Mechanistic insights into the antitumoral potential and in vivo antiproliferative efficacy of a silver-based core@shell nanosystem.

This study delves into the biomolecular mechanisms underlying the antitumoral efficacy of a hybrid nanosystem, comprised of a silver core@shell (Ag@MSNs) functionalized with transferrin (Tf). Employing a SILAC proteomics strategy, we identified over 150 de-regulated proteins following exposure to the nanosystem. These proteins play pivotal roles in diverse cellular processes, including mitochondrial fission, calcium homeostasis, endoplasmic reticulum (ER) stress, oxidative stress response, migration, invasion, protein synthesis, RNA maturation, chemoresistance, and cellular proliferation. Rigorous validation of key findings substantiates that the nanosystem elicits its antitumoral effects by activating mitochondrial fission, leading to disruptions in calcium homeostasis, as corroborated by RT-qPCR and flow cytometry analyses. Additionally, induction of ER stress was validated through western blotting of ER stress markers. The cytotoxic action of the nanosystem was further affirmed through the generation of cytosolic and mitochondrial reactive oxygen species (ROS). Finally, in vivo experiments using a chicken embryo model not only confirmed the antitumoral capacity of the nanosystem, but also demonstrated its efficacy in reducing cellular proliferation. These comprehensive findings endorse the potential of the designed Ag@MSNs-Tf nanosystem as a groundbreaking chemotherapeutic agent, shedding light on its multifaceted mechanisms and in vivo applicability.

Magnetic colloidal nanoformulations to remotely trigger mechanotransduction for osteogenic differentiation.

Nowadays, diseases associated with an ageing population, such as osteoporosis, require the development of new biomedical approaches to bone regeneration. In this regard, mechanotransduction has emerged as a discipline within the field of bone tissue engineering. Herein, we have tested the efficacy of superparamagnetic iron oxide nanoparticles (SPIONs), obtained by the thermal decomposition method, with an average size of 13 nm, when exposed to the application of an external magnetic field for mechanotransduction in human bone marrow-derived mesenchymal stem cells (hBM-MSCs). The SPIONs were functionalized with an Arg-Gly-Asp (RGD) peptide as ligand to target integrin receptors on cell membrane and used in colloidal state. Then, a comprehensive and comparative bioanalytical characterization of non-targeted versus targeted SPIONs was performed in terms of biocompatibility, cell uptake pathways and mechanotransduction effect, demonstrating the osteogenic differentiation of hBM-MSCs. A key conclusion derived from this research is that when the magnetic stimulus is applied in the first 30 min of the in vitro assay, i.e., when the nanoparticles come into contact with the cell membrane surface to initiate endocytic pathways, a successful mechanotransduction effect is observed. Thus, under the application of a magnetic field, there was a significant increase in runt-related transcription factor 2 (Runx2) and alkaline phosphatase (ALP) gene expression as well as ALP activity, when cells were exposed to RGD-functionalized SPIONs, demonstrating osteogenic differentiation. These findings open new expectations for the use of remotely activated mechanotransduction using targeted magnetic colloidal nanoformulations for osteogenic differentiation by drug-free cell therapy using minimally invasive techniques in cases of bone loss.

Immune thrombocytopenia in systemic lupus erythematosus: Prevalence, risk factors, and a novel predictive model for risk assessment.

