Characteristics of health behaviours and health status indicators among pregnant women in Slovenia

Background: Pregnancy is a period when women reconsider their own health and health related behaviour for the sake of their future child. Along with their health providers, they are faced with a number of risk assessments and decisions, which become far more complex as their effect on two organisms rather than one is at play. This paper provides an overview of possible associations between self-reported health status, health behaviours and socio-demographics during pregnancy.Methods: Study data were obtained from the case-control research project “Analysis of folate metabolism biomarkers in the risk assessment for neural tube defects, orofacial clefts and congenital heart defects”, which recruited participants from May 2013 to September 2015. Questionnaires about maternal health, health related behaviour and socio-demographic characteristics were completed by 450 women. The data include pregnancies from the 1980s to 2015.Results: We observed that younger and less educated women more frequently reported positive smoking status during pregnancy, while higher prevalence of folate/multivitamin supplementation was found among more educated, older and nulliparous women. There was a U-shaped distribution of medication intake (over-the-counter and prescribed) with respect to educational level, with the highest intake in mothers with a masters/PhD degree and among those that completed elementary school. Higher medication usage was also reported among older women. With increasing maternal age there was an increase in medication intake, folate/multivitamin intake, as well as incidence of gestational diabetes over the studied time period, with the highest frequencies occurring in later decades. A higher incidence of chronic diseases was observed in a group of multiparous women than among monoparous women.Conclusions: Considerable socio-demographic disparities exist in health-related behaviour among pregnant women. Improved public health campaigns and individual health care counselling are needed to address specific requirements of socio-demographic groups at higher risks of adverse pregnancy outcomes.</p

Radiooznačeni peptidi v nuklearni medicini

Nuklearna medicina pri obravnavi onkoloških bolnikov omogoča slikovni prikaz oziroma lokalizacijo tumorjev, ciljano zdravljenje ter spremljanje uspešnosti zdravljenja. Visoko specifične radiooznačene peptidne učinkovine lahko izkoristimo za ciljanje tumorskih celic, ki imajo na svoji površini prekomerno izražene receptorje za te učinkovine. Enako peptidno učinkovino lahko radiooznačimo tako z diagnostičnimi kot terapevtskimi radionuklidi, kar nam omogoča personaliziran pristop pri obravnavi bolnikov. V preglednem članku opisujemo dva sistema teranostičnih parov, ki jih v nuklearni medicini uporabljamo za diagnosticiranje ter zdravljenje tumorjev. Klasičen primer takšnih teranostičnih parov so radiooznačeni analogi somatostatina, ki se rutinsko uporabljajo v diagnostiki ter zdravljenju nevroendokrinih tumorjev (NET) s prekomerno izraženimi receptorji za somatostatin. Po drugi strani pa so radiooznačeni analogi minigastrina, ki se vežejo na receptorje za holecistokinin-2, primerni za diagnostiko medularnega raka ščitnice (MTC), za njihovo varno zdravljenje pa še potekajo klinična preskušanja

Design and synthesis of amino-substituted N-arylpiperidinyl-based inhibitors of the (immuno)proteasome

The constitutive proteasome and the immunoproteasome represent validated targets for pharmacological intervention in the context of various diseases, such as cancer, inflammation, and autoimmune diseases. The development of novel chemical scaffolds of non-peptidic nature, capable of inhibiting different catalytically active subunits of both isoforms, is a viable approach against these diseases. Such compounds are also useful as leads for the development of biochemical probes that enable the studies of the roles of both isoforms in various biological contexts. Here, we present a ligand-based computational design of (immuno)proteasome inhibitors, which resulted in the amino-substituted N-arylpiperidine-based compounds that can inhibit different subunits of the (immuno)proteasome in the low micromolar range. The compounds represent a useful starting point for further structure-activity relationship studies that will, hopefully, lead to non-peptidic compounds that could be used in pharmacological and biochemical studies of both proteasomes

Harnessing the untapped potential of nucleotide‐binding oligomerization domain ligands for cancer immunotherapy

In the last decade, cancer immunotherapy has emerged as an effective alternative to traditional therapies such as chemotherapy and radiation. In contrast to the latter, cancer immunotherapy has the potential to distinguish between cancer and healthy cells, and thus to avoid severe and intolerable side-effects, since the cancer cells are effectively eliminated by stimulated immune cells. The cytosolic nucleotide binding oligomerization domains 1 and 2 receptors (NOD1 and NOD2) are important components of the innate immune system and constitute interesting targets in terms of strengthening the immune response against cancer cells. Many NOD ligands have been synthesized, in particular NOD2 agonists that exhibit favorable immunostimulatory and anticancer activity. Among them, mifamurtide has already been approved in Europe by the European Medicine Agency for treating patients with osteosarcoma in combination with chemotherapy after complete surgical removal of the primary tumor. This review is focused on NOD receptors as promising targets in cancer immunotherapy as well as summarizing current knowledge of the various NOD ligands exhibiting antitumor and even antimetastatic activity in vitro and in vivo

