Differential modulation of cell morphology, migration, and Neuropilin-1 expression in cancer and non-cancer cell lines by substrate stiffness.

Physical changes in the tumor microenvironment, such as increased stiffness, regulate cancer hallmarks and play an essential role in gene expression, cell morphology, migration, and malignancy. However, the response of cancer cells to stiffness is not homogeneous and varies depending on the cell type and its mechanosensitivity. In this study, we investigated the differential responses of cervical (HeLa) and prostate (PC-3) cancer cell lines, as well as non-tumoral cell lines (HEK293 and HPrEC), to stiffness using polyacrylamide hydrogels mimicking normal and tumoral tissues. We analyzed cell morphology, migration, and the expression of neuropilin 1 (NRP1), a receptor involved in angiogenesis, cell migration, and extracellular matrix remodeling, known to be associated with cancer progression and poor prognosis. Our findings reveal that NRP1 expression increases on substrates mimicking the high stiffness characteristic of tumoral tissue in the non-tumoral cell lines HPrEC and HEK293. Conversely, in tumoral PC-3 cells, stiffness resembling normal prostate tissue induces an earlier and more sustained expression of NRP1. Furthermore, we observed that stiffness influences cell spreading, pseudopodia formation, and the mode of cell protrusion during migration. Soft substrates predominantly trigger bleb cell protrusion, while pseudopodia protrusions increase on substrates mimicking normal and tumor-like stiffnesses in HPrEC cells compared to PC-3 cells. Stiffer substrates also enhance the percentage of migratory cells, as well as their velocity and total displacement, in both non-tumoral and tumoral prostate cells. However, they only improve the persistence of migration in tumoral PC-3 cells. Moreover, we found that NRP1 co-localizes with actin, and its suppression impairs tumoral PC-3 spreading while decreasing pseudopodia protrusion mode. Our results suggest that the modulation of NRP1 expression by the stiffness can be a feedback loop to promote malignancy in non-tumoral and cancer cells, contingent upon the mechanosensitivity of the cells.

Editorial for the Special Issue "Hydrogels for 3D Printing".

Hydrogels, which are three-dimensional networks of hydrophilic polymers capable of absorbing and retaining large amounts of water, have emerged as versatile materials with vast potential in various fields [...].

Sonchus oleraceus L.: ethnomedical, phytochemical and pharmacological aspects.

Sonchus oleraceus L. (Asteraceae) is a cosmopolitan species native to Europe commonly known as lettuce, sowthistle, chicory, or fake dandelion, considered a weed. However, for many years in various cultures around the world, it has been used as food and medicinal plant. The aim of this integrative review is to document the ethnomedical, phytochemical, and pharmacological information of this species. Forty-one papers document the use of S. oleraceus to heal of a wide variety of diseases. However, gastrointestinal problems, diabetes, inflammation, infections, hepatitis, wounds, and to consume it as food are the most common uses. On the other hand, only 11 items highlight that the main groups of secondary metabolites in this species are flavonoids and terpene lactones. Finally, 45 items reveal that antioxidant, antimicrobial, antiproliferative and cytotoxic were the most studied pharmacological activities. In vitro and in vivo studies of extracts and components isolated from different parts of S. oleraceus have provided a concrete overview of the pharmacological properties of this species that supports its ethnomedical uses in cultures from different parts of the world. The reports of this species have focused solely on the study of the complete plant, leaves, and aerial parts, so it is necessary to study other parts of this species to search for bioactive compounds. No clinical studies were found, which creates an opportunity to expand scientific knowledge of this species.

Pellets and gummies: Seeking a 3D printed gastro-resistant omeprazole dosage for paediatric administration.

The production of 3D printed pharmaceuticals has thrived in recent years, as it allows the generation of customised medications in small batches. This is particularly helpful for patients who need specific doses or formulations, such as children. Compounding pharmacies seek alternatives to conventional solid oral doses, opting for oral liquid formulations. However, ensuring quality and stability, especially for pH-sensitive APIs like omeprazole, remains a challenge. This paper presents the application of semi-solid extrusion 3D printing technology to develop patient-tailored medicinal gummies, with an eye-catching appearances, serving as an innovative omeprazole pharmaceutical form for paediatric use. The study compares 3D printing hydrogels with dissolved omeprazole to hydrogels loaded with gastro-resistant omeprazole pellets, a ground-breaking approach.. Gastro-resistance and dissolution profiles were studied using different methods for better comparison and to emphasize the significance of the assay's methodology. Both developed formulas exhibit proper rheology, good printability, and meet content and mass uniformity standards. However, the high gastro-resistance and suitable release profile of 3D printed chewable semi-solid doses with enteric pellets highlight this as an effective strategy to address the challenge of paediatric medication.

