Antiprogestins for breast cancer treatment: We are almost ready.

The development of antiprogestins was initially a gynecological purpose. However, since mifepristone was developed, its application for breast cancer treatment was immediately proposed. Later, new compounds with lower antiglucocorticoid and antiandrogenic effects were developed to be applied to different pathologies, including breast cancer. We describe herein the studies performed in the breast cancer field with special focus on those reported in recent years, ranging from preclinical biological models to those carried out in patients. We highlight the potential use of antiprogestins in breast cancer prevention in women with BRCA1 mutations, and their use for breast cancer treatment, emphasizing the need to elucidate which patients will respond. In this sense, the PR isoform ratio has emerged as a possible tool to predict antiprogestin responsiveness. The effects of combined treatments of antiprogestins together with other drugs currently used in the clinic, such as tamoxifen, CDK4/CDK6 inhibitors or pembrolizumab in preclinical models is discussed since it is in this scenario that antiprogestins will be probably introduced. Finally, we explain how transcriptomic or proteomic studies, that were carried out in different luminal breast cancer models and in breast cancer samples that responded or were predicted to respond to the antiprogestin therapy, show a decrease in proliferative pathways. Deregulated pathways intrinsic of each model are discussed, as well as how these analyses may contribute to a better understanding of the mechanisms involved.

Early improvement of global longitudinal strain after iron deficiency correction in heart failure with reduced ejection fraction.

BACKGROUND: Iron deficiency correction with ferric carboxymaltose improves symptoms and reduces rehospitalization in patients with reduced left ventricular ejection fraction. The mechanisms underlying these improvements are poorly understood. This study aimed to determine changes in left ventricular contractility after iron treatment as reflected in global longitudinal strain. METHODS: Prospective single-center study including 43 adults with reduced ejection fraction, non-anemic iron deficiency, and functional class II-III heart failure despite optimal medical treatment. Global longitudinal strain through speckle-tracking echocardiography was measured at baseline and 4 weeks after ferric carboxymaltose. RESULTS: A significant improvement in global longitudinal strain was detected (from -12.3% ± 4.0% at baseline to -15.6% ± 4.1%, p < .001); ferritin and transferrin saturation index had increased, but ejection fraction presented no significant changes (baseline 35.7% ± 4.6%, follow-up 37.2% ± 6.6%, p = .073). CONCLUSIONS: In patients with heart failure and reduced ejection fraction, the correction of iron deficiency with ferric carboxymaltose is associated with an early improvement in global longitudinal strain, possibly suggesting a direct effect of iron correction on myocardial contractility.

Modulating the sEH/EETs Axis Restrains Specialized Proresolving Mediator Impairment and Regulates T Cell Imbalance in Experimental Periodontitis.

Epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids are short-acting lipids involved in resolution of inflammation. Their short half-life, due to its metabolism by soluble epoxide hydrolase (sEH), limits their effects. Specialized proresolving mediators (SPMs) are endogenous regulatory lipids insufficiently synthesized in uncontrolled and chronic inflammation. Using an experimental periodontitis model, we pharmacologically inhibited sEH, examining its impact on T cell activation and systemic SPM production. In humans, we analyzed sEH in the gingival tissue of periodontitis patients. Mice were treated with sEH inhibitor (sEHi) and/or EETs before ligature placement and treated for 14 d. Bone parameters were assessed by microcomputed tomography and methylene blue staining. Blood plasma metabololipidomics were carried out to quantify SPM levels. We also determined T cell activation by reverse transcription-quantitative PCR and flow cytometry in cervical lymph nodes. Human gingival samples were collected to analyze sEH using ELISA and electrophoresis. Data reveal that pharmacological sEHi abrogated bone resorption and preserved bone architecture. Metabololipidomics revealed that sEHi enhances lipoxin A4, lipoxin B4, resolvin E2, and resolvin D6. An increased percentage of regulatory T cells over Th17 was noted in sEHi-treated mice. Lastly, inflamed human gingival tissues presented higher levels and expression of sEH than did healthy gingivae, being positively correlated with periodontitis severity. Our findings indicate that sEHi preserves bone architecture and stimulates SPM production, associated with regulatory actions on T cells favoring resolution of inflammation. Because sEH is enhanced in human gingivae from patients with periodontitis and connected with disease severity, inhibition may prove to be an attractive target for managing osteolytic inflammatory diseases.

Steroid profile in patients with breast cancer and in mice treated with mifepristone.

Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have proposed that the ratio between PR isoforms A and B (PRA and PRB) predicts antiprogestin responsiveness. The MIPRA trial confirmed the benefit of 200 mg mifepristone, administered to patients with tumors with a high PRA/PRB ratio, but dose-ranging has not been conducted. The aim of this study was to establish the plasma mifepristone levels of patients from the MIPRA trial, along with the resultant steroid profiles, and compare these with those observed in mifepristone-treated mice using therapeutic schemes able to induce the regression of experimental mammary carcinomas with high PRA/PRB ratios: 6 mg pellets implanted subcutaneously, or daily doses of 12 mg/kg body weight. The plasma levels of mifepristone and other 19 plasma steroids were measured by liquid chromatography-tandem mass spectometry. In mifepristone-treated mice, plasma levels were lower than those registered in mifepristone-treated patients (i.e. day 7 after treatment initiation, pellet-treated mice: 8.4 ± 3.9 ng/mL; mifepristone-treated patients: 300.3 ± 31.7 ng/mL (mean ± s.d.; P < 0.001)). The increase in corticoid related steroids observed in patients was not observed in mifepristone-treated mice. The increase in progesterone levels was the most significant side effect detected in mifepristone-treated mice after 14 or 21 days of treatment, probably due to an ovarian compensatory effect not observed in postmenopausal patients. We conclude that in future clinical trials using mifepristone, the possibility of lowering the standard daily dose of 200 mg should be considered.

Characterization of adverse events to hydroxychloroquine, ivermectin, azithromycin and tocilizumab in patients hospitalized due to COVID-19 in a Peruvian Social Health Insurance hospital. / Caracterización de los eventos adversos a hidroxicloroquina, ivermectina, azitromicina y tocilizumab en pacientes hospitalizados por la COVID-19 en un hospital del Seguro Social de Salud del Perú.

OBJECTIVE.: To characterize the adverse events (AEs) related to the off-label use of hydroxychloroquine (HQ), azithromycin (AZI), tocilizumab (TOB) and ivermectin (IVM) for the treatment of COVID-19 in hospitalized patients. MATERIALS AND METHODS.: We conducted a secondary cross-sectional analysis of the Peruvian Social Health Insurance (EsSalud) pharmacovigilance system database of AE notifications to HQ, AZI, TOB and IVM in the Edgardo Rebagliati Martins National Hospital from April to October 2020. Information was collected from digital medical records. We estimated AE reporting rates and evaluated their characteristics by drug type, time of occurrence, type by the affected organ-system, severity and causality. RESULTS.: We identified 154 notifications describing a total of 183 AE possibly related to HQ, AZI, TOB and IVM; the reporting rate was 8%. The median time of AE occurrence was 3 days (IQR: 2-5). Most were cardiovascular events; prolongation of the QT interval was the most frequent. Hepatobiliary AEs were mainly associated with TOB. Most cases were moderate, however, 10.4% were severe. CONCLUSIONS.: We found AEs potentially associated with the use of HQ, AZI, TOB and IVM against COVID-19; cardiovascular events were the most frequent. Although AZI, HQ and IVM have known safety profiles, their use against COVID-19 could increase the occurrence of AE due to the risk factors inherent to this infection. Surveillance systems must be improved, especially those for TOB.

OBJETIVOS.: Caracterizar los eventos adversos (EA) asociados a hidroxicloroquina (HQ), azitromicina (AZI), tocilizumab (TOB) e ivermectina (IVM) prescritos como «fuera de etiqueta¼ en el tratamiento de pacientes hospitalizados por la COVID-19. MATERIALES Y MÉTODOS.: Se realizó un análisis secundario transversal de la base de datos del sistema de farmacovigilancia del Seguro Social de Salud del Perú (EsSalud) de las notificaciones de EA a HQ, AZI, TOB e IVM provenientes del Hospital Nacional Edgardo Rebagliati Martins de abril a octubre del 2020. Se revisaron las historias clínicas digitales, se estimaron las tasas de reporte de EA y se evaluaron sus características por tipo de fármaco, tiempo de aparición, tipo por órgano-sistema afectado, gravedad y causalidad. RESULTADOS.: Se identificaron 154 notificaciones que describen un total de 183 EA posiblemente relacionados con HQ, AZI, TOB e IVM, siendo 8% la tasa de reporte de EA. La mediana de tiempo de aparición de EA fue de 3 días (RIC: 2-5). La mayoría fueron cardiovasculares, destacándose la prolongación del intervalo QT. Se observaron EA hepatobiliares principalmente asociados a TOB. La mayoría de los casos fueron moderados, no obstante, el 10,4% fue grave. CONCLUSIONES.: Se identificaron EA potencialmente asociados al uso de HQ, AZI, TOB e IVM contra la COVID-19, siendo los más frecuentes los de tipo cardiovasculares. A pesar de que la AZI, HQ e IVM poseen perfiles conocidos de seguridad, su empleo en la COVID-19 podría incrementar la aparición de EA por los factores de riesgo propios de esta infección. Se sugiere reforzar la vigilancia, especialmente, de TOB.

