Pt(II)-PLGA Hybrid in a pH-Responsive Nanoparticle System Targeting Ovarian Cancer.

Platinum-based agents are the main treatment option in ovarian cancer (OC). Herein, we report a poly(lactic-co-glycolic acid) (PLGA) nanoparticle (NP) encapsulating platinum (II), which is targeted to a cell-spanning protein overexpressed in above 90% of late-stage OC, mucin 1 (MUC1). The NP is coated with phospholipid-DNA aptamers against MUC1 and a pH-sensitive PEG derivative containing an acid-labile hydrazone linkage. The pH-sensitive PEG serves as an off-on switch that provides shielding effects at the physiological pH and is shed at lower pH, thus exposing the MUC1 ligands. The pH-MUC1-Pt NPs are stable in the serum and display pH-dependent PEG cleavage and drug release. Moreover, the NPs effectively internalize in OC cells with higher accumulation at lower pH. The Pt (II) loading into the NP was accomplished via PLGA-Pt (II) coordination chemistry and was found to be 1.62 wt.%. In vitro screening using a panel of OC cell lines revealed that pH-MUC1-Pt NP has a greater effect in reducing cellular viability than carboplatin, a clinically relevant drug analogue. Biodistribution studies have demonstrated NP accumulation at tumor sites with effective Pt (II) delivery. Together, these results demonstrate a potential for pH-MUC1-Pt NP for the enhanced Pt (II) therapy of OC and other solid tumors currently treated with platinum agents.

Accidental Morcellation of Uterine Leiomyosarcoma Influences Relapse Free Survival but Does Not Negatively Influence Overall Survival.

Background: Uterine leiomyosarcoma (LMS) is a rare entity amongst malignant gynaecological tumours and is mostly diagnosed after surgery for benign leiomyoma (LM) of the uterus. As minimal invasive surgery is widely used, the morcellation of LM and the uterus is rather common. As there is little known about the impact of the morcellation of LMS on local and distant metastases, as well as overall survival, we carried out a large-scale retrospective study. Methods: A total of 301 LMS cases from the German Clinical Competence Centre for Genital Sarcomas and Mixed Tumours were analysed. We distinguished morcellated and non-morcellated LMS from pT1 and >pT1 tumours. Fine−Gray competing risks regressions and cumulative incidence rates were computed for the time to local recurrence, distant metastases, and patient death. Results: The recurrence free interval in pT1 LMS was significantly lower in the morcellation group with a 2-year cumulative incidence rate of 49% vs. 26% in non-morcellated LMS (p = 0.001). No differences were seen in >pT1 tumours. Distant metastases were more frequently found in non-morcellated pT1 LMS compared to the morcellated cases (5-year cumulative incidence: 54% vs. 29%, p < 0.001). There was no significant difference in time to death between both groups neither in the pT1 stages nor in >pT1 disease. Subdistribution hazard ratios estimated by multivariable competing risks regressions for the morcellation of pT1 LMS were 2.11 for local recurrence (95% CI 1.41−3.16, p < 0.001) and 0.52 for distant metastases (95% CI 0.32−0.84, p = 0.008). Conclusions: Tumour morcellation is not associated with OS for pT1 tumours. The morcellation of pT1 LMS seems to prolong the time to distant metastases whereas local recurrence is more likely to occur after the morcellation of pT1 LMS.

Ticagrelor effectively inhibits platelet aggregation in comatose survivors of cardiac arrest undergoing primary percutaneous coronary intervention treated with mild therapeutic hypothermia.

BACKGROUND: Mild therapeutic hypothermia (MTH) is believed to reduce the effectiveness of antiplatelet drugs. Effective dual-antiplatelet therapy after percutaneous coronary intervention (PCI) is mandatory to avoid acute stent thrombosis. The effectiveness of ticagrelor in MTH-treated out-of-hospital cardiac arrest (OHCA) survivors is still a matter of debate. The aim of the study was to evaluate the impact of MTH on the platelet-inhibitory effect of ticagrelor in comatose survivors of OHCA treated with primary PCI. METHODS: Eighteen comatose survivors of OHCA with acute coronary syndrome undergoing immediate PCI treated with MTH were compared with 14 patients with uncomplicated primary myocardial infarction after PCI, matched for gender and age, in a prospective, single-center, observational study. Platelet aggregation was evaluated using VerifyNow P2Y12 point-of-care testing at 3 time points: admission (T0), during MTH (T1), and 48-72 h after rewarming (T2). RESULTS: Ticagrelor effectively inhibits platelet aggregation in OHCA patients subjected to MTH and in all patients in the control group. The effectiveness of ticagrelor did not differ between the MTH group and the control group (p = 0.581). In 2 cases in the MTH population, the platelet response to ticagrelor was inadequate, and in one of them it remained insufficient during the re-warming phase. There was no stent thrombosis in these patients. CONCLUSIONS: The present study confirmed the effectiveness of ticagrelor to inhibit platelets in myocardial infarction patients after OHCA treated with primary PCI undergoing hypothermia. The use of cooling was not associated with an increased risk of stent thrombosis.