INTRODUCTION: Immune thrombocytopenia (ITP) is a potentially severe manifestation of systemic lupus erythematosus (SLE) reported in 7-40% of SLE patients. ITP has been associated with a higher risk of organ damage and mortality. OBJECTIVES: To describe which factors are associated with the presence of ITP in SLE patients. METHODS: Retrospective case-control study. Cases were defined as SLE patients who had ever developed ITP and were sex- and age-matched with two controls. A predictive model was constructed to identify SLE patients who were at risk of developing ITP. RESULTS: ITP prevalence in our SLE cohort was 8.35%. Cases had a higher frequency of hemolytic anemia, while controls had a higher prevalence of arthritis at SLE diagnosis. During SLE progression, cases tested positive for anticardiolipin, anti-ß2-glycoprotein 1, and lupus anticoagulant antibodies more frequently. Cases received mycophenolic acid and azathioprine more often than controls and had a higher SLICC/ACR score. The model demonstrated a sensitivity of 87.53%, a positive predictive value of 81.92%, a specificity of 80.50%, area under the curve of 83.92%, a F1 of 83% and an overall accuracy of 83.68%. The variables that best explain the model were hemolytic anemia, arthritis, oral ulcers, Raynaud's phenomenon, low C4, low CH50, anticardiolipin and anti-ß2GP1 antibodies. CONCLUSION: SLE patients who develop ITP have a distinct phenotype characterized by more hemolytic anemia and less arthritis at SLE onset, and higher prevalence of antiphospholipid syndrome antibodies during SLE progression. This phenotype is associated with heightened organ damage and the need for more intensive therapies and stricter follow-up. Our predictive model has demonstrated an impressive ability to identify SLE patients at risk of developing ITP.

Cell-Free DNA as a Biomarker at Diagnosis and Follow-Up in 256 B and T-Cell Lymphomas.

BACKGROUND: Cell-free DNA (cfDNA) analysis has become a promising tool for the diagnosis, prognosis, and monitoring of lymphoma cases. Until now, research in this area has mainly focused on aggressive lymphomas, with scanty information from other lymphoma subtypes. METHODS: We selected 256 patients diagnosed with lymphomas, including a large variety of B-cell and T-cell non-Hodgkin and Hodgkin lymphomas, and quantified cfDNA from plasma at the time of diagnosis. We further selected 49 large B-cell lymphomas (LBCL) and analyzed cfDNA levels at diagnosis (pre-therapy) and after therapy. In addition, we performed NGS on cfDNA and tissue in this cohort of LBCL. RESULTS: Lymphoma patients showed a statistically significant higher cfDNA concentration than healthy controls (mean 53.0 ng/mL vs. 5.6 ng/mL, p < 0.001). The cfDNA concentration was correlated with lymphoma subtype, lactate dehydrogenase, the International Prognostic Index (IPI) score, Ann Arbor (AA), and B-symptoms. In 49 LBCL cases, the cfDNA concentration decreased after therapy in cases who achieved complete response (CR) and increased in non-responders. The median cfDNA at diagnosis of patients who achieved CR and later relapsed was higher (81.5 ng/mL) compared with levels of those who did not (38.6 ng/mL). A concordance of 84% was observed between NGS results in tumor and cfDNA samples. Higher VAF in cfDNA is correlated with advanced stage and bulky disease. CONCLUSIONS: cfDNA analysis can be easily performed in almost all lymphoma cases. The cfDNA concentration correlated with the characteristics of the aggressiveness of the lymphomas and, in LBCL, with the response achieved after therapy. These results support the utility of cfDNA analysis as a complementary tool in the management of lymphoma patients.

Sex Differences in the Relationship between Personal, Psychological and Biochemical Factors with Blood Pressure in a Healthy Adult Mexican Population: A Cross-Sectional Study.

Hypertension is one of the main risk factors related to cardiovascular mortality, being the levels of blood pressure (BP) related to a variety of personal, anthropometric, biochemical and psychological variables; however, the study evaluating the association of all these factors in systolic blood pressure (SBP) and diastolic blood pressure (DBP) in a sample of relatively healthy subjects has not been performed. The aim of the study was to determine the main variables associated with SBP and DPB in a sample of relatively healthy subjects. A total of 171 participants were included, in which personal, anthropometric, positive and negative psychological variables and biochemical variables were measured. We observed that men showed higher levels of SBP and DBP than women, with more differences for SBP. Among the biochemical factors and SBP, we found that albumin and monocytes were positively correlated with it, while potassium, phosphorus and eosinophils were negatively correlated with it. Additionally, schooling was a constant variable negatively correlated with SBP in all samples (global, men and women). Among psychological variables, we observed that emotional perception was negatively correlated with SBP in men's and women's samples, while autonomy was positively correlated with SBP in the men's sample; however, their association was less when compared with the personal and biochemical variables included in the multivariate model. With regard to DBP, we observed that the biochemical variables, hemoglobin, sodium, uric acid and glucose, were positively correlated with DBP in the global sample, while chloride and BUN were negatively correlated with it. In addition, many personal and behavioral variables, including BMI, age and smoking consumption frequency, also correlated with DBP in the global sample. In conclusion, BP is affected by different factors, and these affect each sex differently.

