Preclinical Assessment of the Combination of PSMA-Targeting Radionuclide Therapy with PARP Inhibitors for Prostate Cancer Treatment

Prostate specific membrane antigen targeted radionuclide therapy (PSMA-TRT) is a promising novel treatment for prostate cancer (PCa) patients. However, PSMA-TRT cannot be used for curative intent yet, thus additional research on how to improve the therapeutic efficacy is warranted. A potential way of achieving this, is combining TRT with poly ADP-ribosylation inhibitors (PARPi), which has shown promising results for TRT of neuroendocrine tumor cells. Currently, several clinical trials have been initiated for this combination for PCa, however so far, no evidence of synergism is available for PCa. Therefore, we evaluated the combination of PSMA-TRT with three classes of PARPi in preclinical PCa models. In vitro viability and survival assays were performed using PSMA-expressing PCa cell lines PC3-PIP and LNCaP to assess the effect of increasing concentrations of PARPi veliparib, olaparib or talazoparib in combination with PSMA-TRT compared to single PARPi treatment. Next, DNA damage analyses were performed by quantifying the number of DNA breaks by immunofluorescent stainings. Lastly, the potential of the combination treatments was studied in vivo in mice bearing PC3-PIP xenografts. Our results show that combining PSMA-TRT with PARPi did not synergistically affect the in vitro clonogenic survival or cell viability. DNA-damage analysis revealed only a significant increase in DNA breaks when combining PSMA-TRT with veliparib and not in the other combination treatments. Moreover, PSMA-TRT with PARPi treatment did not improve tumor control compared to PSMA-TRT monotherapy. Overall, the data presented do not support the assumption that combining PSMA-TRT with PARPi leads to a synergistic antitumor effect in PCa. These results underline that extensive preclinical research using various PCa models is imperative to validate the applicability of the combination strategy for PCa, as it is for other cancer types.     

Biomarkers for the Diagnosis of Alzheimer’s Disease in Clinical Practice: The Role of CSF Biomarkers during the Evolution of Diagnostic Criteria

Alzheimer’s disease (AD) is a progressive condition and the most common cause of dementia worldwide. The neuropathological changes characteristic of the disorder can be successfully detected before the development of full-blown AD. Early diagnosis of the disease constitutes a formidable challenge for clinicians. CSF biomarkers are the in vivo evidence of neuropathological changes developing in the brain of dementia patients. Therefore, measurement of their concentrations allows for improved accuracy of clinical diagnosis. Moreover, AD biomarkers may provide an indication of disease stage. Importantly, the CSF biomarkers of AD play a pivotal role in the new diagnostic criteria for the disease, and in the recent biological definition of AD by the National Institute on Aging, NIH and Alzheimer’s Association. Due to the necessity of collecting CSF by lumbar puncture, the procedure seems to be an important issue not only from a medical, but also a legal, viewpoint. Furthermore, recent technological advances may contribute to the automation of AD biomarkers measurement and may result in the establishment of unified cut-off values and reference limits. Moreover, a group of international experts in the field of AD biomarkers have developed a consensus and guidelines on the interpretation of CSF biomarkers in the context of AD diagnosis. Thus, technological advancement and expert recommendations may contribute to a more widespread use of these diagnostic tests in clinical practice to support a diagnosis of mild cognitive impairment (MCI) or dementia due to AD. This review article presents up-to-date data regarding the usefulness of CSF biomarkers in routine clinical practice and in biomarkers research.     

Eco-Sustainable Silk Fibroin/Pomegranate Peel Extract Film as an Innovative Green Material for Skin Repair

Skin disorders are widespread around the world, affecting people of all ages, and oxidative stress represents one of the main causes of alteration in the normal physiological parameters of skin cells. In this work, we combined a natural protein, fibroin, with antioxidant compounds extracted in water from pomegranate waste. We demonstrate the effective and facile fabrication of bioactive and eco-sustainable films of potential interest for skin repair. The blended films are visually transparent (around 90%); flexible; stable in physiological conditions and in the presence of trypsin for 12 days; able to release the bioactive compounds in a controlled manner; based on Fickian diffusion; and biocompatible towards the main skin cells, keratinocytes and fibroblasts. Furthermore, reactive oxygen species (ROS) production tests demonstrated the high capacity of our films to reduce the oxidative stress induced in cells, which is responsible for various skin diseases.     

Reorganization of the Brain Extracellular Matrix in Hippocampal Sclerosis

The extracellular matrix (ECM) is an important regulator of excitability and synaptic plasticity, especially in its highly condensed form, the perineuronal nets (PNN). In patients with drug-resistant mesial temporal lobe epilepsy (MTLE), hippocampal sclerosis type 1 (HS1) is the most common histopathological finding. This study aimed to evaluate the ECM profile of HS1 in surgically treated drug-resistant patients with MTLE in correlation to clinical findings. Hippocampal sections were immunohistochemically stained for aggrecan, neurocan, versican, chondroitin-sulfate (CS56), fibronectin, Wisteria floribunda agglutinin (WFA), a nuclear neuronal marker (NeuN), parvalbumin (PV), and glial-fibrillary-acidic-protein (GFAP). In HS1, besides the reduced number of neurons and astrogliosis, we found a significantly changed expression pattern of versican, neurocan, aggrecan, WFA-specific glycosylation, and a reduced number of PNNs. Patients with a lower number of epileptic episodes had a less intense diffuse WFA staining in Cornu Ammonis (CA) fields. Our findings suggest that PNN reduction, changed ECM protein, and glycosylation expression pattern in HS1 might be involved in the pathogenesis and persistence of drug-resistant MTLE by contributing to the increase of CA pyramidal neurons’ excitability. This research corroborates the validity of ECM molecules and their modulators as a potential target for the development of new therapeutic approaches to drug-resistant epilepsy.     

