Arabidopsis AGO1 N-terminal extension acts as an essential hub for PRMT5 interaction and post-translational modifications.

Plant ARGONAUTE (AGO) proteins play pivotal roles regulating gene expression through small RNA (sRNA) -guided mechanisms. Among the 10 AGO proteins in Arabidopsis thaliana, AGO1 stands out as the main effector of post-transcriptional gene silencing. Intriguingly, a specific region of AGO1, its N-terminal extension (NTE), has garnered attention in recent studies due to its involvement in diverse regulatory functions, including subcellular localization, sRNA loading and interactions with regulatory factors. In the field of post-translational modifications (PTMs), little is known about arginine methylation in Arabidopsis AGOs. In this study, we show that NTE of AGO1 (NTEAGO1) undergoes symmetric arginine dimethylation at specific residues. Moreover, NTEAGO1 interacts with the methyltransferase PRMT5, which catalyzes its methylation. Notably, we observed that the lack of symmetric dimethylarginine has no discernible impact on AGO1's subcellular localization or miRNA loading capabilities. However, the absence of PRMT5 significantly alters the loading of a subgroup of sRNAs into AGO1 and reshapes the NTEAGO1 interactome. Importantly, our research shows that symmetric arginine dimethylation of NTEs is a common process among Arabidopsis AGOs, with AGO1, AGO2, AGO3 and AGO5 undergoing this PTM. Overall, this work deepens our understanding of PTMs in the intricate landscape of RNA-associated gene regulation.

Resultados oncológicos y factores pronósticos en pacientes con sarcoma sinovial tratados quirúrgicamente / Oncological outcomes and prognostic factors in surgically treated patients with synovial sarcoma

Resumen Introducción : El sarcoma sinovial es un tumor raro (incidencia de 1-3 casos por millón). Es más frecuente en adolescentes y adultos menores de 30 años. Se desarrolla en cualquier parte del cuerpo, siendo, las extremidades el lugar más frecuente de aparición (80% extremidades y 20% otras localizaciones: 8% tronco, retroperitoneal/ abdominal 7%, cabeza y cuello 5%). Los resultados on cológicos de los pacientes con sarcoma sinovial son disímiles. La tasa de supervivencia libre de recurrencia local, la supervivencia libre de eventos y la superviven cia global varían entre las series publicadas. Lo mismo sucede con los factores pronósticos de la enfermedad. Métodos : El objetivo fue analizar un grupo de 43 pacientes con diagnóstico de sarcoma sinovial de las extremidades tratados quirúrgicamente, y determinar (1) tasa de supervivencia global, (2) tasa de superviven cia libre de eventos, (3) tasa de recurrencia local y (4) factores de riesgo oncológicos. Resultados : La supervivencia global a los 2 años fue 90% (IC95%: 76-96%), y 67% (IC95%: 49-80%) a los 5 años. La supervivencia libre de eventos a los 2 años fue 68% (IC95% 51-80%) y a los 5 años 48% (IC95% 32-52%). El riesgo de recurrencia local a 2 años fue 9% (IC95% 3-25%) y a los 5 años 25% (IC95% 13-46%). Los factores de mal pronóstico oncológico fueron el grado histológico y la presencia de metástasis. Discusión : Podemos concluir que nuestros resulta dos oncológicos se asemejan a las series publicadas y que en nuestra serie hubo dos factores de mal pro nóstico.

Abstract Introduction : Synovial sarcoma is an unusual tumor with an incidence of 1-3 cases per million. It is more frequent in teenagers and young adults under 30. It develops anywhere, but the extremities are the most frequent place of appearance (80% extremities, 20% other locations: 8% trunk, 7% retroperitoneal/abdominal, 5% head and neck). Oncological results are different depending on the study. Survival rate free of local recur rence, survival rate free of events and global survival rate vary upon published studies. The same happens with the disease's prognostic factors. Methods : The objective was to analyze a group of 43 patients with diagnosis of synovial sarcoma of the extremities treated surgically and determine (1) global survival rate, (2) survival rate free of events, (3) local recurrence rate and (4) oncological risk factors. Results : The global survival rate at 2 years was 90% (IC95%: 76 - 96%) and 67% (IC95%: 49-80%) at 5 years. The survival rate free of events at 2 years was 68% (IC95% 51-80%) and 48% (IC95% 32-52%) at 5 years. The recurrence rate at 2 years was 9% (IC95% 3-25%) and 25% (IC95% 13-46%) at 5 years. The histological grade and metastatic presence were bad prognostic factors. Discussion : We can conclude that our oncological results are in line with those published in previous series and that there were two factors associated with poor prognosis.