Engineering and Validation of a Peptide-Stabilized Poly(lactic-co-glycolic) Acid Nanoparticle for Targeted Delivery of a Vascular Disruptive Agent in Cancer Therapy.

Developing a biocompatible and biodegradable nanoparticle (NP) carrier that integrates drug-loading capability, active targeting, and imaging modality is extremely challenging. Herein, we report an NP with a core of poly(lactic-co-glycolic) acid (PLGA) chemically modified with the drug combretastatin A4 (CA4), a vascular disrupting agent (VDA) in clinical development for ovarian cancer (OvCA) therapy. The NP is stabilized with a short arginine-glycine-aspartic acid-phenylalanine x3 (RGDFFF) peptide via self-assembly of the peptide on the PLGA surface. Importantly, the use of our RGDFFF coating replaces the commonly used polyethylene glycol (PEG) polymer that itself often induces an unwanted immunogenic response. In addition, the RGD motif of the peptide is well-known to preferentially bind to αvß3 integrin that is implicated in tumor angiogenesis and is exploited as the NP's targeting component. The NP is enhanced with an optical imaging fluorophore label via chemical modification of the PLGA. The RGDFFF-CA4 NPs are synthesized using a nanoprecipitation method and are ∼75 ± 3.7 nm in diameter, where a peptide coating comprises a 2-3 nm outer layer. The NPs are serum stable for 72 h. In vitro studies using human umbilical cord vascular endothelial cells (HUVEC) confirmed the high uptake and biological activity of the RGDFFF-CA4 NP. NP uptake and viability reduction were demonstrated in OvCA cells grown in culture, and the NPs efficiently accumulated in tumors in a preclinical OvCA mouse model. The RGDFFF NP did not induce an inflammatory response when cultured with immune cells. Finally, the NP was efficiently taken up by patient-derived OvCA cells, suggesting a potential for future clinical applications.

Sutureless technique for repositioning and scleral fixation of the capsular bag-intraocular lens complex with permanent use of iris retractors.

A new sutureless technique used for repositioning and scleral fixation of the capsular bag-intraocular lens (IOL) complex in the surgical treatment of subluxated lenses is described. Iris retractors were used not only to induce a tent effect on the capsule but also to permanently fix the capsular bag to the sclera in this method, without the need to prepare scleral or conjunctival flaps. Surgery with the use of a capsular tension ring (CTR) and iris retractors, the ends of which were brought out through the sclera and cauterized, was performed in 7 eyes of 7 patients with moderate or severe subluxation of the crystalline lens. In all cases, simultaneous use of a CTR and iris retractors ensured good centration of the capsular bag-IOL complex. The method was safe and effective in fixing the capsule to the sclera in the case of significant damage to the ligamentous apparatus of the lens.

Optical Spectra of Oligofurans: A Theoretical Approach to the Transition Energies, Reorganization Energies, and the Vibronic Activity.

There is experimental evidence of high vibronic activity that accompanies the allowed transition between the ground state and the lowest electronic singlet excited state of oligofurans that contain two, three, and four furan rings. The absorption and emission spectra of the three lowest oligofurans measured at liquid nitrogen temperature show distinct fine structures that are reproduced using the projection-based model of vibronic coupling (with Dushinsky rotation included) parameterized utilizing either Density Functional Theory (DFT, with several different exchange-correlation functionals) or ab initio (CC2) quantum chemistry calculations. Using as a reference the experimental data concerning the electronic absorption and fluorescence for the eight lowest oligofurans, we first analyzed the performance of the exchange-correlation functionals for the electronic transition energies and the reorganization energies. Subsequently, we used the best functionals alongside with the CC2 method to explore how the reorganization energies are distributed among the totally symmetric vibrations, identify the normal modes that dominate in the fine structures present in the absorption and emission bands, and trace their evolution with the increasing number of rings in the oligofuran series. Confrontation of the simulated spectra with the experiment allows for the verification of the performance of the selected DFT functionals and the CC2 method.