[Deshabituación al consumo de tabaco desde las oficinas de farmacia mediante planes multidisciplinares.] / Smoking cessation from pharmacies through multidisciplinary plans.

OBJECTIVE: Tobacco is the most consumed drug in the world and each year it causes the death of more than eight million people. The pharmacist is the healthcare professional most accessible to smokers, therefore they are essential in the treatment and prevention of smoking. The study´s aim was to implement a multidisciplinary anti-smoking program in a pharmacy and evaluate the effect of pharmaceutical care on smoking cessation. METHODS: The study was carried out in two army pharmacies located in Spain and Lebanon in which a smoking cessation plan was developed in 2020 and 2021. As the requirements for participants selection, all those patients in the area of influence of pharmacies that agreed to participate in the program were accepted, with a sample size of thirty-eight people. The patients underwent an addiction, motivation and smoking habit test, and a descriptive analysis of the data provided was carried out, using the chi-square test for the comparison of values. Only those with a probability value less than 0.05 are considered statistically significant. RESULTS: The multidisciplinary work allowed treatment with prescription drugs. The study shows that 63% of patients managed to quit smoking. CONCLUSIONS: Pharmacies can implement and lead smoking cessation programs that facilitate cessation and adherence to treatments. The classification of patients according to their history of smoking is key to carrying out an adequate and personalized treatment.

OBJETIVO: El tabaco es la droga más consumida en el mundo y cada año provoca la muerte de más de ocho millones de personas. El farmacéutico es el profesional de la salud más accesible a los fumadores, por lo que es fundamental en el tratamiento y prevención del tabaquismo. El objetivo de este estudio fue implantar un programa antitabaco multidisciplinar en una oficina de farmacia y evaluar el efecto de la atención farmacéutica en la cesación del consumo de tabaco. METODOS: El estudio se realizó en dos farmacias del Ejército de Tierra situadas en España y Líbano en las que se desarrolló un plan de deshabituación al consumo de tabaco durante los años 2020 y 2021. Como criterio de selección de participantes se aceptó a todos aquellos pacientes del área de influencia de las farmacias que aceptasen participar en el programa, siendo el tamaño muestral de treinta y ocho personas. Los pacientes se sometieron a test de adicción, motivación y hábito de consumo de tabaco, y se realizó un análisis descriptivo de los datos aportados, usando el test de chi-cuadrado para la comparación de valores, considerándose estadísticamente significativos solo aquellos con un valor de probabilidad inferior a 0,05. RESULTADOS: El trabajo multidisciplinar permitió el tratamiento con medicamentos mediante prescripción médica. El 63% de los pacientes del estudio consiguieron dejar de fumar. CONCLUSIONES: Las oficinas de farmacia pueden implantar y liderar programas de deshabituación al consumo de tabaco que faciliten la cesación y la adhesión a los tratamientos. La clasificación de los pacientes según su historial de tabaquismo resulta clave para realizar un tratamiento adecuado y personalizado.

Genetic Variant HLA-DRB1*0403 and Therapeutic Response to Disease-Modifying Therapies in Multiple Sclerosis: A Case-Control Study.

Multiple sclerosis (MS) is a chronic and demyelinating disease with an autoimmune origin, which leads to neurodegeneration and progressive disability. Approximately 30 to 50% of patients do not respond optimally to disease-modifying therapies (DMTs), and therapeutic response may be influenced by genetic factors such as genetic variants. Therefore, our study aimed to investigate the association of the HLA-DRB1*0403 genetic variant and therapeutic response to DMTs in MS. We included 105 patients with MS diagnosis. No evidence of disease activity based on the absence of clinical relapse, disability progression or radiological activity (NEDA-3) was used to classify the therapeutic response. Patients were classified as follows: (a) controls: patients who achieved NEDA-3; (b) cases: patients who did not achieve NEDA-3. DNA was extracted from peripheral blood leukocytes. HLA-DRB1*0403 genetic variant was analyzed by quantitative polymerase chain reaction (qPCR) using TaqMan probes. NEDA-3 was achieved in 86.7% of MS patients treated with DMTs. Genotype frequencies were GG 50.5%, GA 34.3%, and AA 15.2%. No differences were observed in the genetic variant AA between patients who achieved NEDA-3 versus patients who did not achieve NEDA-3 (48.7% vs. 43.1%, p = 0.6). We concluded that in Mexican patients with MS, HLA-DRB1*0403 was not associated with the therapeutic response to DMTs.