Simultaneous quantification of intracellular concentrations of clinically important metabolites of folate-homocysteine cycle by LC-MS/MS

Inadequate folate status is detrimental to human development. Deficiency has been implicated in congenital birth defects and cancer, whereas excess has been linked to various negative neurocognitive development outcomes. We developed a method for translational studies involving lymphoblastoid cell models for studying role of folates in vital cell processes. We describe a simple, sensitive, and fast liquid chromatography–tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of intracellular concentrations of clinically important metabolites of folate-homocysteine cyclenamely, folic acid (FA), 5-methyltetrahydrofolate (5-Me-THF), and homocysteine (Hcy). The method was validated for specificity, linearity, limits of quantification, repeatability, reproducibility, matrix effects, and stability. Method had a wide linear range between 0.341 and 71.053 ng Hcy/mg protein for Hcy, 0.004–0.526 ng FA/mg protein for FA and 0.003–0.526 ng 5-Me-THF/mg protein for 5-Me-THF. The method overcomes challenges associated with the quantification of endogenous molecules, poor stability, and extremely small amounts of the analytes. The method was successfully applied to evaluate the effects of FA and 5-Me-THF treatment of cells in vitro mimicking supplement therapy with various metabolically active species, and showed that 5-Me-THF is more effective than FA in increasing intracellular levels of the biologically active form of folate

The enhanced cytotoxic effects in B-cell leukemia and lymphoma following activation of prostaglandin EP4 receptor and targeting of CD20 antigen by monoclonal antibodies

Anti-CD20 monoclonal antibodies (MAbs) have revolutionized the treatment of B-cell leukemia and lymphoma. However, many patients do not respond to such treatment due to either deficiency of the complementary immune response or resistance to apoptosis. Other currently available treatments are often inadequate or induce major side effects. Therefore, there is a constant need for improved therapies. The prostaglandin E2 receptor 4 (EP4) receptor has been identified as a promising therapeutic target for hematologic B-cell malignancies. Herein, we report that EP4 receptor agonists PgE1-OH and L-902688 have exhibited enhanced cytotoxicity when applied together with anti-CD20 MAbs rituximab, ofatumumab and obinutuzumab in vitro in Burkitt lymphoma cells Ramos, as well as in p53-deficient chronic lymphocytic leukemia (CLL) cells MEC-1. Moreover, the enhanced cytotoxic effects of EP4 receptor agonists and MAbs targeting CD20 have been identified ex vivo on primary lymphocytes B obtained from patients diagnosed with CLL. Incubation of cells with PgE1-OH and L-902688 preserved the expression of CD20 molecules, further confirming the anti-leukemic potential of EP4 receptor agonists in combination with anti-CD20 MAbs. Additionally, we demonstrated that the EP4 receptor agonist PgE-1-OH induced apoptosis and inhibited proliferation via the EP4 receptor triggering in CLL. This work has revealed very important findings leading towards the elucidation of the anticancer potential of PgE1-OH and L-902688, either alone or in combination with MAbs. This may contribute to the development of potential therapeutic alternatives for patients with B-cell malignancies

A Putative Serine Protease is Required to Initiate the RIPK3-MLKL-Mediated Necroptotic Death Pathway in Neutrophils.

Adhesion receptors, such as CD44, have been shown to activate receptor interacting protein kinase-3 (RIPK3)-mixed lineage kinase-like (MLKL) signaling, leading to a non-apoptotic cell death in human granulocyte/macrophage colony-stimulating factor (GM-CSF) - primed neutrophils. The signaling events of this necroptotic pathway, however, remain to be investigated. In the present study, we report the design, synthesis, and characterization of a series of novel serine protease inhibitors. Two of these inhibitors, compounds 1 and 3, were able to block CD44-triggered necroptosis in GM-CSF-primed neutrophils. Both inhibitors prevented the activation of MLKL, p38 mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3'-kinase (PI3K), hence blocking the increased levels of reactive oxygen species (ROS) required for cell death. Although compounds one and three partially inhibited isolated human neutrophil elastase (HNE) activity, we obtained no pharmacological evidence that HNE is involved in the initiation of this death pathway within a cellular context. Interestingly, neither serine protease inhibitor had any effect on FAS receptor-mediated apoptosis. Taken together, these results suggest that a serine protease is involved in non-apoptotic CD44-triggered RIPK3-MLKL-dependent neutrophil cell death, but not FAS receptor-mediated caspase-dependent apoptosis. Thus, a pharmacological block on serine proteases might be beneficial for preventing exacerbation of disease in neutrophilic inflammatory responses