Essential Guide to Hydrogel Rheology in Extrusion 3D Printing: How to Measure It and Why It Matters?

Rheology plays a crucial role in the field of extrusion-based three-dimensional (3D) printing, particularly in the context of hydrogels. Hydrogels have gained popularity in 3D printing due to their potential applications in tissue engineering, regenerative medicine, and drug delivery. The rheological properties of the printing material have a significant impact on its behaviour throughout the 3D printing process, including its extrudability, shape retention, and response to stress and strain. Thus, understanding the rheological characteristics of hydrogels, such as shear thinning behaviour, thixotropy, viscoelasticity, and gelling mechanisms, is essential for optimising the printing process and achieving desired product quality and accuracy. This review discusses the theoretical foundations of rheology, explores different types of fluid and their properties, and discusses the essential rheological tests necessary for characterising hydrogels. The paper emphasises the importance of terminology, concepts, and the correct interpretation of results in evaluating hydrogel formulations. By presenting a detailed understanding of rheology in the context of 3D printing, this review paper aims to assist researchers, engineers, and practitioners in the field of hydrogel-based 3D printing in optimizing their printing processes and achieving desired product outcomes.

Gold-catalyzed endo-selective cyclization of alkynylcyclobutanecarboxamides: synthesis of cyclobutane-fused dihydropyridones.

Cyclobutane-fused dihydropyridones can be efficiently synthesized by a completely endo-selective gold-catalyzed cyclization of alkynylcyclobutanes bearing an appended amide, which proceeds under mild conditions. The observed selectivity, which is reversed from that previously observed for the cyclization of related alcohols and acids, is supported by DFT calculations.

Subclassification of B-acute lymphoblastic leukemia according to age, immunophenotype and microenvironment, predicts MRD risk in Mexican children from vulnerable regions.

Introduction: The decisive key to disease-free survival in B-cell precursor acute lymphoblastic leukemia in children, is the combination of diagnostic timeliness and treatment efficacy, guided by accurate patient risk stratification. Implementation of standardized and high-precision diagnostic/prognostic systems is particularly important in the most marginalized geographic areas in Mexico, where high numbers of the pediatric population resides and the highest relapse and early death rates due to acute leukemias are recorded even in those cases diagnosed as standard risk. Methods: By using a multidimensional and integrated analysis of the immunophenotype of leukemic cells, the immunological context and the tumor microenvironment, this study aim to capture the snapshot of acute leukemia at disease debut of a cohort of Mexican children from vulnerable regions in Puebla, Oaxaca and Tlaxcala and its potential use in risk stratification. Results and discussion: Our findings highlight the existence of a distinct profile of ProB-ALL in children older than 10 years, which is associated with a six-fold increase in the risk of developing measurable residual disease (MRD). Along with the absence of CD34+ seminal cells for normal hematopoiesis, this ProB-ALL subtype exhibited several characteristics related to poor prognosis, including the high expression level of myeloid lineage markers such as MPO and CD33, as well as upregulation of CD19, CD34, CD24, CD20 and nuTdT. In contrast, it showed a trend towards decreased expression of CD9, CD81, CD123, CD13, CD15 and CD21. Of note, the mesenchymal stromal cell compartment constituting their leukemic niche in the bone marrow, displayed characteristics of potential suppressive microenvironment, such as the expression of Gal9 and IDO1, and the absence of the chemokine CXCL11. Accordingly, adaptive immunity components were poorly represented. Taken together, our results suggest, for the first time, that a biologically distinct subtype of ProB-ALL emerges in vulnerable adolescents, with a high risk of developing MRD. Rigorous research on potential enhancing factors, environmental or lifestyle, is crucial for its detection and prevention. The use of the reported profile for early risk stratification is suggested.

