Stimuli-Responsive and Multifunctional Nanogels in Drug Delivery.

Nanogels represent promising drug delivery systems in the biomedical field, designed to overcome challenges associated with standard treatment approaches. Stimuli-responsive nanogels, often referred to as intelligent materials, have garnered significant attention for their potential to enhance control over properties such as drug release and targeting. Furthermore, researchers have recently explored the application of nanogels in diverse sectors beyond biomedicine including sensing materials, catalysts, or adsorbents for environmental applications. However, to fully harness their potential as practical delivery systems, further research is required to better understand their pharmacokinetic behaviour, interactions between nanogels and bio distributions, as well as toxicities. One promising future application of stimuli-responsive multifunctional nanogels is their use as delivery agents in cancer treatment, offering an alternative to overcome the challenges with conventional approaches. This review discusses various synthetic methods employed in developing nanogels as efficient carriers for drug delivery in cancer treatment. The investigations explore, the key aspects of nanogels, including their multifunctionality and stimuli-responsive properties, as well as associated toxicity concerns. The discussions presented herein aim to provide the readers a comprehensive understanding of the potential of nanogels as smart drug delivery systems in the context of cancer therapy.

Aptamers: Features, Synthesis and Applications.

Aptamers have become a topic of interest among the researchers and scientists since they not only possess all of the benefits of antibodies but also possess special qualities including heat stability, low cost, and limitless uses⋅ Here we give a review about the features, applications, and challenges of aptamers and also how they are beneficial over the antibodies for biomedical applications. Their unique features make aptamers a prominent tool in therapeutics, diagnostics, biosensors and targeted drug delivery. In conclusion, aptamers represent exciting materials for a variety of applications and can be modified to improve their properties and to extend their applications in biomedical field.

Orthogonally Protected Furanoid Sugar Diamino Acids for Solid-Phase Synthesis of Oligosaccharide Mimetics.

Sugar diamino acids (SDAs), which differ from the widely used sugar amino acids in the presence of a second amino group connected to the carbohydrate core, share structural features of both amino acids and carbohydrates. They can be used for the preparation of linear and branched amide-linked oligosaccharide mimetics. Such oligomers carry free amino groups, which are positively charged at neutral pH, in a spatially defined way and, thus, represent a potential class of aminoglycoside mimetics. We report here the first examples of orthogonally protected furanoid SDAs and their use in solid-phase synthesis. Starting from d-glucose, we developed a divergent synthetic route to three derivatives of 3,5-diamino-3,5-dideoxy-d-ribofuranose. These building blocks are compatible with solid-phase peptide synthesis following the 9-fluorenylmethoxycarbonyl (Fmoc) strategy, which we demonstrate by the synthesis of an SDA tetramer.

Block Copolymer Encapsulation of Disarib, an Inhibitor of BCL2 for Improved Chemotherapeutic Potential.

A chemical inhibitor of antiapoptotic protein, BCL2, known as Disarib, suffers poor solubility in aqueous environments; thereby limiting its potential as a chemotherapeutic agent. To overcome this limitation and enhance the therapeutic efficacy of Disarib, we have employed the encapsulation of this small molecule inhibitor within P123 copolymer matrix. Micelles were synthesized using a thin-film hydration technique, and a comprehensive analysis was undertaken to evaluate the resulting micelle properties, including morphology, particle size, intermolecular interactions, encapsulation efficiency, and in vitro release characteristics. This assessment utilized various physicochemical techniques including UV spectroscopy, FTIR spectroscopy, dynamic light scattering (DLS), transmission electron microscopy (TEM), and small-angle X-ray scattering (SAXS). Disarib-loaded P123 micelle formulation denoted as P123D exhibited a well-defined particle size of approximately 29.2 nm spherical core-shell morphology. Our investigations revealed a notable encapsulation efficiency of 75%, and we observed a biphasic release pattern for the encapsulated Disarib. Furthermore, our cytotoxicity assessment of P123D micelles against mouse breast adenocarcinoma, mouse lymphoma, and human leukemic cell lines showed 40-45% increase in cytotoxicity compared with the administration of Disarib alone in the breast adenocarcinoma cell line. Enhancement in the cytotoxicity of P123D was found to be higher or limited; however, it is important to observe that the encapsulation method significantly enhanced the aqueous solubility of Disarib as it has the best solubility in dimethyl sulfoxide (DMSO) in the unencapsulated state.

Design and Synthesis of Ketenimine Sulfonamide Conjugates through Multicomponent Reactions; A Combined Cytotoxic Analysis and Computational Exploration.