Comprehensive Overview of Bottom-Up Proteomics using Mass Spectrometry.

Proteomics is the large scale study of protein structure and function from biological systems through protein identification and quantification. "Shotgun proteomics" or "bottom-up proteomics" is the prevailing strategy, in which proteins are hydrolyzed into peptides that are analyzed by mass spectrometry. Proteomics studies can be applied to diverse studies ranging from simple protein identification to studies of proteoforms, protein-protein interactions, protein structural alterations, absolute and relative protein quantification, post-translational modifications, and protein stability. To enable this range of different experiments, there are diverse strategies for proteome analysis. The nuances of how proteomic workflows differ may be challenging to understand for new practitioners. Here, we provide a comprehensive overview of different proteomics methods to aid the novice and experienced researcher. We cover from biochemistry basics and protein extraction to biological interpretation and orthogonal validation. We expect this work to serve as a basic resource for new practitioners in the field of shotgun or bottom-up proteomics.

[Oncological outcomes and prognostic factors in surgically treated patients with synovial sarcoma]. / Resultados oncológicos y factores pronósticos en pacientes con sarcoma sinovial tratados quirúrgicamente.

INTRODUCTION: Synovial sarcoma is an unusual tumor with an incidence of 1-3 cases per million. It is more frequent in teenagers and young adults under 30. It develops anywhere, but the extremities are the most frequent place of appearance (80% extremities, 20% other locations: 8% trunk, 7% retroperitoneal/abdominal, 5% head and neck). Oncological results are different depending on the study. Survival rate free of local recurrence, survival rate free of events and global survival rate vary upon published studies. The same happens with the disease's prognostic factors. METHODS: The objective was to analyze a group of 43 patients with diagnosis of synovial sarcoma of the extremities treated surgically and determine (1) global survival rate, (2) survival rate free of events, (3) local recurrence rate and (4) oncological risk factors. RESULTS: The global survival rate at 2 years was 90% (IC95%: 76 - 96%) and 67% (IC95%: 49-80%) at 5 years. The survival rate free of events at 2 years was 68% (IC95% 51-80%) and 48% (IC95% 32-52%) at 5 years. The recurrence rate at 2 years was 9% (IC95% 3-25%) and 25% (IC95% 13-46%) at 5 years. The histological grade and metastatic presence were bad prognostic factors. DISCUSSION: We can conclude that our oncological results are in line with those published in previous series and that there were two factors associated with poor prognosis.

Introducción: El sarcoma sinovial es un tumor raro (incidencia de 1-3 casos por millón). Es más frecuente en adolescentes y adultos menores de 30 años. Se desarrolla en cualquier parte del cuerpo, siendo, las extremidades el lugar más frecuente de aparición (80% extremidades y 20% otras localizaciones: 8% tronco, retroperitoneal/ abdominal 7%, cabeza y cuello 5%). Los resultados oncológicos de los pacientes con sarcoma sinovial son disímiles. La tasa de supervivencia libre de recurrencia local, la supervivencia libre de eventos y la supervivencia global varían entre las series publicadas. Lo mismo sucede con los factores pronósticos de la enfermedad. Métodos: El objetivo fue analizar un grupo de 43 pacientes con diagnóstico de sarcoma sinovial de las extremidades tratados quirúrgicamente, y determinar (1) tasa de supervivencia global, (2) tasa de supervivencia libre de eventos, (3) tasa de recurrencia local y (4) factores de riesgo oncológicos. Resultados: La supervivencia global a los 2 años fue 90% (IC95%: 76-96%), y 67% (IC95%: 49-80%) a los 5 años. La supervivencia libre de eventos a los 2 años fue 68% (IC95% 51-80%) y a los 5 años 48% (IC95% 32-52%). El riesgo de recurrencia local a 2 años fue 9% (IC95% 3-25%) y a los 5 años 25% (IC95% 13-46%). Los factores de mal pronóstico oncológico fueron el grado histológico y la presencia de metástasis. Discusión: Podemos concluir que nuestros resultados oncológicos se asemejan a las series publicadas y que en nuestra serie hubo dos factores de mal pronóstico.

Polymorphism of Carbamazepine Pharmaceutical Cocrystal: Structural Analysis and Solubility Performance.