Caracterización de eventos adversos a hidroxicloroquina, ivermectina, azitromicina y tocilizumab en pacientes hospitalizados por COVID-19 en un hospital del Seguro Social de Salud del Perú / Characterization of adverse events to hydroxychloroquine, ivermectin, azithromycin and tocilizumab in patients hospitalized due to COVID-19 in a Peruvian Social Health Insurance hospital

Objetivos. Caracterizar los eventos adversos (EA) asociados a hidroxicloroquina (HQ), azitromicina (AZI), tocilizumab (TOB) e ivermectina (IVM) prescritos como «fuera de etiqueta» en el tratamiento de pacientes hospitalizados por la COVID-19. Materiales y métodos. Se realizó un análisis secundario transversal de la base de datos del sistema de farmacovigilancia del Seguro Social de Salud del Perú (EsSalud) de las notificaciones de EA a HQ, AZI, TOB e IVM provenientes del Hospital Nacional Edgardo Rebagliati Martins de abril a octubre del 2020. Se revisaron las historias clínicas digitales, se estimaron las tasas de reporte de EA y se evaluaron sus características por tipo de fármaco, tiempo de aparición, tipo por órgano-sistema afectado, gravedad y causalidad. Resultados. Se identificaron 154 notificaciones que describen un total de 183 EA posiblemente relacionados con HQ, AZI, TOB e IVM, siendo 8% la tasa de reporte de EA. La mediana de tiempo de aparición de EA fue de 3 días (RIC: 2-5). La mayoría fueron cardiovasculares, destacándose la prolongación del intervalo QT. Se observaron EA hepatobiliares principalmente asociados a TOB. La mayoría de los casos fueron moderados, no obstante, el 10,4% fue grave. Conclusiones. Se identificaron EA potencialmente asociados al uso de HQ, AZI, TOB e IVM contra la COVID-19, siendo los más frecuentes los de tipo cardiovasculares. A pesar de que la AZI, HQ e IVM poseen perfiles conocidos de seguridad, su empleo en la COVID-19 podría incrementar la aparición de EA por los factores de riesgo propios de esta infección. Se sugiere reforzar la vigilancia, especialmente, de TOB.

Objective. To characterize the adverse events (AEs) related to the off-label use of hydroxychloroquine (HQ), azithromycin (AZI), tocilizumab (TOB) and ivermectin (IVM) for the treatment of COVID-19 in hospitalized patients. Materials and Methods. We conducted a secondary cross-sectional analysis of the Peruvian Social Health Insurance (EsSalud) pharmacovigilance system database of AE notifications to HQ, AZI, TOB and IVM in the Edgardo Rebagliati Martins National Hospital from April to October 2020. Information was collected from digital medical records. We estimated AE reporting rates and evaluated their characteristics by drug type, time of occurrence, type by the affected organ-system, severity and causality. Results. We identified 154 notifications describing a total of 183 AE possibly related to HQ, AZI, TOB and IVM; the reporting rate was 8%. The median time of AE occurrence was 3 days (IQR: 2-5). Most were cardiovascular events; prolongation of the QT interval was the most frequent. Hepatobiliary AEs were mainly associated with TOB. Most cases were moderate, however, 10.4% were severe. Conclusions. We found AEs potentially associated with the use of HQ, AZI, TOB and IVM against COVID-19; cardiovascular events were the most frequent. Although AZI, HQ and IVM have known safety profiles, their use against COVID-19 could increase the occurrence of AE due to the risk factors inherent to this infection. Surveillance systems must be improved, especially those for TOB.

Soluble epoxide hydrolase inhibition enhances production of specialized pro-resolving lipid mediator and promotes macrophage plasticity.