Recommendations for the Clinical Approach to Immune Thrombocytopenia: Spanish ITP Working Group (GEPTI).

Primary immune thrombocytopenia (ITP) is a complex autoimmune disease whose hallmark is a deregulation of cellular and humoral immunity leading to increased destruction and reduced production of platelets. The heterogeneity of presentation and clinical course hampers personalized approaches for diagnosis and management. In 2021, the Spanish ITP Group (GEPTI) of the Spanish Society of Hematology and Hemotherapy (SEHH) updated a consensus document that had been launched in 2011. The updated guidelines have been the reference for the diagnosis and management of primary ITP in Spain ever since. Nevertheless, the emergence of new tools and strategies makes it advisable to review them again. For this reason, we have updated the main recommendations appropriately. Our aim is to provide a practical tool to facilitate the integral management of all aspects of primary ITP management.

Deshabituación al consumo de tabaco desde las oficinas de farmacia mediante planes multidisciplinares / Smoking cessation from pharmacies through multidisciplinary plans

Fundamentos: El tabaco es la droga más consumida en el mundo y cada año provoca la muerte de más de ocho millones depersonas. El farmacéutico es el profesional de la salud más accesible a los fumadores, por lo que es fundamental en el tratamientoy prevención del tabaquismo. El objetivo de este estudio fue implantar un programa antitabaco multidisciplinar en una oficina defarmacia y evaluar el efecto de la atención farmacéutica en la cesación del consumo de tabaco. Métodos: El estudio se realizó en dos farmacias del Ejército de Tierra situadas en España y Líbano en las que se desarrolló unplan de deshabituación al consumo de tabaco durante los años 2020 y 2021. Como criterio de selección de participantes se aceptó atodos aquellos pacientes del área de influencia de las farmacias que aceptasen participar en el programa, siendo el tamaño muestralde treinta y ocho personas. Los pacientes se sometieron a test de adicción, motivación y hábito de consumo de tabaco, y se realizóun análisis descriptivo de los datos aportados, usando el test de chi-cuadrado para la comparación de valores, considerándoseestadísticamente significativos solo aquellos con un valor de probabilidad inferior a 0,05. Resultados: El trabajo multidisciplinar permitió el tratamiento con medicamentos mediante prescripción médica. El 63% de lospacientes del estudio consiguieron dejar de fumar. Conclusiones: Las oficinas de farmacia pueden implantar y liderar programas de deshabituación al consumo de tabaco quefaciliten la cesación y la adhesión a los tratamientos. La clasificación de los pacientes según su historial de tabaquismo resulta clavepara realizar un tratamiento adecuado y personalizado.(AU)

Background: Tobacco is the most consumed drug in the world and each year it causes the death of more than eight millionpeople. The pharmacist is the healthcare professional most accessible to smokers, therefore they are essential in the treatment andprevention of smoking. The study´s aim was to implement a multidisciplinary anti-smoking program in a pharmacy and evaluate theeffect of pharmaceutical care on smoking cessation. Methods: The study was carried out in two army pharmacies located in Spain and Lebanon in which a smoking cessation plan wasdeveloped in 2020 and 2021. As the requirements for participants selection, all those patients in the area of influence of pharmaciesthat agreed to participate in the program were accepted, with a sample size of thirty-eight people. The patients underwent an addiction,motivation and smoking habit test, and a descriptive analysis of the data provided was carried out, using the chi-square test for thecomparison of values. Only those with a probability value less than 0.05 are considered statistically significant.Results: The multidisciplinary work allowed treatment with prescription drugs. The study shows that 63% of patients managedto quit smoking. Conclusions: Pharmacies can implement and lead smoking cessation programs that facilitate cessation and adherence to treat-ments. The classification of patients according to their history of smoking is key to carrying out an adequate and personalized treatment.(AU)

Adjunctive Diagnostic Studies Completed Following Detection of Candidemia in Children: Secondary Analysis of Observed Practice From a Multicenter Cohort Study Conducted by the Pediatric Fungal Network.