Polymorphism is a common phenomenon among single- and multicomponent molecular crystals that has a significant impact on the contemporary drug development process. A new polymorphic form of the drug carbamazepine (CBZ) cocrystal with methylparaben (MePRB) in a 1:1 molar ratio as well as the drug's channel-like cocrystal containing highly disordered coformer molecules have been obtained and characterized in this work using various analytical methods, including thermal analysis, Raman spectroscopy, and single-crystal and high-resolution synchrotron powder X-ray diffraction. Structural analysis of the solid forms revealed a close resemblance between novel form II and previously reported form I of the [CBZ + MePRB] (1:1) cocrystal in terms of hydrogen bond networks and overall packing arrangements. The channel-like cocrystal was found to belong to a distinct family of isostructural CBZ cocrystals with coformers of similar size and shape. Form I and form II of the 1:1 cocrystal appeared to be related by a monotropic relationship, with form II being proven to be the thermodynamically more stable phase. The dissolution performance of both polymorphs in aqueous media was significantly enhanced when compared with parent CBZ. However, considering the superior thermodynamic stability and consistent dissolution profile, the discovered form II of the [CBZ + MePRB] (1:1) cocrystal seems a more promising and reliable solid form for further pharmaceutical development.

Impact of Biomass Drying Process on the Extraction Efficiency of C-Phycoerythrin.

Drying the biomass produced is one of the critical steps to avoid cell degradation; however, its high energy cost is a significant technological barrier to improving this type of bioprocess's technical and economic feasibility. This work explores the impact of the biomass drying method of a strain of Potamosiphon sp. on the extraction efficiency of a phycoerythrin-rich protein extract. To achieve the above, the effect of time (12-24 h), temperature (40-70 °C), and drying method (convection oven and dehydrator) were determined using an I-best design with a response surface. According to the statistical results, the factors that most influence the extraction and purity of phycoerythrin are temperature and moisture removal by dehydration. The latter demonstrates that gentle drying of the biomass allows removing the most significant amount of moisture from the biomass without affecting the concentration or quality of temperature-sensitive proteins.

Multiplatform molecular profiling uncovers two subgroups of malignant peripheral nerve sheath tumors with distinct therapeutic vulnerabilities.

Malignant peripheral nerve sheath tumor (MPNST) is a highly aggressive sarcoma, and a lethal neurofibromatosis type 1-related malignancy, with little progress made on treatment strategies. Here, we apply a multiplatform integrated molecular analysis on 108 tumors spanning the spectrum of peripheral nerve sheath tumors to identify candidate drivers of MPNST that can serve as therapeutic targets. Unsupervised analyses of methylome and transcriptome profiles identify two distinct subgroups of MPNSTs with unique targetable oncogenic programs. We establish two subgroups of MPNSTs: SHH pathway activation in MPNST-G1 and WNT/ß-catenin/CCND1 pathway activation in MPNST-G2. Single nuclei RNA sequencing characterizes the complex cellular architecture and demonstrate that malignant cells from MPNST-G1 and MPNST-G2 have neural crest-like and Schwann cell precursor-like cell characteristics, respectively. Further, in pre-clinical models of MPNST we confirm that inhibiting SHH pathway in MPNST-G1 prevent growth and malignant progression, providing the rational for investigating these treatments in clinical trials.

Virtual Screening, Structural Analysis, and Formation Thermodynamics of Carbamazepine Cocrystals.

In this study, the existing set of carbamazepine (CBZ) cocrystals was extended through the successful combination of the drug with the positional isomers of acetamidobenzoic acid. The structural and energetic features of the CBZ cocrystals with 3- and 4-acetamidobenzoic acids were elucidated via single-crystal X-ray diffraction followed by QTAIMC analysis. The ability of three fundamentally different virtual screening methods to predict the correct cocrystallization outcome for CBZ was assessed based on the new experimental results obtained in this study and data available in the literature. It was found that the hydrogen bond propensity model performed the worst in distinguishing positive and negative results of CBZ cocrystallization experiments with 87 coformers, attaining an accuracy value lower than random guessing. The method that utilizes molecular electrostatic potential maps and the machine learning approach named CCGNet exhibited comparable results in terms of prediction metrics, albeit the latter resulted in superior specificity and overall accuracy while requiring no time-consuming DFT computations. In addition, formation thermodynamic parameters for the newly obtained CBZ cocrystals with 3- and 4-acetamidobenzoic acids were evaluated using temperature dependences of the cocrystallization Gibbs energy. The cocrystallization reactions between CBZ and the selected coformers were found to be enthalpy-driven, with entropy terms being statistically different from zero. The observed difference in dissolution behavior of the cocrystals in aqueous media was thought to be caused by variations in their thermodynamic stability.

Influence of Co-amorphization on the Physical Stability and Dissolution Performance of an Anthelmintic Drug Flubendazole.