False recognitions in short-term memory - Age-differences in neural activity.

While the knowledge on age-related differences in susceptibility to episodic false memories is extensive, little is known about this phenomenon in visual short-term memory (STM). Our previous behavioural research indicated that older adults are more confident of their erroneous STM recognitions than young adults. However, unlike in episodic memory, we did not find support for older adults' higher rate of false alarms. To further understand this specific age-difference, here we investigated its neural correlates. First, the pattern of behavioural results replicated the one from our previous experiment. Second, younger adults, when compared to older adults, exhibited higher false recognition-related activity of the visual cortex, the anterior cingulate cortex, the frontal operculum/insular cortex as well as regions within the anterior and dorsolateral prefrontal cortex. No age-differences were observed in hippocampal activity. Third, younger but not older adults presented higher activity in the anterior cingulate cortex and the frontal operculum/insular cortex for false recognitions when compared to highly confident correct rejections. Finally, frontal activity was influenced by both the individuals' performance and their metacognitive abilities. The results suggest that age-related differences in confidence of STM false recognitions may arise from age-differences in performance monitoring and uncertainty processing rather than in hippocampal-mediated binding.

MR spectroscopy differences between lipomatosis of nerve and neuromuscular choristoma: a potential adjunctive diagnostic tool.

OBJECTIVE: To describe differences between lipomatosis of nerve (LN) and neuromuscular choristoma (NMC) evaluated with MR spectroscopy (MRS). MATERIALS AND METHODS: Eight patients were included in this prospective pilot study: three patients with LNs and five with NMCs. Single voxel PRESS MRS of the tumors were acquired with 3 T MRI. MRS data were processed with LCModel version 6.3-1J using the internal "lipid-8" basis set. From individual lipid peak and water content measurements, total fatty acid molecules (TFAM), unsaturated fatty acid molecules (UFAM), and glycerol molecules (GM) were computed and analyzed, as well as ratios of UFAM/TFAM, TFAM/GM, and a fatty-acid chain-length index (CLI). RESULTS: The LN group included two men and one woman (average age 58.3 years); the NMC group included two men and three women (average age 20.4 years). Lipid composition analysis showed that LN had considerably more fat than NMC: TFAM: LN = 15.29 vs NMC = 7.14; UFAM: LN = 4.48 vs NMC = 2.63; GM: LN = 5.20 vs NMC = 1.02. Both tumors had a similar fraction of unsaturated fatty acids: UFAM/TFAM: LN = 0.29 vs NMC = 0.37. LN had the usual number of FA molecules/glycerol molecule, while NMC had considerably more: TFAM/GM: LN = 2.94 vs NMC = 6.98. Finally, average FA chains were longer in NMC: CLI: LN = 17.39 vs NMC = 22.55. CONCLUSION: Our analysis suggests measurable differences in the amount and composition of lipid in LN and NMC. While a larger, statistically powered study is needed, these initial findings may be helpful to properly diagnose ambiguous cases and thereby avoid surgical intervention such as biopsy.

Determination of In Vitro Membrane Permeability by Analysis of Intracellular and Extracellular Fluorescein Signals in Renal Cells.

BACKGROUND/AIM: The structural integrity of the eukaryotic cytoplasmic membrane is of crucial importance for its cell biological function and thus for the survival of the cell. Physical and chemical noxae can interact in various ways with components of the cytoplasmic membrane, influence its permeability and thus mediate toxic effects. In the study presented, changes in membrane permeability were quantified by intracellular accumulation of a fluorescent dye and by the release of the fluorescent dye from dye-loaded cells. MATERIALS AND METHODS: Non-malignant (RC-124) and malignant (786-O, Caki-1) renal cells were permeabilized with different concentrations of Triton X-100. The permeability of the membrane was determined at the single-cell level by the uptake of the dye into the cell inner by flow cytometry. In addition, a fluorescence plate reader was used to detect and quantify the release of the dye into the cell culture supernatant. RESULTS: Both malignant and non-malignant cells showed a dose-dependent alteration of membrane permeability after treatment with Triton X-100. In the presence of the fluorescent dye, significantly more dye was introduced into the permeabilized cells compared to control incubations. Vice versa, Triton X-100-treated and dye-loaded cells released significantly more dye into the cell culture supernatant. CONCLUSION: The combination of measurement of intracellular accumulated and extracellular released dye can quantifiably detect changes in membrane permeability due to cell-membrane damage. The combination of two different measurement methods offers additional value in reliable detection of membrane-damaging, potentially toxic influences.