BACKGROUND AND PURPOSE: Epoxyeicosatrienoic acids (EETs) and other epoxy fatty acids (EpFA) are lipid mediators that are rapidly inactivated by soluble epoxide hydrolase (sEH). Uncontrolled and chronic inflammatory disorders fail to sufficiently activate endogenous regulatory pathways, including the production of specialized pro-resolving mediators (SPMs). Here, we addressed the relationship between SPMs and the EET/sEH axis and explored the effects of sEH inhibition on resolving macrophage phenotype. EXPERIMENTAL APPROACH: Mice were treated with a sEH inhibitor, EETs, or sEH inhibitor + EETs (combination) before ligature placement to induce experimental periodontitis. Using RT-qPCR, gingival samples were used to examine SPM receptors and osteolytic and inflammatory biomarkers. Maxillary alveolar bone loss was quantified by micro-CT and methylene blue staining. SPM levels were analysed by salivary metabolo-lipidomics. Gingival macrophage phenotype plasticity was determined by RT-qPCR and flow cytometry. Effects of sEH inhibition on macrophage polarization and SPM production were assessed with bone marrow-derived macrophages (BMDMs). KEY RESULTS: Pharmacological inhibition of sEH suppressed bone resorption and the inflammatory cytokine storm in experimental periodontitis. Lipidomic analysis revealed that sEH inhibition augmented levels of LXA4, RvE1, RvE2, and 4-HDoHE, concomitant with up-regulation of LTB4R1, CMKLR1/ChemR23, and ALX/FPR2 SPM receptors. Notably, there is an impact on gingival macrophage plasticity was affected suggesting an inflammation resolving phenotype with sEH inhibition. In BMDMs, sEH inhibition reduced inflammatory macrophage activation, and resolving macrophages were triggered to produce SPMs. CONCLUSION AND IMPLICATIONS: Pharmacological sEH inhibition increased SPM synthesis associated with resolving macrophages, suggesting a potential target to control osteolytic inflammatory disorders.

Beneficial Effects of Mifepristone Treatment in Patients with Breast Cancer Selected by the Progesterone Receptor Isoform Ratio: Results from the MIPRA Trial.

PURPOSE: Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcinomas that express higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB). Thus, we designed a presurgical window of opportunity trial to determine the therapeutic effects of mifepristone in patients with breast cancer, based on their high PRA/PRB isoform ratio (MIPRA; NCT02651844). PATIENTS AND METHODS: Twenty patients with luminal breast carcinomas with PRA/PRB > 1.5 (determined by Western blots), and PR ≥ 50%, naïve from previous treatment, were included for mifepristone treatment (200 mg/day orally; 14 days). Core needle biopsies and surgical samples were formalin fixed for IHC studies, while others were snap-frozen to perform RNA sequencing (RNA-seq), proteomics, and/or Western blot studies. Plasma mifepristone levels were determined using mass spectrometry. The primary endpoint was the comparison of Ki67 expression pretreatment and posttreatment. RESULTS: A 49.62% decrease in Ki67 staining was observed in all surgical specimens compared with baseline (P = 0.0003). Using the prespecified response parameter (30% relative reduction), we identified 14 of 20 responders. Mifepristone induced an increase in tumor-infiltrating lymphocytes; a decrease in hormone receptor and pSer118ER expression; and an increase in calregulin, p21, p15, and activated caspase 3 expression. RNA-seq and proteomic studies identified downregulated pathways related to cell proliferation and upregulated pathways related to immune bioprocesses and extracellular matrix remodeling. CONCLUSIONS: Our results support the use of mifepristone in patients with luminal breast cancer with high PRA/PRB ratios. The combined effects of mifepristone and estrogen receptor modulators warrant clinical evaluation to improve endocrine treatment responsiveness in these patients. See related commentary by Ronchi and Brisken, p. 833.

Conocimientos, habilidades, actitudes y prácticas en telesalud de los profesionales de la salud durante la pandemia de COVID-19

Introducción: La pandemia por el SARS-CoV-2 estableció desafíos para los sistemas de salud en función de dar continuidad a la atención de los pacientes por medio de la rápida adopción de la telesalud. Esto conllevó retos para los profesionales que se enfrentaron a las tecnologías de la información y la comunicación. Objetivos: Identificar conocimientos, habilidades, actitudes y prácticas de los profesionales de la salud que emplearon la telesalud en el ámbito ambulatorio durante la pandemia y analizar los posibles factores relacionados con las barreras que presentan los profesionales para implementar de forma efectiva los servicios de telesalud. Métodos: Estudio descriptivo de corte transversal analítico. Se aplicó una encuesta electrónica a profesionales de salud de tres centros médicos de Colombia. Resultados: Se aplicaron 430 encuestas. La mediana de edad fue de 39 años y el 79 % fueron mujeres. El 57 % no habían sido capacitados en aspectos técnicos, normativos y éticos de la telesalud; el 46 % reportó dificultad para administrar el tiempo; el 81 % manifestó el aumento en su carga laboral. La dificultad para emplear las herramientas tecnológicas se asoció 4,67 veces más a la percepción de alteración de su propio estado de salud; sin embargo, el 92 % manifestó que seguiría usando la telesalud. Conclusiones: La actitud frente al uso de la telesalud fue positiva; el conocimiento, habilidades y entrenamiento en telesalud parece determinar su aceptabilidad. Esta es una primera evaluación que revela los puntos a trabajar en el caso de los profesionales, en función de la permanencia de la telesalud como herramienta para la atención de pacientes.