In this work, the co-amorphization approach was applied to flubendazole (FluBZ), resulting in the formation of two novel solid forms of FluBZ with l-phenylalanine (Phe) and l-tryptophan (Trp). A variety of physicochemical techniques have been used to describe new systems, including powder X-ray diffraction, thermal methods, infrared spectroscopy, and scanning electron microscopy. Co-amorphization has been shown to suppress crystallization tendency and considerably increase the shelf-life storage of amorphous flubendazole solid across a wide range of relative humidities. The dissolution behavior of the amorphous forms in biorelevant media at pH = 1.6, pH = 6.5, and 37 °C has been studied in terms of Cmax (maximum FluBZ concentration), Tmax (time to attain peak drug concentration), and AUC (concentration area under the curve during dissolution). At pH = 6.5, a continuous supersaturation and the highest AUC value of all examined systems were observed for the FluBZ-Phe (1:1) system. The phase solubility diagrams revealed that the reason for the better dissolution performance of FluBZ-Phe (1:1) at pH = 6.5 is a complexation between the components in a solution. This work highlights the applicability of co-amorphous systems in improving the physical stability and dissolution performance of drug compounds with poor biopharmaceutical characteristics.

Permeability of New Antifungal Fluconazole Derivatives through a Lipophilic Membrane: Experiment and Modeling.

Relationships between the structures of molecules and their properties form the basis of modern chemistry and lay the foundation for structure-based drug design. Being the main two determinants of bioavailability, solubility and permeability of drugs are widely investigated experimentally and predicted from physicochemical parameters and structural descriptors. In the present study, we measure the passive diffusion permeability of a series of new fluconazole derivatives with triazole and thiazolo-pyrimidine moieties connected by different linker bridges through the PermeaPad barrier-a relatively new biomimetic lipophilic membrane that has been increasingly used in recent years. The permeability coefficients of new derivatives are shown to be dependent both on the structure of the linker fragment and on the substituent in the phenyl ring of the thiazolo-pyrimidine moiety. The impact of the compound ionization state on the permeability is revealed. Reliable correlations of the permeability with the antifungal activity and distribution coefficient are found. In addition, the solubility-diffusion approach is shown to be able to successfully predict the permeability of the studied derivatives. The obtained results can be considered another step in the development of permeability databases and design of schemes for in vitro permeability prediction.

New Solid Forms of Nitrofurantoin and 4-Aminopyridine Salt: Influence of Salt Hydration Level on Crystal Packing and Physicochemical Properties.

The crystallization of the poorly soluble drug nitrofurantoin (NFT) with 4-aminopyridine (4AmPy) resulted in three multicomponent solid forms with different hydration levels: anhydrous salt [NFT+4AmPy] (1:1), salt monohydrate [NFT+4AmPy+H2O] (1:1:1), and salt tetrahydrate [NFT+4AmPy+H2O] (1:1:4). Each salt was selectively prepared by liquid-assisted grinding in the presence of acetonitrile or ethanol/water mixture at a specific composition. The NFT hydrated salts were characterized using single crystal X-ray diffraction. The [NFT+4AmPy+H2O] salt (1:1:1) crystallized as an isolated site hydrate, while the [NFT+4AmPy+H2O] salt (1:1:4) crystallized as a channel hydrate. The dehydration processes of the NFT salt hydrates were investigated using differential scanning calorimetry and thermogravimetric analysis. A powder dissolution experiment was carried out for all NFT multicomponent solid forms in pH 7.4 phosphate buffer solution at 37 °C.

Plants with antioxidant activity and their potential use as sun protector agents in Costa Rica

SUMMARY Aims: To carry out a bibliographic review related to plants available in Costa Rica that have demonstrated antioxidant power and a sun protection factor (SPF) suitable to be used in sunscreen products. Methods: The bibliographic review was carried out using different descriptors and by consulting different databases. Results: Information about antioxidant power about acerola, avocado, carrots, passion fruit, moringa, banana, pumpkin and amaranth, guava, matico, ginkgo, blackberry, mango, coffee was obtained. The information obtained suggests that the mentioned plants could be used for the formulation of sunscreens. Conclusion: Sun protection products should be used every day to prevent skin damage; some sunscreens produce allergic reactions, so it is necessary to investigate natural options to be used in sun protection products. Some natural products exhibit SPF values that allow their incorporation as sun protection agents, adjuvants, or enhancers in sunscreens.