A Tripeptide-Stabilized Nanoemulsion of Oleic Acid.

We describe a method to produce a nanoemulsion composed of an oleic acids-Pt(II) core and a lysine-tyrosine-phenylalanine (KYF) coating (KYF-Pt-NE). The KYF-Pt-NE encapsulates Pt(II) at 10 wt. %, has a diameter of 107 ± 27 nm and a negative surface charge. The KYF-Pt-NE is stable in water and in serum, and is biologically active. The conjugation of a fluorophore to KYF allows the synthesis of a fluorescent nanoemulsion that is suitable for biological imaging. The synthesis of the nanoemulsion is performed in an aqueous environment, and the KYF-Pt-NE forms via self-assembly of a short KYF peptide and an oleic acids-platinum(II) conjugate. The self-assembly process depends on the temperature of the solution, the molar ratio of the substrates, and the flow rate of the substrate addition. Crucial steps include maintaining the optimal stirring rate during the synthesis, permitting sufficient time for self-assembly, and pre-concentrating the nanoemulsion gradually in a centrifugal concentrator.

Increased risk profile in the treatment of patients with symptomatic degenerative aortic valve stenosis over the last 10 years.

INTRODUCTION: Currently, Cardiology Centres are overfilled with patients with degenerative aortic valve stenosis (DAS), usually eldery, with severe concommittant comorbidities, who are referred for further decisions and possible intervention. AIM: To evaluate changes in the risk profile of patients with severe DAS admitted to the cardiology department a decade ago compared with patients currently being admitted. MATERIAL AND METHODS: We retrospectively evaluated all patients admitted with confirmed severe DAS, hospitalized during 2005-2006 (group I: 140 patients) and in 2016 (group II: 152 patients), admitted for aortic valve intervention. A standard transthoracic echocardiogram, cardiovascular symptom and risk factor distribution, perioperative risk with the logistic EuroSCORE II and STS mortality scores were obtained. RESULTS: Patients in group II were significantly older (p < 0.001), had more cardiovascular risk factors, and more often presented with atrial fibrillation (27% vs. 11.4%, p = 0.001), renal impairment (34.9% vs. 22.8%; p = 0.024), severe lung disease (17.1% vs. 2.1%, p < 0.001), and extracardiac arteriopathy (40.1% vs. 17.8%, p < 0.001). The aortic valve area (AVA) (p = 0.356), mean-transvalvular pressure gradient (p = 0.215), and left ventricular ejection fraction (p = 0.768) were similar in both groups. However, the prevalence of pulmonary hypertension, severe mitral regurgitation, and low-flow, low-gradient DAS were 3.1-, 8.4- and 1.84-fold more frequent in group II than group I. The percentages of subjects with EuroSCORE II and STS scores ≥ 4% in 2005-2006 were 7.1% and 6.4%, as compared to 27% and 26.3% in 2016 (both p < 0.001). 22% of patients in 2016, as compared to 31% in 2005/2006, were considered ineligible for DAS intervention. CONCLUSIONS: In just a decade, the risk profile of patients admitted with DAS has increased hugely, mainly due to older age, accumulation of comorbidities and more advanced disease at presentation. Although transcatheter aortic valve intervention has expanded the indications for intervention in high-risk patients, the number of patients disqualified from interventional treatment remains high.

Tripeptide-Stabilized Oil-in-Water Nanoemulsion of an Oleic Acids-Platinum(II) Conjugate as an Anticancer Nanomedicine.

We report a nanoemulsion (NE) which is stabilized by self-assembling tripeptide lysine-tyrosine-phenylalanine (KYF) and encapsulates an oleic acids-platinum conjugate formed using simple Pt (II) coordination chemistry. The KYF-Pt-NE is evaluated both in cultured ovarian cancer cells and in an in vivo preclinical cancer model and shows pH dependent Pt (II) release, which is low at physiological pH and enhanced at tumoral pH. The biological activity of KYF-Pt-NE, evaluated in multiple ovarian cancer cell lines, is significantly higher when compared to the analogous Pt (II) complex used in the clinic. Concurrently, the KYF-Pt-NE platform shows good compatibility with the immune system. Preliminary in vivo testing of KYF-Pt-NE with tumor bearing mice indicates efficient Pt (II) delivery to the tumor. Together, these results demonstrate the potential of peptide-stabilized nanoemulsions, specifically KYF-Pt-NE as an effective nanomedicine against cancer.