Albumin Binds Doxorubicin via Self–Assembling Dyes as Specific Polymolecular Ligands

Congo red (CR) type self–assembled ribbon–like structures (SRLS) were previously shown to interact with some proteins, including albumin. SRLS also complex with some drugs with a flat, ring–shaped structure with aromatic characteristics, intercalating them into their ribbon structure. The combination of interaction with proteins and drug binding by SRLS enables the use of such systems for immunotargeting. It is especially interesting in the case of chemotherapeutic agents. The present experiments aimed to show that the model carrier system composed of supramolecular albumin and Congo red efficiently binds doxorubicin (Dox) and that the drug can be released at reduced pH. The presented results come from the studies on such complexes differing in the molar ratio of CR to Dox. The following methods were used for the analysis: electrophoresis, dialysis, gel filtration, spectral analysis, and analysis of the size of the hydrodynamic radius using the dynamic light scattering method (DLS). The applied methods confirmed the formation of the CR–Dox complex, with large dimensions and changed properties compared with free CR. The presented results show that albumin binds both CR and its complex with Dox. Various CR–Dox molar ratios, 5:1, 2:1, and 1:1, were analyzed. The confirmation of the possibility of releasing the drug from the carriers thus formed was also obtained. The presented research is important due to the search for optimal solutions for the use of SRLS in drug immunotargeting, with particular emphasis on chemotherapeutic agents.     

Consumer neuroscience: Assessing the brain response to marketing stimuli using electroencephalogram (EEG) and eye tracking

Application of neuroscience methods to analyze and understand human behavior related to markets and marketing exchange has recently gained research attention. The basic aim is to guide design and presentation of products to optimize them to be as compatible as possible with consumer preferences. This paper investigates physiological decision processes while participants undertook a choice task designed to elicit preferences for a product. The task required participants to choose their preferred crackers described by shape (square, triangle, round), flavor (wheat, dark rye, plain) and topping (salt, poppy, no topping). The two main research objectives were (1) to observe and evaluate the cortical activity of the different brain regions and the interdependencies among the Electroencephalogram (EEG) signals from these regions; and (2) unlike most research in this area that has focused mainly on liking/disliking certain products, we provide a way to quantify the importance of different cracker features that contribute to the product design based on mutual information. We used the commercial Emotiv EPOC wireless EEG headset with 14 channels to collect EEG signals from participants. We also used a Tobii-Studio eye tracker system to relate the EEG data to the specific choice options (crackers). Subjects were shown 57 choice sets; each choice set described three choice options (crackers). The patterns of cortical activity were obtained in the five principal frequency bands, Delta (0–4 Hz), Theta (3–7 Hz), Alpha (8–12 Hz), Beta (13–30 Hz), and Gamma (30–40 Hz). There was a clear phase synchronization between the left and right frontal and occipital regions indicating interhemispheric communications during the chosen task for the 18 participants. Results also indicated that there was a clear and significant change (p < 0.01) in the EEG power spectral activities taking a place mainly in the frontal (delta, alpha and beta across F3, F4, FC5 and FC6), temporal (alpha, beta, gamma across T7), and occipital (theta, alpha, and beta across O1) regions when participants indicated their preferences for their preferred crackers. Additionally, our mutual information analysis indicated that the various cracker flavors and toppings of the crackers were more important factors affecting the buying decision than the shapes of the crackers.     

Influence of superplasticizers on pore solution composition and on expansion of concrete due to alkali-silica reaction

The use of superplasticizers (SP) is widespread in today’s concrete production. Usually, SP are used when specific demands in regard to workability, strength or durability have to be met. As they contain sodium sulphate, they have the potential to increase the alkalinity in the pore solution and the risk of damages due to alkali-silica reaction. In this study, the effect of two SP on the potential reactivity of concrete is examined by analyzing pore solutions of pastes and mortars and by measuring concrete expansion. The use of a naphthalene–sulphonate-based SP (Na content referred to liquid: 2.8%) leads to an increase in hydroxide concentration in the pore solution during the first two weeks going together with an accelerated concrete expansion during this period. The effects of a polycarboxylate-based SP (Na content referred to liquid: 0.5%) are less pronounced and do not result in an increased concrete expansion.     

Structural purity of magnetite nanoparticles in magnetotactic bacteria

Magnetosome biomineralization and chain formation in magnetotactic bacteria are two processes that are highly controlled at the cellular level in order to form cellular magnetic dipoles. However, even if the magnetosome chains are well characterized, controversial results about the microstructure of magnetosomes were obtained and its possible influence in the formation of the magnetic dipole is to be specified. For the first time, the microstructure of intracellular magnetosomes was investigated using high-resolution synchrotron X-ray diffraction. Significant differences in the lattice parameter were found between intracellular magnetosomes from cultured magnetotactic bacteria and isolated ones. Through comparison with abiotic control materials of similar size, we show that this difference can be associated with different oxidation states and that the biogenic nanomagnetite is stoichiometric, i.e. structurally pure whereas isolated magnetosomes are slightly oxidized. The hierarchical structuring of the magnetosome chain thus starts with the formation of structurally pure magnetite nanoparticles that in turn might influence the magnetic property of the magnetosome chains.     

彩虹·洞——巴塞罗那Imaginarium儿童产品旗舰店

儿童总是喜爱玩耍的,神秘的洞穴更是对他们有着无穷的吸引力。在孩子的眼中,色彩是丰富世界的一个缩影。因此,迫庆一郎先生在设计巴塞罗那儿童品牌Imaginarium旗舰店时,就以洞穴·彩虹作为了设计的主题。