Siderosis idiopática del sistema nervioso central y asociación con atrofia óptica e infarto cerebral. Caso clínico / Superficial siderosis of the central nervous system. Report of one case

Superficial siderosis of the central nervous system is produced by the deposit of hemosiderin within the subpial layers of the central nervous system and central parts of the cranial nerves, leading to progressive degeneration. We report a 55-year-old male who consulted for hearing loss and long-standing progressive decrease in visual acuity, associated with sudden onset of left hemiparesis. A brain CAT scan showed subacute ischemic lesions in the territory of the right posterior cerebral artery (thalamus and right subcortical temporal regions), old ischemic lesions in the right subcortical occipital regions and cerebellar atrophy. A magnetic resonance confirmed the lesions and the presence of superficial diffuse siderosis. A cerebrospinal fluid analysis showed slight xanthochromia, 26 leukocytes/mm3, glucose 51 mg/dL and proteins 1.23 g/L. He was managed with aspirin in low doses and statins. His motor function improved and was discharged two weeks after admission.

The role of growth hormone in hippocampal function.

Growth hormone is a multifunctional molecule with broad cellular targets. This pituitary hormone is currently used as a therapeutic agent against several brain injuries due to its neurotrophic activity. The hippocampus is one of the brain regions where the growth hormone plays a role in normal and pathologic conditions. This brain structure is associated with several cognitive functions such as learning, memory, and mood, which are frequently affected by brain traumatism. The present chapter describes the experimental and clinical evidence that supports a central role of growth hormone in the hippocampus functionality.

Effect on Rheological Properties and 3D Printability of Biphasic Calcium Phosphate Microporous Particles in Hydrocolloid-Based Hydrogels.

The production of patient-specific bone substitutes with an exact fit through 3D printing is emerging as an alternative to autologous bone grafting. To the success of tissue regeneration, the material characteristics such as porosity, stiffness, and surface topography have a strong influence on the cell-material interaction and require significant attention. Printing a soft hydrocolloid-based hydrogel reinforced with irregularly-shaped microporous biphasic calcium phosphate (BCP) particles (150-500 µm) is an alternative strategy for the acquisition of a complex network with good mechanical properties that could fulfill the needs of cell proliferation and regeneration. Three well-known hydrocolloids (sodium alginate, xanthan gum, and gelatin) have been combined with BCP particles to generate stable, homogenous, and printable solid dispersions. Through rheological assessment, it was determined that the crosslinking time, printing process parameters (infill density percentage and infill pattern), as well as BCP particle size and concentration all influence the stiffness of the printed matrices. Additionally, the swelling behavior on fresh and dehydrated 3D-printed structures was investigated, where it was observed that the BCP particle characteristics influenced the constructs' water absorption, particle diffusion out of the matrix and degradability.

[Superficial siderosis of the central nervous system. Report of one case]. / Siderosis idiopática del sistema nervioso central y asociación con atrofia óptica e infarto cerebral. Caso clínico.

Superficial siderosis of the central nervous system is produced by the deposit of hemosiderin within the subpial layers of the central nervous system and central parts of the cranial nerves, leading to progressive degeneration. We report a 55-year-old male who consulted for hearing loss and long-standing progressive decrease in visual acuity, associated with sudden onset of left hemiparesis. A brain CAT scan showed subacute ischemic lesions in the territory of the right posterior cerebral artery (thalamus and right subcortical temporal regions), old ischemic lesions in the right subcortical occipital regions and cerebellar atrophy. A magnetic resonance confirmed the lesions and the presence of superficial diffuse siderosis. A cerebrospinal fluid analysis showed slight xanthochromia, 26 leukocytes/mm3, glucose 51 mg/dL and proteins 1.23 g/L. He was managed with aspirin in low doses and statins. His motor function improved and was discharged two weeks after admission.

Management experience of pediatric meningioma in a Mexican reference center.

OBJECTIVE: Determine the histopathological and clinical characteristics of patients diagnosed with meningiomas and to establish the frequency of these tumors in the pediatric population Mexican. Determine the NF1/2 frequency in meningioma pediatric. METHODS: Samples from the histopathology file were reviewed, and from the complete clinical file the following patient data was reviewed: age, gender, diagnosis, diagnosis year, surgical resection, location, tumor size, symptoms, and family background. The frequency of NF1/2 in pediatric meningioma was reviewed in literature. RESULTS: Forty-four de novo cases were collected from pediatric patients; 19 were female patients and 25 males. The most frequent histological subtype was transitional meningioma. Of all the cases, 75% had a supratentorial localization and 20% had an extramedullary intrarachidian localization. Some clinical manifestations included seizures, paresis, headache, and visual disturbances. CONCLUSION: There is a low incidence of meningiomas in the pediatric population, more than 70% are Grade I, and they have supratentorial localization.