Introduction: The SARS-CoV-2 pandemic posed challenges for health systems in terms of providing continuity of patient care through the rapid adoption of telehealth. This brought challenges for professionals who dealt with information and communication technologies. Objectives: To identify knowledge, skills, attitudes, and practices of health professionals who used telehealth in the outpatient setting during the pandemic and to analyze possible factors related to the barriers that professionals present to effectively implement telehealth services. Methods: This is a descriptive analytical cross-sectional study. An electronic survey was used on health professionals from three medical centers in Colombia. Results: Four hundred thirty (430) surveys were used. The median age was 39 years and 79% were women. 57% had not been trained in technical, regulatory and ethical aspects of telehealth; 46% reported difficulty managing time; 81% reported an increase in their workload. The difficulty in using technological tools was associated 4.67 times more with the perception of alteration of their own state of health; however, 92% said they would continue to use telehealth. Conclusions: The attitude towards the use of telehealth was positive; knowledge, skills, and training in telehealth seem to determine its acceptability. This is a first evaluation that reveals the points to work on in the case of professionals, based on the permanence of telehealth as a tool for patient care.

Corrigendum: RvE1 Impacts the Gingival Inflammatory Infiltrate by Inhibiting the T Cell Response in Experimental Periodontitis.

[This corrects the article DOI: 10.3389/fimmu.2021.664756.].

Knowledge, attitudes and practices of pharmacovigilance in the context of COVID-19 in health professionals of the peruvian social insurance. / Conocimientos, actitudes y prácticas de farmacovigilancia en el contexto de la COVID-19 en profesionales de la salud del Seguro Social del Perú.

The study aimed to evaluate a group of health professionals' knowledge, attitudes, and practices on pharmacovigilance in the context of COVID-19 in the Peruvian Social Health Insurance (EsSalud). A descriptive secondary analysis was carried out on a database that included responses from an online survey conducted by the Institutional Referral Center for Pharmacovigilance and Technovigilance of EsSalud. Of 144 participants, 66% showed a high level of knowledge and 81.2% had a positive attitude; however, 71.5% had an inadequate level of pharmacovigilance practice. Although EsSalud professionals demonstrated a high level of knowledge and positive attitude to implement pharmacovigilance, this is not reflected in the practice of this activity during the SARS-CoV-2 pandemic. Strategies should be implemented to integrate pharmacovigilance into healthcare activities to benefit patient safety.

El estudio tuvo como objetivo evaluar el conocimiento, las actitudes y prácticas de un grupo de profesionales de la salud sobre la farmacovigilancia en el contexto de la COVID-19 en el Seguro Social de Salud del Perú (EsSalud). Se realizó un análisis secundario descriptivo de una base de datos que incluía las respuestas de una encuesta en línea realizada por el Centro de Referencia Institucional de Farmacovigilancia y Tecnovigilancia de EsSalud. De 144 participantes, el 66% mostró alto nivel de conocimiento y el 81,2%, actitud positiva; sin embargo, el 71,5% tuvo un inadecuado nivel de práctica de farmacovigilancia. Si bien los profesionales de EsSalud demostraron tener alto conocimiento y actitud positiva para implementar farmacovigilancia, esto no se ve reflejado en la práctica de esta actividad en la época de pandemia por el SARS-CoV-2. Se deben emplear estrategias para integrar a la farmacovigilancia en las actividades asistenciales en beneficio de la seguridad del paciente.