Objetivo: llevar a cabo una investigación bibliográfica sobre plantas disponibles en Costa Rica que han demostrado su poder antioxidante y un factor de protector solar (SPF) apto para ser utilizados en protectores solares. Métodos: la revisión bibliográfica se realizó utilizando diferentes descriptores y mediante la consulta en diferentes bases de datos. Resultados: se obtuvo información sobre el poder antioxidante de las plantas: acerola, aguacate, zanahoria, maracuyá, moringa, banano, calabaza y amaranto, guayaba, matico, ginkgo, mora, mango, café. La información obtenida sugiere que las plantas mencionadas podrían ser utilizadas para la formulación de protectores solares. Conclusiones: los protectores solares deben ser utilizados diariamente para prevenir el daño sobre la piel. Algunos de estos productos generan reacciones alérgicas y por esta razón es necesario investigar posibles opciones naturales para ser incorporadas en bloqueadores solares. Algunos productos naturales exhiben valores de SPF que permiten su uso como agentes protectores solares, adyuvantes o potenciadores en los bloqueadores solares.

Objetivo: realizar uma pesquisa bibliográfica sobre plantas disponíveis na Costa Rica que demonstraram poder antioxidante e um fator de proteção solar (FPS) adequado para uso em protetores solares. Métodos: a revisão bibliográfica foi realizada usando diferentes descritores e consultando diferentes bases de dados. Resultados: foram obtidas informações sobre o poder antioxidante das plantas: acerola, abacate, cenoura, maracujá, moringa, banana, abóbora e amaranto, goiaba, matico, ginkgo, amora, manga, café. As informações sugerem que as referidas plantas poderiam ser utilizadas para a formulação de protetores solares. Conclusões: protetores solares devem ser usados diariamente para prevenir danos à pele. Alguns desses produtos geram reações alérgicas e por isso é necessário investigar possíveis opções naturais para serem incorporadas aos protetores solares. Alguns produtos naturais apresentam valores de FPS que permitem seu uso como protetores solares, adjuvantes ou potencializadores em protetores solares.

Experimental Examination of Solubility and Lipophilicity as Pharmaceutically Relevant Points of Novel Bioactive Hybrid Compounds.

The important physicochemical properties of three novel bioactive hybrid compounds with different groups (-CH3, -F and -Cl) were studied, including kinetic and thermodynamic solubility in pharmaceutically relevant solvents (buffer solutions and 1-octanol) as well as partition coefficient in system 1-octanol/buffer pH 7.4. The aqueous solubility of these chemicals is poor and ranged from 0.67 × 10-4 to 1.98 × 10-3 mol·L-1. The compounds studied are more soluble in the buffer pH 2.0, simulating the gastrointestinal tract environment (by an order of magnitude) than in the buffer pH 7.4 modelling plasma of blood. The solubility in 1-octanol is significantly higher; that is because of the specific interactions of the compounds with the solvent. The prediction solubility behaviour of the hybrid compounds using Hansen's three-parameter approach showed acceptable results. The experimental solubility of potential drugs was successfully correlated by means of two commonly known equations: modified Apelblat and van't Hoff. The temperature dependencies of partition coefficients of new hybrids in the model system 1-octanol/buffer pH 7.4 as a surrogate lipophilicity were measured by the shake flask method. It was found that compounds demonstrated a lipophilic nature and have optimal values of partition coefficients for oral absorption. Bioactive assay manifested that prepared compounds showed antifungal activities equal to or greater than fluconazole. In addition, the thermodynamic aspects of dissolution and partition processes have been examined. Bioactive assay manifested that prepared compounds showed antifungal activities equal to or greater than the reference drug.

Formation Thermodynamics of Carbamazepine with Benzamide, Para-Hydroxybenzamide and Isonicotinamide Cocrystals: Experimental and Theoretical Study.

Formation thermodynamic parameters for three cocrystals of carbamazepine (CBZ) with structurally related coformers (benzamide (BZA), para-hydroxybenzamide (4-OH-BZA) and isonicotinamide (INAM)) were determined by experimental (cocrystal solubility and competitive reaction methods) and computational techniques. The experimental solubility values of cocrystal components at eutectic points and solubility product of cocrystals [CBZ + BZA], [CBZ + 4-OH-BZA], and [CBZ + INAM] in acetonitrile at 293.15 K, 298.15 K, 303.15 K, 308.15 K, and 313.15 K were measured. All the thermodynamic functions (Gibbs free energy, enthalpy, and entropy) of cocrystals formation were evaluated from the experimental data. The crystal structure of [CBZ + BZA] (1:1) cocrystal was solved and analyzed by the single crystal X-ray diffractometry. A correlation between the solubility products and pure coformers solubility values has been found for CBZ cocrystals. The relationship between the entropy term and the molecular volume of the cocrystal formation has been revealed. The effectiveness of the estimation of the cocrystal formation thermodynamic parameters, based on the knowledge of the melting temperatures of active pharmaceutical ingredients, coformers, cocrystals, as well as the sublimation Gibbs energies and enthalpies of the individual components, was proven. A new method for the comparative assessment of the cocrystal stability based on the H-bond propensity analysis was proposed. The experimental and theoretical results on the thermodynamic parameters of the cocrystal formation were shown to be in good agreement. According to the thermodynamic stability, the studied cocrystals can be arranged in the following order: [CBZ + 4-OH-BZA] > [CBZ + BZA] > [CBZ + INAM].