Platinum (II) complex-nuclear localization sequence peptide hybrid for overcoming platinum resistance in cancer therapy.

Platinum therapy represents first line of treatment in many malignancies but its high systemic toxicity limits the therapeutic dosage. Herein, we report the synthesis of carboplatin-like complexes with azide and alkyne functional groups and the formation of a platinum (II) - nuclear localization sequence peptide (Pt-NLS) hybrid to improve the import of platinum (II) complexes directly into the cell's nucleus. The Pt-NLS hybrid successfully enters cells and their nuclei, forming Pt-induced nuclear lesions. The in vitro efficacy of Pt-NLS is high, superior to native carboplatin at the same concentration. The methodology used is simple and cost-effective and most importantly can easily be extended to load the Pt (II) onto other supports, opening new possibilities for enhanced delivery of Pt (II) therapy.

Error-related oscillatory activity is modulated by novelty seeking in the reward condition.

Behavioural research has revealed the influence of motivation conditions on cognitive task performance and demonstrated that these influences are modulated by temperament factors. Modern neuroimaging methods enable analysis of neuropsychological mechanisms through which individual differences in reinforcement sensitivity may influence cognitive functioning. In the study, fifty-six participants were scored on the Cloninger's Temperament and Character Inventory to assess punishment and reward sensitivity. Then, subjects participated in an EEG experiment using the numerical Stroop task under different motivational conditions. In one condition, they were punished for erroneous responses; in the other, they were rewarded for correct performance. We analysed event related changes in EEG spectral power to investigate the influence of temperamentally driven differences on error-related oscillatory brain activity. In agreement with previous findings, after incorrect responses an increase in frontocentral theta (3-7Hz) and a decrease in occipital alpha (10-11Hz) power were observed. Moreover, a multivariate regression analysis showed that these spectral markers were modulated by temperamental trait Novelty Seeking in the reward condition. To our knowledge, we are the first to demonstrate such a relationship between individual differences and error-related oscillatory activity. This neuronal pattern may explain why participants that score high on Novelty Seeking trait are highly motivated and strongly engaged in a task when a reward might be earned. Thus, in conclusion we emphasise that to understand an individual's response to errors, it is necessary to account simultaneously for motivational conditions as well as temperament traits.

Pharmacokinetic Studies of Oxathio-Heterocycle Fused Chalcones.

BACKGROUND AND OBJECTIVES: Chalcone constitutes one of the most used molecular frameworks in medicinal chemistry and its derivatives exhibit a broad spectrum of biological activities. Low absolute bioavailability, poor distribution, intensive metabolism and elimination of chalcones are the main problems in designing new drugs based on their structure. One of the fundamental steps in evaluation of drug candidates is a comparative analysis of pharmacokinetic parameters. The aim of the studies was the pharmacokinetic characterization of the selected oxathio-heterocycle fused chalcones. METHODS: The pharmacokinetic parameters of 19 compounds were reported. The analyzed chalcones were examined after a single intravenous administration to forty 7-week-old mature male rats of Wistar stock. Pharmacokinetic analysis was performed independently using SHAM (slopes, highest, amounts, and moments) and the two-compartment model. Basic physiochemical parameters were calculated. The bioanalytical methods were validated in terms of repeatability, linearity, accuracy, precision, and selectivity. RESULTS: The pharmacokinetics of the examined group of chalcones are compatible with the two-compartment model. The physicochemical characteristics of this group are quite homogeneous. The kinetics of the examined chalcones are indicative of a distribution to the tissue compartment with the predominance of a rate constant from central to peripheral compartments (k12) over the rate constant from peripheral to central compartments (k21). The elimination from the central compartment (k10) is higher than the transfer from the central compartment to the tissues (k10 > k12) in almost all examined cases. CONCLUSIONS: The presented group of compounds may form a starting point for studies into drugs treating autoimmune diseases of the gastro-intestinal tract.

Influence of S-Oxidation on Cytotoxic Activity of Oxathiole-Fused Chalcones.