Three-dimensional bioprinted cancer models: A powerful platform for investigating tunneling nanotube-like cell structures in complex microenvironments.

Bioprinting technology offers layer-by-layer positioning of cells within 3D space with complexity and a defined architecture. Cancer models based in this biofabrication technique are important tools to achieve representative and realistic in vivo conditions of the tumor microenvironment. Here, we show the development of a proof-of-concept three-dimensional bioprinted cancer model that successfully recapitulates the intercellular communication via the assembly of functional tunneling nanotube (TNT)-like cell projections. Different combinations of collagen-containing culture medium, sodium alginate and gelatin were initially prepared and rheologically evaluated. The optimized mixture was used to print two preliminary 3D models for cancer cell seeding. Favourable results in cell viability and proliferation led to the inclusion of 786-O renal cancer cells into the biomaterial mixture to directly bioprint the most suitable 3D model with embedded cells. Bioprinted cells remained viable for at least 15 days of culture and proliferated. More importantly, these cancer cells were able to build TNT-like cellular projections inside the hydrogel that established direct contacts between distant cells. We show that these structures were used as channels for the scrolling and intercellular transfer of mitochondria thus reproducing TNT's function in 2D culture systems. This 3D bioprinted renal cancer model provides a novel alternative tool for studying the functional relevance of TNT-like structures in tumorigenesis and anticancer drug susceptibility in a highly controlled and reproducible tumor microenvironment.

Mannich bases of hydroxycoumarins: synthesis, DFT/QTAIM computational study and assessment of biological activity.

The synthesis of six Mannich bases derived from hydroxycoumarins was carried out in moderate yields, two of these derivatives were described for the first time. Conformational analysis was performed through DFT theoretical calculations explaining the formation of stable six membered rings based on intramolecular hydrogen bonds within the structure. These findings were correlated with the antiproliferative activity. The biological activity of the Mannich bases through their antiproliferative activity in the HeLa cancer cell line is described for the first time, showing that the compounds were able to inhibit proliferation in cervical cancer by more than 60%. Likewise, the theoretical modeling of the photophysical properties was realized with promising results, showing that the HOMO-LUMO energies of the new compounds present the lowest electronic gap values for those with donor groups in their structure, which makes them potential fluorophores.

Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma.

Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.

3D printed gummies: Personalized drug dosage in a safe and appealing way.

Obtention of customized dosage forms is one of the main attractions of 3D printing in pharmaceuticals. In this sense, children are one of the groups within the population with a greater need for drug doses adapted to their requirements (age, weight, pathological state…), but most 3D printed oral dosages are solid forms and, therefore, not suitable for them. This work developed patient-tailored medicinal gummies, an alternative oral dosage form with eye-catching appearance and appropriate organoleptic characteristics. Four inks were formulated, characterised and 3D printed by means of syringe-based extrusion mechanism. Different tests were performed to ensure reproducibility of the process and validate work methodology for dosage unit fabrication applying basic manufacturing standards. Rheological test helped in evaluating inks printability. Visual characterization concluded that drugmies, apart from a high fidelity in the 3D model shape reproduction, had a bright and uniformly coloured appearance and a pleasant aroma, which made them highly appetising and attractive. The printed gummy oral dosages complied comfortably with the mass uniformity assay regardless of the formulated ink used or the 3D model selected for printing. Ranitidine hydrochloride individual contents were determined using uv-vis spectrophotometry, showing successful results both in dose accuracy, uniformity of drug content and dissolution.

Predictors of anthracycline-induced cardiotoxicity in a retro-prolective cohort of children surviving cancer.

INTRODUCTION: Cardiotoxicity is an adverse reaction associated with the use of anthracyclines. OBJECTIVE: To estimate the factors associated with the development of anthracycline cardiotoxicity in pediatric patients surviving cancer. METHOD: Retro-prolective cohort of children diagnosed with cancer and treated with anthracyclines. Baseline echocardiographic determination of ejection fraction (LVEF0) was carried out before the start of treatment and again at 12 months (LVEF1). Demographic characteristics and treatment were obtained from the medical record. A multiple logistic regression (MLR) model was constructed; LVEF1 < 50 % was the dependent variable, which was adjusted for the main confounding variables. RESULTS: Sixty-five patients were included, out of which 36.9 % were females and 56.8 % had a solid tumor. LVEF0 was 74.79 ± 7.3 % and LVEF1, 67.96 ± 6.7 % (p = 0.001); 60 % developed cardiotoxicity. In the MLR, only a cumulative dose > 430 mg was associated with cardiotoxicity (p = 0.001). CONCLUSIONS: In Mexican children, an anthracycline cumulative dose > 430 mg should be avoided in order to prevent cardiotoxicity.

