpopulations.
and
of the predominant ENP population of OC patients were in the range 20-30 nm (diameter 40-60 nm). In thawed samples, larger particles (
mostly above 100 nm) were detected as well. The shape parameter ρ of both particle populations was around 1, which is typical for spherical particles with mass concentrated on the rim, as in vesicles. The
and
of ENPs in BP patients were larger than in OC patients, with ρ ≈ 1.1-2, implying a more elongated/distorted shape. These results show that SLS and DLS are promising methods for the analysis of morphological features of ENPs and have the potential to discriminate between OC and BP patients. However, further development of the methodology is required.
Despite advances in surgical techniques and chemotherapy, ovarian cancer is still a leading cause of death among gynecological cancers. In addition to the late detection of the disease, the main ...reason for poor prognosis is resistance to pharmacotherapy, mostly platinum compounds. About a third of patients do not respond to primary platinum-based chemotherapy treatment, and over time, eventually, 80% of other patients develop chemoresistance, which makes the recurrence of disease incurable. In this review, we describe a difficult clinical hurdle faced in ovarian cancer therapy as a result of platinum resistance, as well as resistance to newer targeted therapy with PARP inhibitors and bevacizumab. We, furthermore, give attention also to the role of the tumor microenvironment as it is less well understood than the tumor cell-intrinsic mechanism. Because a central goal in ovarian cancer research is the development of novel strategies to overcome chemoresistance, treatment for cancer is moving toward personalized therapy.
Platinum-resistant high-grade serous ovarian cancer (HGSOC) is invariably a fatal disease. A central goal of ovarian cancer research is therefore to develop new strategies to overcome platinum ...resistance. Treatment is thus moving towards personalized therapy. However, validated molecular biomarkers that predict patients' risk of developing platinum resistance are still lacking. Extracellular vesicles (EVs) are promising candidate biomarkers. EpCAM-specific EVs are largely unexplored biomarkers for predicting chemoresistance. Using transmission electron microscopy, nanoparticle tracking analysis and flow cytometry, we compared the characteristics of EVs released from a cell line derived from a clinically confirmed cisplatin-resistant patient (OAW28) and EVs released from two cell lines from tumors sensitive to platinum-based chemotherapy (PEO1 and OAW42). We demonstrated that EVs released from the HGSOC cell line of chemoresistant patients exhibited greater size heterogeneity, a larger proportion of medium/large (>200 nm) Evs and a higher number of released EpCAM-positive EVs of different sizes, although the expression of EpCAM was predominant in EVs larger than 400 nm. We also found a strong positive correlation between the concentration of EpCAM-positive EVs and the expression of cellular EpCAM. These results may contribute to the prediction of platinum resistance in the future, although they should first be validated in clinical samples.
Alzheimerjeva bolezen je kronična progresivna nevrodegenerativna bolezen, za katero oboleva vse večje število ljudi po vsem svetu. Je najpogostejši vzrok za demenco (pri 50–80 % vseh primerov) in ...obenem tudi najhujša oblika demence, za katero so značilne kognitivne in vedenjske motnje pri ljudeh, večinoma starejših od 65 let. Patogeneza bolezni še ni popolnoma pojasnjena. Obstaja več hipotez, ki vključujejo kombinacijo genetskih in okoljskih dejavnikov ter načina življenja. Glede na začetek bolezni lahko bolezen opredelimo kot obliko z zgodnjim začetkom, običajno pred 65. letom starosti, in obliko s poznim začetkom, običajno po 65. letu starosti. Redka oblika bolezni z zgodnjim začetkom je povezana z mutacijami v genu za amiloidni prekurzorski protein ter v genih za presenilin 1 in 2. Genetski dejavnik tveganja za nastanek bolezni s poznim začetkom je prisotnost alela ε4 za apolipoprotein E. Za nastanek oblike s poznim začetkom obstaja več vzročnih hipotez: a) holinergična hipoteza, b) amiloidna hipoteza, c) hipoteza o hiperfosforilaciji proteina tau, č) hipoteza o mitohondrijski kaskadi, d) vnetna hipoteza, e) nevro-vaskularna hipoteza, f) hipoteza o kovinskih ionih ter g) hipoteza limfnega sistema. Poleg tega obstajajo tudi presnovni in drugi dejavniki tveganja za nastanek Alzheimerjeve bolezni, med katere sodijo: zvišana raven holesterola v krvi, debelost, zvišan krvni tlak, sladkorna bolezen tipa 2, motnje spanja idr. Kljub velikemu številu raziskav etiopatogeneza do danes še ni dokončno pojasnjena, prav tako ne poznamo zdravila, ki bi preprečilo nastanek bolezni ali ustavilo njeno napredovanje. Zdravljenje Alzheimerjeve bolezni trenutno temelji na farmakološkem zdravljenju, ki poteka na osnovi doslej znane etiologije bolezni. Veliko obeta tudi imunoterapija z antiamiloidnimi protitelesi.
Abstract Cannabis sativa L. contains more than 100 phytocannabinoids that can interact with cannabinoid receptors CB 1 and CB 2 . None of the cannabinoid receptor ligands is entirely CB 1 - or CB 2 ...-specific. The effects of cannabinoids therefore differ not just because of different potency at cannabinoid receptors but also because they can interact with other non-CB 1 and non-CB 2 targets, such as TRPV1, GPR55, and GPR119. The most studied phytocannabinoid is Δ 9 -tetrahydrocannabinol (THC). THC is a partial agonist at both cannabinoid receptors, but its psychotomimetic effect is produced primarily via activation of the CB 1 receptor, which is strongly expressed in the central nervous system, with the noteworthy exception of the brain stem. Although acute cognitive and other effects of THC are well known, the risk of irreversible neuropsychological effects of THC needs further research to elucidate the association. Unlike THC, phytocannabinoid cannabidiol (CBD) does not appear to have psychotomimetic effects but may interact with some of the effects of THC if taken concomitantly. CBD administered orally has recently undergone well-controlled clinical trials to assess its safety in the treatment of paediatric epilepsy syndromes. Their findings point to increased transaminase levels as a safety issue that calls for postmarketing surveillance for liver toxicity. The aim of this review is to summarise what is known about acute and chronic toxicological effects of both compounds and address the gaps in knowledge about the safety of exogenous cannabinoids that are still open.
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