BACKGROUND: Adjunctive diagnostic studies (aDS) are recommended to identify occult dissemination in patients with candidemia. Patterns of evaluation with aDS across pediatric settings are unknown. METHODS: Candidemia episodes were included in a secondary analysis of a multicenter comparative effectiveness study that prospectively enrolled participants age 120 days to 17 years with invasive candidiasis (predominantly candidemia) from 2014 to 2017. Ophthalmologic examination (OE), abdominal imaging (AbdImg), echocardiogram, neuroimaging, and lumbar puncture (LP) were performed per clinician discretion. Adjunctive diagnostic studies performance and positive results were determined per episode, within 30 days from candidemia onset. Associations of aDS performance with episode characteristics were evaluated via mixed-effects logistic regression. RESULTS: In 662 pediatric candidemia episodes, 490 (74%) underwent AbdImg, 450 (68%) OE, 426 (64%) echocardiogram, 160 (24%) neuroimaging, and 76 (11%) LP; performance of each aDS per episode varied across sites up to 16-fold. Longer durations of candidemia were associated with undergoing OE, AbdImg, and echocardiogram. Immunocompromised status (58% of episodes) was associated with undergoing AbdImg (adjusted odds ratio [aOR] 2.38; 95% confidence intervals [95% CI] 1.51-3.74). Intensive care at candidemia onset (30% of episodes) was associated with undergoing echocardiogram (aOR 2.42; 95% CI 1.51-3.88). Among evaluated episodes, positive OE was reported in 15 (3%), AbdImg in 30 (6%), echocardiogram in 14 (3%), neuroimaging in 9 (6%), and LP in 3 (4%). CONCLUSIONS: Our findings show heterogeneity in practice, with some clinicians performing aDS selectively, potentially influenced by clinical factors. The low frequency of positive results suggests that targeted application of aDS is warranted.

Genomic Regions Associated with Resistance to Three Rusts in CIMMYT Wheat Line "Mokue#1".

Understanding the genetic basis of rust resistance in elite CIMMYT wheat germplasm enhances breeding and deployment of durable resistance globally. "Mokue#1", released in 2023 in Pakistan as TARNAB Gandum-1, has exhibited high levels of resistance to stripe rust, leaf rust, and stem rust pathotypes present at multiple environments in Mexico and Kenya at different times. To determine the genetic basis of resistance, a F5 recombinant inbred line (RIL) mapping population consisting of 261 lines was developed and phenotyped for multiple years at field sites in Mexico and Kenya under the conditions of artificially created rust epidemics. DArTSeq genotyping was performed, and a linkage map was constructed using 7892 informative polymorphic markers. Composite interval mapping identified three significant and consistent loci contributed by Mokue: QLrYr.cim-1BL and QLrYr.cim-2AS on chromosome 1BL and 2AS, respectively associated with stripe rust and leaf rust resistance, and QLrSr.cim-2DS on chromosome 2DS for leaf rust and stem rust resistance. The QTL on 1BL was confirmed to be the Lr46/Yr29 locus, whereas the QTL on 2AS represented the Yr17/Lr37 region on the 2NS/2AS translocation. The QTL on 2DS was a unique locus conferring leaf rust resistance in Mexico and stem rust resistance in Kenya. In addition to these pleiotropic loci, four minor QTLs were also identified on chromosomes 2DL and 6BS associated with stripe rust, and 3AL and 6AS for stem rust, respectively, using the Kenya disease severity data. Significant decreases in disease severities were also demonstrated due to additive effects of QTLs when present in combinations.

B cell receptor-induced protein dynamics and the emerging role of SUMOylation revealed by proximity proteomics.