Multicomponent reactions involving zwitterion generated from dimethyl acetylenedicarboxylate, aryl sulfonamide, and isocyanide to generate sulfonamide-conjugated ketenimines is reported. The synthetic strategy adopted is highly atom economical and stereoselective. Ketenimine sulfonamide analogues are key intermediates for further synthetic conversions to generate a combinatorial library of compounds. Furthermore, sulfonamide compounds are known to possess a broad spectrum of biological applications. All the novel molecules synthesized exhibit the potential to target the nonhomologous DNA end-joining (NHEJ) pathway with cytotoxic ability. Computational studies compliment the in vitro biological assays of the 8 small-molecule inhibitors. DNA double-strand breaks (DSBs) are considered as the most lethal among different DNA damages. NHEJ repairs about 70% of the DSBs generated in cells within mammals. The DNA-dependent protein kinase catalytic subunit is one of the PI3 kinases associated with NHEJ. Compounds DK01-DK08 were investigated for their ability to induce cancer cell death by treating with two leukemic cell lines where NHEJ is high. Results showed that bromoaryl (DK04)- and nitroaryl (DK05)-conjugated molecules showed excellent biological activity, having IC50 values of ∼2 µM in Nalm6 cell lines.

Correction to "Design and Synthesis of Ketenimine Sulfonamide Conjugates through Multicomponent Reactions; A Combined Cytotoxic Analysis and Computational Exploration".

[This corrects the article DOI: 10.1021/acsomega.3c05816.].

Diffusion Tensor Imaging and Tractography Utilized in the Resection of a Midbrain Cavernous Malformation.

Background: Diffusion tensor imaging (DTI) is a magnetic resonance-based imaging technique that can provide important information about the underlying structure and integrity of the white matter in the brain. Tractography, a DTI postprocessing technique, can provide a detailed model of individual white matter fiber tracts. Knowledge of these tracts may be beneficial in the surgical planning and execution for neurosurgical patients. Case Report: We review the basic principles behind DTI and present an illustrative case in which DTI was used to delineate the relationship of eloquent white matter tracts to a cavernous malformation in a patient undergoing resection. Conclusion: The use of DTI during preoperative planning allows the neurosurgeon to understand if a lesion is disrupting, infiltrating, or altering the course of local white matter tracts. With the combined use of DTI and intraoperative neuronavigation, the neurosurgeon can better identify and avoid white matter tracts, not only in the local area of resection but also during approach to the lesion, thereby reducing the risk of damage to vital cortical pathways and subsequent functional impairment.

Autocyclized and oxidized forms of SCR7 induce cancer cell death by inhibiting nonhomologous DNA end joining in a Ligase IV dependent manner.

Nonhomologous DNA end joining (NHEJ) is the major DNA double-strand break (DSB) repair pathway in mammals. Previously, we have described a small molecule inhibitor, SCR7, which can inhibit NHEJ in a Ligase IV-dependent manner. Administration of SCR7 within the cells resulted in the accumulation of DNA breaks, cell death, and inhibition of tumor growth in mice. In the present study, we report that parental SCR7, which is unstable, can be autocyclized into a stable form. Both parental SCR7 and cyclized SCR7 possess the same molecular weight (334.09) and molecular formula (C18 H14 N4 OS), whereas its oxidized form, SCR7-pyrazine, possesses a different molecular formula (C18 H12 N4 OS), molecular weight (332.07), and structure. While cyclized form of SCR7 showed robust inhibition of NHEJ in vitro, both forms exhibited efficient cytotoxicity. Cyclized and oxidized forms of SCR7 inhibited DNA end joining catalyzed by Ligase IV, whereas their impact was minimal on Ligase III, Ligase I, and T4 DNA Ligase-mediated joining. Importantly, both forms inhibited V(D)J recombination, although the effect was more pronounced for SCR7-cyclized. Both forms blocked NHEJ in a Ligase IV-dependent manner leading to the accumulation of DSBs within the cells. Although cytotoxicity due to SCR7-cyclized was Ligase IV specific, the pyrazine form exhibited nonspecific cytotoxicity at higher concentrations in Ligase IV-null cells. Finally, we demonstrate that both forms can potentiate the effect of radiation. Thus, we report that cyclized and oxidized forms of SCR7 can inhibit NHEJ in a Ligase IV-dependent manner, although SCR7-pyrazine is less specific to Ligase IV inside the cell.

Enhanced efficacy of pluronic copolymer micelle encapsulated SCR7 against cancer cell proliferation.