Conocimientos, actitudes y prácticas de farmacovigilancia en el contexto de la COVID-19 en profesionales de la salud del Seguro Social del Perú / Knowledge, attitudes and practices of pharmacovigilance in the context of COVID-19 in health professionals of the peruvian social insurance

RESUMEN El estudio tuvo como objetivo evaluar el conocimiento, las actitudes y prácticas de un grupo de profesionales de la salud sobre la farmacovigilancia en el contexto de la COVID-19 en el Seguro Social de Salud del Perú (EsSalud). Se realizó un análisis secundario descriptivo de una base de datos que incluía las respuestas de una encuesta en línea realizada por el Centro de Referencia Institucional de Farmacovigilancia y Tecnovigilancia de EsSalud. De 144 participantes, el 66% mostró alto nivel de conocimiento y el 81,2%, actitud positiva; sin embargo, el 71,5% tuvo un inadecuado nivel de práctica de farmacovigilancia. Si bien los profesionales de EsSalud demostraron tener alto conocimiento y actitud positiva para implementar farmacovigilancia, esto no se ve reflejado en la práctica de esta actividad en la época de pandemia por el SARS-CoV-2. Se deben emplear estrategias para integrar a la farmacovigilancia en las actividades asistenciales en beneficio de la seguridad del paciente.

ABSTRACT The study aimed to evaluate a group of health professionals' knowledge, attitudes, and practices on pharmacovigilance in the context of COVID-19 in the Peruvian Social Health Insurance (EsSalud). A descriptive secondary analysis was carried out on a database that included responses from an online survey conducted by the Institutional Referral Center for Pharmacovigilance and Technovigilance of EsSalud. Of 144 participants, 66% showed a high level of knowledge and 81.2% had a positive attitude; however, 71.5% had an inadequate level of pharmacovigilance practice. Although EsSalud professionals demonstrated a high level of knowledge and positive attitude to implement pharmacovigilance, this is not reflected in the practice of this activity during the SARS-CoV-2 pandemic. Strategies should be implemented to integrate pharmacovigilance into healthcare activities to benefit patient safety.

Galectin-1 confers resistance to doxorubicin in hepatocellular carcinoma cells through modulation of P-glycoprotein expression.

Galectin-1 (GAL1), a ß-galactoside-binding protein abundantly expressed in the tumor microenvironment, has emerged as a key mechanism of chemoresistance developed by different tumors. Although increased expression of GAL1 is a hallmark of hepatocellular carcinoma (HCC) progression, aggressiveness and metastasis, limited information is available on the role of this endogenous lectin in HCC resistance to chemotherapy. Moreover, the precise mechanisms underlying this effect are uncertain. HCC has evolved different mechanisms of resistance to chemotherapy including those involving the P-glycoprotein (P-gp), an ATP-dependent drug efflux pump, which controls intracellular drug concentration. Here, we investigated the molecular mechanism underlying GAL1-mediated chemoresistance in HCC cells, particularly the involvement of P-gp in this effect. Our results show that GAL1 protected HepG2 cells from doxorubicin (DOX)- and sorafenib-induced cell death in vitro. Accordingly, GAL1-overexpressing HepG2 cells generated DOX-resistant tumors in vivo. High expression of GAL1 in HepG2 cells reduced intracellular accumulation of DOX likely by increasing P-gp protein expression rather than altering its membrane localization. GAL1-mediated increase of P-gp expression involved activation of the phosphatidylinositol-3 kinase (PI3K) signaling pathway. Moreover, 'loss-of-function' experiments revealed that P-gp mediates GAL1-driven resistance to DOX, but not to sorafenib, in HepG2 cells. Conversely, in PLC/PRF/5 cells, P-gp protein expression was undetectable and GAL1 did not control resistance to DOX or sorafenib, supporting the critical role of P-gp in mediating GAL1 effects. Collectively, our findings suggest that GAL1 confers chemoresistance in HCC through mechanisms involving modulation of P-gp, thus emphasizing the role of this lectin as a potential therapeutic target in HCC.

Progesterone receptor isoform ratio dictates antiprogestin/progestin effects on breast cancer growth and metastases: A role for NDRG1.

Progesterone receptors (PRs) ligands are being tested in luminal breast cancer. There are mainly two PR isoforms, PRA and PRB, and their ratio (PRA/PRB) may be predictive of antiprogestin response. Our aim was to investigate: the impact of the PR isoform ratio on metastatic behaviour, the PR isoform ratio in paired primary tumours and lymph node metastases (LNM) and, the effect of antiprogestin/progestins on metastatic growth. Using murine and human metastatic models, we demonstrated that tumours with PRB > PRA (PRB-H) have a higher proliferation index but less metastatic ability than those with PRA > PRB (PRA-H). Antiprogestins and progestins inhibited metastatic burden in PRA-H and PRB-H models, respectively. In breast cancer samples, LNM retained the same PRA/PRB ratio as their matched primary tumours. Moreover, PRA-H LNM expressed higher total PR levels than the primary tumours. The expression of NDRG1, a metastasis suppressor protein, was higher in PRB-H compared to PRA-H tumours and was inversely regulated by antiprogestins/progestins. The binding of the corepressor SMRT at the progesterone responsive elements of the NDRG1 regulatory sequences, together with PRA, impeded its expression in PRA-H cells. Antiprogestins modulate the interplay between SMRT and AIB1 recruitment in PRA-H or PRB-H contexts regulating NDRG1 expression and thus, metastasis. In conclusion, we provide a mechanistic interpretation to explain the differential role of PR isoforms in metastatic growth and highlight the therapeutic benefit of using antiprogestins in PRA-H tumours. The therapeutic effect of progestins in PRB-H tumours is suggested.