Successful B cell activation, which is critical for high-affinity antibody production, is controlled by the B cell antigen receptor (BCR). However, we still lack a comprehensive protein-level view of the very dynamic multi-branched cellular events triggered by antigen binding. Here, we employed APEX2 proximity biotinylation to study antigen-induced changes, 5-15 min after receptor activation, at the vicinity of the plasma membrane lipid rafts, wherein BCR enriches upon activation. The data reveals dynamics of signaling proteins, as well as various players linked to the subsequent processes, such as actin cytoskeleton remodeling and endocytosis. Interestingly, our differential expression analysis identified dynamic responses in various proteins previously not linked to early B cell activation. We demonstrate active SUMOylation at the sites of BCR activation in various conditions and report its functional role in BCR signaling through the AKT and ERK1/2 axes.

Large-scale production of superparamagnetic iron oxide nanoparticles by flame spray pyrolysis: In vitro biological evaluation for biomedical applications.

Despite the large number of synthesis methodologies described for superparamagnetic iron oxide nanoparticles (SPIONs), the search for their large-scale production for their widespread use in biomedical applications remains a mayor challenge. Flame Spray Pyrolysis (FSP) could be the solution to solve this limitation, since it allows the fabrication of metal oxide nanoparticles with high production yield and low manufacture costs. However, to our knowledge, to date such fabrication method has not been upgraded for biomedical purposes. Herein, SPIONs have been fabricated by FSP and their surface has been treated to be subsequently coated with dimercaptosuccinic acid (DMSA) to enhance their colloidal stability in aqueous media. The final material presents high quality in terms of nanoparticle size, homogeneous size distribution, long-term colloidal stability and magnetic properties. A thorough in vitro validation has been performed with peripheral blood cells and mesenchymal stem cells (hBM-MSCs). Specifically, hemocompatibility studies show that these functionalized FSP-SPIONs-DMSA nanoparticles do not cause platelet aggregation or impair basal monocyte function. Moreover, in vitro biocompatibility assays show a dose-dependent cellular uptake while maintaining high cell viability values and cell cycle progression without causing cellular oxidative stress. Taken together, the results suggest that the FSP-SPIONs-DMSA optimized in this work could be a worthy alternative with the benefit of a large-scale production aimed at industrialization for biomedical applications.

Method for siRNA delivery in retina explants.

Several barriers prevent the delivery of nucleic acids to the retina and limit the application of established technologies, such as RNA interference (RNAi), in the study of retinae biology. Organotypic culture of retinal explants is a convenient method to decrease the complexity of the biological environment surrounding the retina while preserving most of its physiological features. Nevertheless, eliciting significant, non-toxic RNAi in retina explants is not straightforward. Retina explants are mainly constituted by neurons organized in discrete circuits embedded within a complex 3D extracellular matrix. About 70% of these neurons are post-mitotic ciliated cells that respond to light. Unfortunately, like the other cells of the retina, photoreceptors are refractory to transfection, and a toxic delivery of nucleic acid often results in permanent cell loss. RNAi has been applied to retina explants using electroporation, viral, and non-viral vectors but with reproducible, poor gene silencing efficiency. In addition, only a few superficial cells can be transduced/transfected in adult retina explants. Therefore, viruses are often injected into the eye of embryos prior to excision of the retina. However, embryonic explants are not the best model to study most retina diseases since even if they are viable for several weeks, the pathological phenotype often appears later in development. We describe a robust and straightforward method to elicit significant RNAi in adult retina explant using Reverse Magnetofection. This transfection method offers a simple tool for non-toxic gene knockdown of specific genes in adult retina explants by using cationic magnetic nanoparticles (MNPs) to complex and deliver short interfering-RNAs (siRNA) in retina cells under the action of a magnetic field.

Analysis of Local Recurrence Risk in Ductal Carcinoma In Situ and External Validation of the Memorial Sloan Kettering Cancer Center Nomogram.