Comportamiento del condrosarcoma óseo en pacientes menores de 40 años / Chondrosarcoma of bone in young patients

Resumen El condrosarcoma ocupa el segundo lugar en frecuencia, entre los tumores malignos primarios óseos, en pacientes adultos. Típicamente afecta a adultos de entre 40 y 70 años, siendo la mayoría de las series publicadas de este grupo etario. El objetivo de este estudio fue comunicar una serie de pacientes adultos jóvenes (16 a 40 años) con diagnóstico de condrosarcoma óseo, que buscó describir las particularida des en la forma de presentación en esta población. De un total de 37 pacientes de 16 a 40 años operados por condrosarcoma en nuestro centro, entre los años 2008 y 2019, 18 presentaron tumores de bajo grado (G1/tumor cartilaginoso atípico), 16 de grado intermedio (G2), quedando una minoría con tumores de alto grado (2 con condrosarcoma G3 y 1 con un condrosarcoma desdiferenciado). La tasa de supervivencia global fue del 97% (IC 95% 82%-99%) a 2 años y 90.5% (IC 95% 73%-96%) a 5 años y la tasa libre de recurrencia local fue de 92% (IC 95% 77%-97.5%) a los 12 meses y de 89% a los 2 y 5 años (IC 95% 73%-96%). El grado histológico fue el factor pronóstico más relevante. La concordancia del grado histológico entre el diagnóstico preoperatorio de la biopsia y el material de resección quirúrgica fue del 81% (30/37).

Abstract Chondrosarcoma is the second most frequent primary malignant bone tumor. It is typically described in adults between 40 and 70 years of age, being the majority of the series published in this age group. The objective of this study was to report a series of young adults (16-40 years old) with a diagnosis of chondrosarcoma of bone in order to describe the particularities of this tumor in this population. From a total of 37 patients between 16 and 40 years old, surgically treated for chondrosar coma in our institution, 18 had low-grade tumors (G1/atypical cartilaginous tumor), 16 had an intermediate-grade (G2), and a minority had high-grade tumors (2 with a G3 and 1 with a dedifferentiated chondrosarcoma). The overall survival rate was 97% (95% CI 82%-99%) at 2 years of follow-up and 90.5% (95% CI 73-96) at 5 years of follow-up. The local recurrence free rate was 92% (95% CI % 77%-97.5%) at 1 year of follow-up and 89% at 2 and 5 years of follow-up (95% CI 73%-96%). Histological grade was the most relevant prognostic factor. The concordance of the histological grade between the preoperative diagnosis of the biopsy and the surgical resection material was 81% (30/37).

Another Move towards Bicalutamide Dissolution and Permeability Improvement with Acetylated ß-Cyclodextrin Solid Dispersion.

The complex formation of antiandrogen bicalutamide (BCL) with methylated (Me-ß-CD) and acetylated (Ac-ß-CD) ß-cyclodextrins was investigated in buffer solution pH 6.8. A two-fold strongly binding of BCL to Ac-ß-CD as compared to Me-ß-CD was revealed. The solid dispersion of BCL with Ac-ß-CD was prepared by the mechanical grinding procedure to obtain the complex in the solid state. The BCL/Ac-ß-CD complex was characterized by DSC, XPRD, FTIR, and SEM techniques. The effect of Ac-ß-CD in the BCL solid dispersions on the non-sink dissolution/permeation simultaneous processes was disclosed using the side-by-side diffusion cell with the help of the cellulose membrane. The elevated dissolution of the ground complex, as compared to the raw drug as well as the simple physical mixture, accompanied by the supersaturation was revealed. Two biopolymers-polyvinylpyrrolidone (PVP, Mn = 58,000) and hydroxypropylmethylcellulose (HPMC, Mn ~ 10,000)-were examined as the precipitation inhibitors and were shown to be useful in prolonging the supersaturation state. The BCL/Ac-ß-CD complex has the fastest dissolution rate in the presence of HPMC. The maximal concentration of the complex was achieved at a time of 20, 30, and 90 min in the pure buffer, with PVP and with HPMC, respectively. The effectiveness of the BCL dissolution (release) processes (illustrated by the AUCC(t) parameter) was estimated to be 7.8-, 5.8-, 3.0-, and 1.8-fold higher for BCL/Ac-ß-CD (HPMC), BCL/Ac-ß-CD (PVP), BCL/Ac-ß-CD (buffer), and the BCL/Ac-ß-CD physical mixture, respectively, as compared to the BCL_raw sample. The excipient gain factor (EGF), calculated for the dissolution of the BCL complex, was shown to be 2.6 in the presence of HPMC, which is 1.3-fold greater as compared to PVP. From the experimental dissolution results, it can be concluded that the formation of BCL ground complex with Ac-ß-CD enhances the dissolution rate of the compound. The permeation was also shown to be advantageous in the presence of the polymers, which was demonstrated by the elevated fluxes of BCL through the membrane. The comparison of the dissolution/permeation processes was illustrated and discussed. The conclusion was made that the presence of HPMC as a stabilizer of the supersaturation state is promising and seems to be a useful tool for the optimization of BCL pharmaceutical formulations manufacturing.