5,6-Bis(benzylideneamino)-2-mercaptopyrimidin-4-ol (SCR7) is a new anti cancer molecule having capability to selectively inhibit non-homologous end joining (NHEJ), one of the DNA double strand break (DSB) repair pathways inside the cells. In spite of the promising potential as an anticancer agent, hydrophobicity of SCR7 decreases its bioavailability. Herein the entrapment of SCR7 in Pluronic copolymer is reported. The size of the aggregates was determined by transmission electron microscopy (TEM) and dynamic light scattering (DLS) which yields an average diameter of 23 nm. SCR7 encapsulated micelles (ES) were also characterized by small-angle neutron scattering (SANS). Evaluation of its biological properties by using a variety of techniques, including Trypan blue, MTT and Live-dead cell assays, reveal that encapsulated SCR7 can induce cytotoxicity in cancer cell lines, being more effective in breast cancer cell line. Encapsulated SCR7 treatment resulted in accumulation of DNA breaks within the cells, resulting in cell cycle arrest at G1 phase and activation of apoptosis. More importantly, we found ≈ 5 fold increase in cell death, when encapsulated SCR7 was used in comparison with SCR7 alone.

Pluronic copolymer encapsulated SCR7 as a potential anticancer agent.

Nonhomologous end joining (NHEJ) of DNA double strand breaks (DSBs) inside cells can be selectively inhibited by 5,6-bis-(benzylideneamino)-2-mercaptopyrimidin-4-ol (SCR7) which possesses anticancer properties. The hydrophobicity of SCR7 decreases its bioavailability which is a major setback in the utilization of this compound as a therapeutic agent. In order to circumvent the drawback of SCR7, we prepared a polymer encapsulated form of SCR7. The physical interaction of SCR7 and Pluronic® copolymer is evident from different analytical techniques. The in vitro cytotoxicity of the drug formulations is established using the MTT assay.

Severe coronary disease in an adult considered at low cardiovascular disease risk with a healthy lifestyle.

Lipoprotein(a) [Lp(a)] is a lipoprotein subclass well-known among the lipid community to accelerate atherosclerosis and promote thrombosis through incompletely understood mechanism. We report a case of a young man with a healthy lifestyle and no major coronary or vascular risk factors who presented to the emergency department with an acute coronary syndrome and was ultimately found to have severe coronary artery disease. A diagnostic workup revealed elevated Lp(a). He was treated with consequent reduction in Lp(a) concentration. This case highlights the need to better understand atypical lipoproteins, how they relate to cardiovascular disease, the implications for screening family members, and the need to standardize patient management guidelines for the purpose of mortality risk reduction.

Aprendizaje Multimedia y el efecto de las modalidades instruccionales / Multimedia learning and the effect of instructional modalities

El aprendizaje multimedia es un fenómeno estrechamente vinculado con el uso de tecnologías de la información y comunicación en entornos educativos. Diferentes posturas han surgido para abordar sus características, siendo la de Mayer la más destacada. Se realizó una investigación de tipo documental conocida como meta-análisis, la cual consiste en una revisión sistemática cualitativa o cuantitativa de un conjunto de informes o artículos de investigación, realizados con el ánimo de estudiar el efecto de una variable en particular; El presente estudio se realizó de forma cuantitativa mediante un estadístico conocido como el coeficiente de Cohen (d) a través del cual se puede determinar cuál es la magnitud del efecto de una variable (Nulo, Bajo, moderado, alto). Como resultado de este proceso se encuentra que la modalidad instruccional tiene un efecto alto (44% de las mediciones consultadas en las diferentes publicaciones), así como que la investigación en esta área ha ido disminuyendo en los últimos cinco años. Finalmente se encuentra un dato muy interesante, según el cual dentro de las publicaciones analizadas, solamente una se realizó en tareas de memoria implícita

Multimedia learning is a phenomenon closely linked to the use of information and communication technologies in educational environments. Different approaches have arisen to address its characteristics, being Mayer's position the most outstanding. A documentary investigation was carried out which consisted of a quantitative systematic review of Cohen's Kappa coefficient (d) through which the magnitude of the effect of a variable can be determined (null, low, moderate, high). Results suggest that the effect of instructional modality is high (44% of the measurements consulted in different publications) and that research in this area decreased in the observation window. There is a very interesting fact: among all the publications analyzed only one was on implicit memory tasks, this opens up the possibility of working in this field

Synthesis of truncated analogues for studying the process of glycosyl phosphatidylinositol modification.

Many eukaryotic proteins are modified with a glycosylphosphatidylinositol (GPI) anchor at their C-termini. This post-translational modification causes these proteins to be noncovalently tethered to the plasma membrane. The synthesis of truncated GPI anchor analogues is reported; these compounds were designed for use as soluble substrates for GPI transamidase (GPI-T), the enzyme that appends the GPI anchor onto proteins.