BACKGROUND: Adjuvant radiotherapy and hormonotherapy after breast-conserving surgery (BCS) in ductal carcinoma in situ (DCIS) have been shown to reduce the risk of local recurrence. To predict the risk of ipsilateral breast tumor relapse (IBTR) after BCS, the Memorial Sloan Kettering Cancer Center (MSKCC) developed a nomogram to analyze local recurrence (LR) risk in our cohort and to assess its external validation. METHODS: A historical cohort study using data from 296 patients treated for DCIS at the Hospital Clínic of Barcelona was carried out. Patients who had had a mastectomy were excluded from the analysis. RESULTS: The mean age was 58 years (42-75), and the median follow-up time was 10.64 years. The overall local relapse rate was 13.04% (27 patients) during the study period. Actuarial 5- and 10-year IBTR rates were 5.8 and 12.9%, respectively. The external validation of the MSKCC nomogram was performed using a multivariate logistic regression analysis on a total of 207 patients, which did not reach statistical significance in the studied population for predicting LR (p = 0.10). The expression of estrogen receptors was significantly associated with a decreased risk of LR (OR: 0.25; p = 0.004). CONCLUSIONS: In our series, the LR rate was 13.4%, which was in accordance with the published series. The MSKCC nomogram did not accurately predict the IBTR in this Spanish cohort of patients treated for DCIS (p = 0.10).

Integrated transcriptomics and metabolomics analysis reveals the biomolecular mechanisms associated to the antitumoral potential of a novel silver-based core@shell nanosystem.

A combination of omics techniques (transcriptomics and metabolomics) has been used to elucidate the mechanisms responsible for the antitumor action of a nanosystem based on a Ag core coated with mesoporous silica on which transferrin has been anchored as a targeting ligand against tumor cells (Ag@MSNs-Tf). Transcriptomics analysis has been carried out by gene microarrays and RT-qPCR, while high-resolution mass spectrometry has been used for metabolomics. This multi-omics strategy has enabled the discovery of the effect of this nanosystem on different key molecular pathways including the glycolysis, the pentose phosphate pathway, the oxidative phosphorylation and the synthesis of fatty acids, among others.

Attenuation of Tumor Burden in Response to Rucaparib in Lung Adenocarcinoma: The Contribution of Oxidative Stress, Apoptosis, and DNA Damage.

In cancer, overactivation of poly (ADPribose) polymerases (PARP) plays a relevant role in DNA repair. We hypothesized that treatment with the PARP inhibitor rucaparib may reduce tumor burden via several biological mechanisms (apoptosis and oxidative stress) in mice. In lung tumors (LP07 lung adenocarcinoma) of mice treated/non-treated (control animals) with PARP inhibitor (rucaparib,150 mg/kg body weight/24 h for 20 day), PARP activity and expression, DNA damage, apoptotic nuclei, cell proliferation, and redox balance were measured using immunoblotting and immunohistochemistry. In lung tumors of rucaparib-treated mice compared to non-treated animals, tumor burden, PARP activity, and cell proliferation decreased, while DNA damage, TUNEL-positive nuclei, protein oxidation, and superoxide dismutase content (SOD)2 increased. In this experiment on lung adenocarcinoma, the pharmacological PARP inhibitor rucaparib elicited a significant improvement in tumor size, probably through a reduction in cell proliferation as a result of a rise in DNA damage and apoptosis. Oxidative stress and SOD2 also increased in response to treatment with rucaparib within the tumor cells of the treated mice. These results put the line forward to the contribution of PARP inhibitors to reduced tumor burden in lung adenocarcinoma. The potential implications of these findings should be tested in clinical settings of patients with lung tumors.

Tailoring surface properties of liposomes for dexamethasone intraocular administration.