Synthesis, in vitro cytotoxic activity, and interaction with tubulin of oxidized, isomeric 1-(5-alkoxybenzo[d][1,3]oxathiol-6-yl)-3-phenylprop-2-en-1-ones and 1-(6-alkoxybenzo[d][1,3]oxathiol-5-yl)-3-phenylprop-2-en-1-ones are described. Most of the compounds demonstrated cytotoxic activity at submicromolar concentrations. It was found that oxidation of sulfur atom of the oxathiole-fused chalcones strongly influenced activity of the parent compounds, and that depending on relative position of the sulfur atom in the molecule, the activity was either increased or diminished. For isomers with sulfur atom para to the chalcone carbonyl group, oxidation led to increase in activity, while for isomers with sulfur atom meta to the carbonyl the activity dropped down. It was demonstrated that the compounds interact with tubulin at the colchicine binding site, and the interaction was evaluated using molecular modeling. It was concluded that the observed profound influence of oxidation of the sulfur atom on cytotoxic activity cannot be solely related to interaction of the compounds with tubulin.

Chemosensitization of multidrug resistant Candida albicans by the oxathiolone fused chalcone derivatives.

Three structurally related oxathiolone fused chalcone derivatives appeared effective chemosensitizers, able to restore in part sensitivity to fluconazole of multidrug-resistant C. albicans strains. Compound 21 effectively chemosensitized cells resistant due to the overexpression of the MDR1 gene, compound 6 reduced resistance of cells overexpressing the ABC-type drug transporters CDR1/CDR2 and derivative 18 partially reversed fluconazole resistance mediated by both types of yeast drug efflux pumps. The observed effect of sensitization of resistant strains of Candida albicans to fluconazole activity in the presence of active compounds most likely resulted from inhibition of the pump-mediated efflux, as was revealed by the results of studies involving the fluorescent probes, Nile Red, Rhodamine 6G and diS-C3(3).

Structural factors affecting affinity of cytotoxic oxathiole-fused chalcones toward tubulin.

Synthesis, in vitro cytotoxic activity, and interaction with tubulin of (E)-1-(6-alkoxybenzo[d][1,3]oxathiol-5-yl)-3-phenylprop-2-en-1-one derivatives (2) are described. Some of the compounds demonstrated cytotoxic activity at submicromolar concentrations, and the activity could be related to interaction with tubulin at the colchicine binding site. Interaction of selected derivatives with tubulin was evaluated using molecular modeling, and two different modes of the interaction were identified. The proposed models demonstrate how particular structural fragments participate in binding to the tubulin and explain the importance of the fragments for cytotoxic activity. It was demonstrated that concerning binding to tubulin, the 6-alkoxybenzoxathiole ring can be considered as structural equivalent of trimethoxyphenyl motif of colchicine, podophyllotoxin or combretastatin A4. The observation opened new ways of rational modifications of several groups of tubulin binders.

Inconvenient correlation - RT-BOLD relationship for homogeneous and fast reactions.

Reaction time (RT), a widely used measure of human performance in experimental psychology, has recently been included as a regressor of interest in functional magnetic resonance imaging (fMRI) data analysis. Few studies reported RT-related brain regions, but the nature of this activity is not fully understood. We aimed at exploring this topic by implementing a simple saccadic task which evokes fast and homogeneous reactions that require only the basic neural processes. Thus, a spatial cueing paradigm was chosen and implemented in a simultaneous fMRI and eye-tracking experiment. As a result, we found a wide set of brain regions showing trial-by-trial correlations of blood-oxygenation-level-dependent (BOLD) signal with saccadic RT. These regions included medial and lateral frontal lobes, bilateral intraparietal sulci, anterior insular cortices as well as the right thalamus and medial visual cortex. Further analysis was conducted in order to verify quantitatively the impact of a "time on task" effect on task-related hemodynamic responses (HDRs). The results provide evidence that even a small difference in RTs can be linked with significant increase of HDR in task-related areas. Moreover, this increase is not linear, but rather quadratic. Our findings highlight the importance of controlling for RT in fMRI data analysis when contrasting conditions that vary in RT to avoid the misinterpretation of results.

Structural factors affecting cytotoxic activity of (E)-1-(Benzo[d ][1,3]oxathiol-6-yl)-3-phenylprop-2-en-1-one derivatives.

Derivatives of (E)-1-(5-alkoxybenzo[d][1,3]oxathiol-6-yl)-3-phenylprop-2-en-1-one demonstrated exceptionally high in vitro cytotoxic activity, with IC50 values of the most active derivatives in the nanomolar range. To identify structural fragments necessary for the activity, several analogs deprived of selected fragments were prepared, and their cytotoxic activity was tested. It was found that the activity depends on combined effects of (i) the heterocyclic ring, (ii) the alkoxy group at position 5 of the benzoxathiole ring, and (iii) the substituents in the phenyl ring B. Replacement of the sulfur atom by oxygen does not influence the activity. None of the listed structural fragments alone assured high cytotoxic activity.