Aplicaciones de los nanoanticuerpos en la medicina / Nanoantibodies applications in medicine

Introducción: Los nanoanticuerpos están compuestos únicamente por la región variable de la cadena pesada y se obtienen a partir de algunas especies de camélidos y tiburones. Tienen alta capacidad de unión, alta especificidad, tamaño pequeño, alta accesibilidad y alta penetración de los tejidos, por lo que potencialmente podrían ser utilizados para el tratamiento, diagnóstico y prevención de diferentes enfermedades. Método: Se realizó una revisión bibliográfica de las aplicaciones médicas de los nanoanticuerpos. Se examinaron artículos científicos publicados en inglés y español desde 2015 a 2021 en las bases de datos Google Académico, ElSevier, PubMed, Clinical trials, Annual Reviews y ScienceDirect. Se prefirieron los estudios que demostraron mayor valor según el idioma, veracidad de la información y fecha de publicación. Resultados y discusión: En total, se seleccionaron 21 artículos para ser evaluados y analizados, de los cuales 20 fueron estudios preclínicos y un estudio clínico. Los nanoanticuerpos destacan como alternativas terapéuticas, diagnósticas y preventivas contra el cáncer, la hepatitis C, el Alzheimer, el Parkinson, la diarrea provocada por rotavirus y el COVID-19. Conclusiones: Los nanoanticuerpos pueden ser de gran utilidad para la prevención, diagnóstico y tratamiento de distintas enfermedades; sin embargo, se requiere continuar con el desarrollo de estudios clínicos y preclínicos que respalden la seguridad y eficacia de estos fármacos(AU)

Introduction: Nanoantibodies are composed solely of the variable region of the heavy chain and are obtained from some species of camelids and sharks. They have high binding capacity, high specificity, small size, high accessibility, and high tissue penetration, so they could potentially be used to treat, diagnose, and prevent several diseases. Method: A bibliographic review of the medical applications of nanoantibodies was carried out. Scientific articles were examined, published in English and Spanish from 2015 to 2021 in Google Academic, Elsevier, PubMed, Clinical trials, Annual Reviews, and ScienceDirect databases. Studies that showed greater value according to language, information accuracy, and publication date were preferred.Results and discussion:21 articles were selected to be evaluated and analyzed, of which 20 were preclinical studies and one clinical study. Nanoantibodies stand out as therapeutic, diagnostic, and preventive alternatives against cancer, hepatitis C, Alzheimer’s disease, Parkinson’s disease, diarrhea caused by rotavirus, and COVID-19. Conclusions: Nanoantibodies can be very useful for the prevention, diagnosis, and treatment of different diseases; however, it is necessary to continue developing clinical and preclinical studies that support the safety and efficacy of these drugs(AU)

[Chondrosarcoma of bone in young patients]. / Comportamiento del condrosarcoma óseo en pacientes menores de 40 años.

Chondrosarcoma is the second most frequent primary malignant bone tumor. It is typically described in adults between 40 and 70 years of age, being the majority of the series published in this age group. The objective of this study was to report a series of young adults (16-40 years old) with a diagnosis of chondrosarcoma of bone in order to describe the particularities of this tumor in this population. From a total of 37 patients between 16 and 40 years old, surgically treated for chondrosarcoma in our institution, 18 had low-grade tumors (G1/atypical cartilaginous tumor), 16 had an intermediate-grade (G2), and a minority had high-grade tumors (2 with a G3 and 1 with a dedifferentiated chondrosarcoma). The overall survival rate was 97% (95% CI 82%-99%) at 2 years of follow-up and 90.5% (95% CI 73-96) at 5 years of follow-up. The local recurrence free rate was 92% (95% CI % 77%-97.5%) at 1 year of follow-up and 89% at 2 and 5 years of follow-up (95% CI 73%-96%). Histological grade was the most relevant prognostic factor. The concordance of the histological grade between the preoperative diagnosis of the biopsy and the surgical resection material was 81% (30/37).