Characterization of the emerging B.1.621 variant of interest of SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) genetic diversity has the potential to impact the virus transmissibility and the escape from natural infection- or vaccine-elicited neutralizing antibodies. Here, representative samples from circulating SARS-CoV-2 in Colombia between January and April 2021, were processed for genome sequencing and lineage determination following the nanopore amplicon ARTIC network protocol and PANGOLIN pipeline. This strategy allowed us to identify the emergence of the B.1.621 lineage, considered a variant of interest (VOI) with the accumulation of several substitutions affecting the Spike protein, including the amino acid changes I95I, Y144T, Y145S and the insertion 146 N in the N-terminal domain, R346K, E484K and N501Y in the Receptor binding Domain (RBD) and P681H in the S1/S2 cleavage site of the Spike protein. The rapid increase in frequency and fixation in a relatively short time in Magdalena, Atlantico, Bolivar, Bogotá D.C, and Santander that were near the theoretical herd immunity suggests an epidemiologic impact. Further studies will be required to assess the biological and epidemiologic roles of the substitution pattern found in the B.1.621 lineage.

Patterns of digital information and communication technology use among patients at primary health care centres in Colombia: Phase I of the DIADA project.

OBJECTIVE: Assess the prevalence and types of digital technology use, as well as the extent to which patients use the internet and mobile devises. Evaluate the socioeconomic characteristics of patients and the possible relation to patterns of technology use in Colombia. Understand the nature of patient technology use in primary care for finding medical information. METHODS: A survey was applied to adult patients who attended primary health care centers systems in 6 Colombian cities. The survey inquired about demographic characteristics, insurance, access to services, cell phone use, internet access, and the use of such technology to access health-related services and information. Data was collected and managed using REDCap. Summary statistics on each survey item were calculated and the differences between discrete variables were analyzed using chi-square. Multivariate analyses were performed using logistic regression analysis for binary dependent variables. RESULTS: A total of 1580 patients were surveyed across the six study sites. 93% of the patients reported they have a cell phone. Patients from urban healthcare centers showed a higher use of the Internet on their phone than less urban settings. Around half of the surveyed patients reported Internet use (49.7%). Among Internet users, 65% of participants use the Internet looking for health care information. Around one-third of patients use cellphones to arrange clinic visits. Around 24% of participants answered positively for both Whooley's questions. Of those who screened positive on the Whooley questions, 43% reported being moderately anxious, 47% reported being very anxious. 51% reported having moderate pain; 52% reported having severe pain. CONCLUSIONS: The patterns of technology use identified in this study are essential for developing future health interventions based on ICT. The design of ICT clinical interventions must take into account the cellphone payment plans, availability of internet connection, advantages, and disadvantages of messenger services, including SMS as a possible alternative to people who do not have smartphones.

RvE1 Impacts the Gingival Inflammatory Infiltrate by Inhibiting the T Cell Response in Experimental Periodontitis.

Periodontitis is a chronic inflammatory disease associated with the formation of dysbiotic plaque biofilms and characterized by the progressive destruction of the alveolar bone. The transition from health to disease is characterized by a shift in periodontal immune cell composition, from mostly innate (neutrophils) to adaptive (T lymphocytes) immune responses. Resolvin E1 (RvE1) is a specialized pro-resolution mediator (SPMs), produced in response to inflammation, to enhance its resolution. Previous studies have indicated the therapeutic potential of RvE1 in periodontal disease; however, the impact of RvE1 in the microbial-elicited osteoclastogenic immune response remains uncharacterized in vivo. In the present study, we studied the impact of RvE1 on the gingival inflammatory infiltrate formation during periodontitis in a mouse model. First, we characterized the temporal-dependent changes of the main immune cells infiltrating the gingiva by flow cytometry. Then, we evaluated the impact of early or delayed RvE1 administration on the gingival immune infiltration and cervical lymph nodes composition. We observed a consistent inhibitory outcome on T cells -particularly effector T cells- and a protective effect on regulatory T cells (Tregs). Our data further demonstrated the wide range of actions of RvE1, its preventive role in the establishment of the adaptive immune response during inflammation, and bone protective capacity.