INTRODUCCIÓN: La cardiotoxicidad es una reacción adversa asociada al uso de antraciclinas. OBJETIVO: Estimar los factores asociados al desarrollo de cardiotoxicidad por antraciclinas en pacientes pediátricos supervivientes de cáncer. MÉTODO: Cohorte retroprolectiva de niños con diagnóstico de cáncer tratados con antraciclinas. Se realizó determinación ecocardiográfica basal de la fracción de expulsión (FEVi0) antes del inicio del tratamiento y a los 12 meses (FEVi1). Del expediente se obtuvieron las características demográficas y el tratamiento. Se realizó un modelo de regresión logística múltiple (RLM); la FEVi1 < 50 % fue la variable dependiente, que se ajustó por las principales variables confusoras. RESULTADOS: Se incluyeron 65 pacientes, 36.9 % fue del sexo femenino y 56.8 % presentó un tumor sólido. La FEVi0 fue de 74.79 ± 7.3 % y la FEVi1, de 67.96 ± 6.7 % (p = 0.001); 60 % desarrolló cardiotoxicidad. En la RLM solo la dosis acumulada > 430 mg se asoció a cardiotoxicidad (p = 0.001). CONCLUSIONES: En los niños mexicanos se debe evitar una dosis acumulada > 430 mg de antraciclinas para evitar la cardiotoxicidad.

Factores predictivos de cardiotoxicidad inducida por antraciclinas en una cohorte retroprolectiva de niños supervivientes de cáncer / Predictors of anthracycline-induced cardiotoxicity in a retro-prolective cohort of children surviving cancer

Resumen Introducción: La cardiotoxicidad es una reacción adversa asociada al uso de antraciclinas. Objetivo: Estimar los factores asociados al desarrollo de cardiotoxicidad por antraciclinas en pacientes pediátricos supervivientes de cáncer. Método: Cohorte retroprolectiva de niños con diagnóstico de cáncer tratados con antraciclinas. Se realizó determinación ecocardiográfica basal de la fracción de expulsión (FEVi0) antes del inicio del tratamiento y a los 12 meses (FEVi1). Del expediente se obtuvieron las características demográficas y el tratamiento. Se realizó un modelo de regresión logística múltiple (RLM); la FEVi1 < 50 % fue la variable dependiente, que se ajustó por las principales variables confusoras. Resultados: Se incluyeron 65 pacientes, 36.9 % fue del sexo femenino y 56.8 % presentó un tumor sólido. La FEVi0 fue de 74.79 ± 7.3 % y la FEVi1, de 67.96 ± 6.7 % (p = 0.001); 60 % desarrolló cardiotoxicidad. En la RLM solo la dosis acumulada > 430 mg se asoció a cardiotoxicidad (p = 0.001). Conclusiones: En los niños mexicanos se debe evitar una dosis acumulada > 430 mg de antraciclinas para evitar la cardiotoxicidad.

Abstract Introduction Cardiotoxicity is an adverse reaction associated with the use of anthracyclines. Objective: To estimate the factors associated with the development of anthracycline cardiotoxicity in pediatric patients surviving cancer. Method: Retro-prolective cohort of children diagnosed with cancer and treated with anthracyclines. Baseline echocardiographic determination of ejection fraction (LVEF0) was carried out before the start of treatment and again at 12 months (LVEF1). Demographic characteristics and treatment were obtained from the medical record. A multiple logistic regression (MLR) model was constructed; LVEF1 < 50 % was the dependent variable, which was adjusted for the main confounding variables. Results: Sixty-five patients were included, out of which 36.9 % were females and 56.8 % had a solid tumor. LVEF0 was 74.79 ± 7.3 % and LVEF1, 67.96 ± 6.7 % (p = 0.001); 60 % developed cardiotoxicity. In the MLR, only a cumulative dose > 430 mg was associated with cardiotoxicity (p = 0.001). Conclusions: In Mexican children, an anthracycline cumulative dose > 430 mg should be avoided in order to prevent cardiotoxicity.