El condrosarcoma ocupa el segundo lugar en frecuencia, entre los tumores malignos primarios óseos, en pacientes adultos. Típicamente afecta a adultos de entre 40 y 70 años, siendo la mayoría de las series publicadas de este grupo etario. El objetivo de este estudio fue comunicar una serie de pacientes adultos jóvenes (16 a 40 años) con diagnóstico de condrosarcoma óseo, que buscó describir las particularidades en la forma de presentación en esta población. De un total de 37 pacientes de 16 a 40 años operados por condrosarcoma en nuestro centro, entre los años 2008 y 2019, 18 presentaron tumores de bajo grado (G1/tumor cartilaginoso atípico), 16 de grado intermedio (G2), quedando una minoría con tumores de alto grado (2 con condrosarcoma G3 y 1 con un condrosarcoma desdiferenciado). La tasa de supervivencia global fue del 97% (IC 95% 82%-99%) a 2 años y 90.5% (IC 95% 73%-96%) a 5 años y la tasa libre de recurrencia local fue de 92% (IC 95% 77%-97.5%) a los 12 meses y de 89% a los 2 y 5 años (IC 95% 73%-96%). El grado histológico fue el factor pronóstico más relevante. La concordancia del grado histológico entre el diagnóstico preoperatorio de la biopsia y el material de resección quirúrgica fue del 81% (30/37).

Simultaneous Improvement of Dissolution Behavior and Oral Bioavailability of Antifungal Miconazole via Cocrystal and Salt Formation.

Miconazole shows low oral bioavailability in humans due to poor aqueous solubility, although it has demonstrated various pharmacological activities such as antifungal, anti-tubercular and anti-tumor effects. Cocrystal/salt formation is one of the effective methods for solving this problem. In this study, different methods (liquid-assisted grinding, slurrying and lyophilization) were used to investigate their impact on the formation of the miconazole multicomponent crystals with succinic, maleic and dl-tartaric acids. The solid state of the prepared powder was characterized by differential scanning calorimetry, powder X-ray diffraction and scanning electron microscopy. It was found that lyophilization not only promotes partial amorphization of both salts but also allows obtaining a new polymorph of the miconazole salt with dl-tartaric acid. The lyophilized salts compared with the same samples prepared by two other methods showed better dissolution rates but low stability during the studies due to rapid recrystallization. Overall, it was determined that the preparation method of multicomponent crystals affects the solid-state characteristics and miconazole physicochemical properties significantly. The in vivo studies revealed that the miconazole multicomponent crystals indicated the higher peak blood concentration and area under the curve from 0 to 32 h values 2.4-, 2.9- and 4.6-fold higher than the pure drug. Therefore, this study demonstrated that multicomponent crystals are promising formulations for enhancing the oral bioavailability of poorly soluble compounds.

Chiral Recognition R- and RS- of New Antifungal: Complexation/Solubilization/Dissolution Thermodynamics and Permeability Assay.

Novel potential antifungal of 1,2,4-triazole class have been synthesized as pure enantiomer (R-98) and racemic (RS-186). The effect of 2-hydroxypropyl-ß-cyclodextrin (CD) on the solubility and permeability of RS-186 and R-98 in terms of chiral recognition was investigated. Phase solubility studies were carried out at 4 temperatures in 0-0.05 M CD concentration range for pH 2.0 and pH 7.4. AL- and AL--type phase-solubility profiles were obtained for both compounds in pH 2.0 and pH 7.4. The racemic formed more stable complexes with CD as compared to R-isomer. Disclosing of chiral discrimination was facilitated using the approach based on the complex consideration of the derived complexation/solubilization/inherent dissolution thermodynamic functions, including the differential parameters between the racemic compound and R-enantiomer. The differences in the thermodynamic parameters determined by the chirality were discussed in terms of the driving forces of the processes and the main interactions of the compounds with CD in solution. The membrane permeability of both samples in the presence of CD was accessed in order to evaluate the specificity of enantioselective transport through the lipophilic membrane. The solubility/permeability interrelation was disclosed. The investigated compounds were classified as medium permeable in pure buffers and low permeable in the presence of 0.01 M CD. The obtained results can be useful for the design of pharmaceutical products in the form of liquid formulations based on the investigated substances.