Diseases of the posterior eye segment are often characterized by intraocular inflammation, which causes, in the long term, severe impairment of eye functions and, ultimately, vision loss. Aimed at enhancing the delivery of anti-inflammatory drugs to the posterior eye segment upon intravitreal administration, we developed liposomes with an engineered surface to control their diffusivity in the vitreous and retina association. Hydrogenated soybean phosphatidylcholine (HSPC)/cholesterol liposomes were coated with (agmatinyl)6-maltotriosyl-acetamido-N-(octadec-9-en-1-yl)hexanamide (Agm6-M-Oleate), a synthetic non-peptidic cell penetration enhancer (CPE), and/or 5% of mPEG2kDa-DSPE. The zeta potential of liposomes increased, and the mobility in bovine vitreous and colloidal stability decreased with the Agm6-M-Oleate coating concentration. Oppositely, mPEG2kDa-DSPE decreased the zeta potential of liposomes and restored both the diffusivity and the stability in vitreous. Liposomes with 5 mol% Agm6-M-Oleate coating were well tolerated by ARPE-19 retina cells either with or without mPEG2kDa-DSPE, while 10 mol% Agm6-M-Oleate showed cytotoxicity. Agm6-M-Oleate promoted the association of liposomes to ARPE-19 cells with respect to plain liposomes, while mPEG2kDa-DSPE slightly reduced the cell interaction. Dexamethasone hemisuccinate (DH) was remotely loaded into liposomes with a loading capacity of ∼10 wt/wt%. Interestingly, mPEG2kDa-DSPE coating reduced the rate of DH release and enhanced the disposition of Agm6-M-Oleate coated liposomes in the ARPE-19 cell cytosol resulting in a more efficient anti-inflammatory effect. Finally, mPEG2kDa-DSPE enhanced the association of DH-loaded Agm6-M-Oleate coated liposomes to explanted rat retina, which reflected in higher viability of inner and outer nuclear layer cells.

Evaluation of 4 prognostic indices in follicular lymphoma treated in first line with immunochemotherapy.

Several clinical risk models have been proposed to predict the outcome of follicular lymphoma (FL). The development of next-generation sequencing technologies has allowed the integration of somatic gene mutations into clinical scores to build genotyped-based risk models, such as the m7-Follicular Lymphoma International Prognostic Index (FLIPI). We explored 4 clinical or clinicogenetic-risk models in patients with symptomatic FL who received frontline immunochemotherapy. Of 191 patients with FL grades 1 to 3a, 109 were successfully genotyped. The treatment consisted of rituximab (R) plus cyclophosphamide, vincristine, and prednisone (R-CVP)/cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) (72.5%) or R-bendamustine (R-B) (27.5%). The proportion of cases classified as high risk for FLIPI, FLIPI-2, PRIMA-prognostic index, or m7-FLIPI were 39.3%, 14%, 30.3%, and 22%, respectively. No case with low-intermediate FLIPI was upgraded in the m7-FLIPI, but 18 of the 42 high-risk patients with FLIPI were downgraded to low-risk m7-FLIPI. The sensitivity and specificity for the prediction of POD24 were highest for FLIPI. The discrimination between progression-free survival (PFS) and overall survival (OS) was the best for FLIPI (c-index: 0.644 and 0.727, respectively). When analyzed only in patients treated with R-B, m7-FLIPI showed a higher discrimination between PFS and OS. Thus, the FLIPI remains the clinical risk score with higher discrimination in patients with advanced FL treated with immunochemotherapy; however, the performance of the m7-FLIPI should be further investigated in patients treated with R-B.

HER2DX ERBB2 mRNA expression in advanced HER2-positive breast cancer treated with T-DM1.

In advanced HER2-positive (HER2+) breast cancer, the new antibody-drug conjugate trastuzumab deruxtecan is more effective compared with trastuzumab emtansine (T-DM1). However, trastuzumab deruxtecan can have considerable toxicities, and the right treatment sequence is unknown. Biomarkers to guide the use of anti-HER2 therapies beyond HER2 status are needed. Here, we evaluated if preestablished levels of ERBB2 mRNA expression according to the HER2DX standardized assay are associated with response and survival following T-DM1. In ERBB2 low, medium, and high groups, the overall response rate was 0%, 29%, and 56%, respectively (P < .001). ERBB2 mRNA was statistically significantly associated with better progression-free survival (P = .002) and overall survival (OS; P = .02). These findings were independent of HER2 immunohistochemistry (IHC) levels, hormone receptor, age, brain metastasis, and line of therapy. The HER2DX risk score (P = .04) and immunoglobulin signature (P = .04) were statistically significantly associated with overall survival since diagnosis. HER2DX provides prognostic and predictive information following T-DM1 in advanced HER2+ breast cancer.