Factores de riesgo para infección por pseudomonas aeruginosa multirresistente en pacientes con neumonía asociada a ventilación mecánica de la unidad de cuidados intensivos. Estudio multicéntrico / Risk factors for multi-resistant aeruginous pseudomonas infection in patients with pneumonia associated with mechanical ventilation of the intensive care unit. Multicentric study

Objetivo:Determinar los factores de riesgo de infección para Pseudomonas aeruginosa multirresistente en pacientes con Neumonía asociada a ventilación de la unidad de cuidados intensivos.:Serealizóunestudioobservacional,analítico, MaterialyMétodosretrospectivo, de casos y controles en el cual se seleccionaron mediante aleatorización simple 84 historias clínicas de pacientes con edad ≥ 18 años, con diagnóstico de neumonía asociada a ventilación mecánica en el Hospital Alta Complejidad Virgen de la Puerta (HACVP) y Hospital Belén de Trujillo (HBT) durante el periodo de enero-2014 a diciembre-2019. En el análisis de datos se utilizó la prueba Chi-cuadrado para determinar la significancia estadística de asociación en las variables de estudio. :La edad, uso de antibioticoterapia previa Resultadosde amplio espectro, uso de sonda vesical, tiempo de uso de sonda vesical y postoperado de cirugía abdominal, se asociaron significativamente (P<0,05) a infección por Pseudomonas aeruginosa multirresistente en pacientes con neumonía asociada a ventilación mecánica de la unidad de cuidados intensivos. El tiempo de exposición de sonda vesical es factor de riesgo para infección por Pseudomonas aeruginosa multirresistente (p<0.001). : El Conclusionestiempo de uso de sonda vesical por más de 7 días sin recambio de sonda es un factor de riesgo para infección por Pseudomonas aeruginosa multirresistente en pacientes con neumonía asociada a ventilación mecánica.

Objective:Determine the risk factors for multidrug-resistant Pseudomonas aeruginosa infection in patients with pneumonia associated with mechanical ventilation in the intensive care unit. :An observational, analytical, retrospective, case-control Material and Methodsstudy was carried out in which 84 medical records of patients aged ≥ 18 years with a diagnosis of ventilator-associatedpneumoniawereselectedbysimplerandomizationattheAlta Complejidad Hospital Virgen de la Puerta (HACVP) and Hospital Belén de Trujillo (HBT) during the period from January-2014 to December-2019. In the data analysis, the Chi-square test was used to determine the statistical significance of association in the study variables. :ResultsAge, use of prior broad-spectrum antibiotic therapy, use of urinary catheter, time of urinary catheter use, and postoperative abdominal surgery were significantly associated (P<0,05) with multidrug-resistant Pseudomonas aeruginosa infection in patients with pneumonia associated with intensive care unit mechanical ventilation. Urinary catheter exposure time is a risk factor for multidrug-resistant Pseudomonas aeruginosa infection (p <0.001). :The time Conclusionsof use of the urinary catheter for more than 7 days without change the catheter is a risk factor for infection by multidrug-resistant Pseudomonas aeruginosa in patients with pneumonia associated with mechanical ventilation.

Factores de riesgo para infección por pseudomonas aeruginosa multirresistente en pacientes con neumonía asociada a ventilación mecánica de la unidad de cuidados intensivos. Estudio multicéntrico / Risk factors for multi-resistant aeruginous pseudomonas infection in patients with pneumonia associated with mechanical ventilation of the intensive care unit. Multicentric study

RESUMEN Objetivo: Determinar los factores de riesgo de infección para Pseudomonas aeruginosa multirresistente en pacientes con Neumonía asociada a ventilación de la unidad de cuidados intensivos. Material y Métodos: Se realizó un estudio observacional, analítico, retrospectivo, de casos y controles en el cual se seleccionaron mediante aleatorización simple 84 historias clínicas de pacientes con edad ≥ 18 años, con diagnóstico de neumonía asociada a ventilación mecánica en el Hospital Alta Complejidad Virgen de la Puerta (HACVP) y Hospital Belén de Trujillo (HBT) durante el periodo de enero-2014 a diciembre-2019. En el análisis de datos se utilizó la prueba Chi-cuadrado para determinar la significancia estadística de asociación en las variables de estudio. Resultados: La edad, uso de antibioticoterapia previa de amplio espectro, uso de sonda vesical, tiempo de uso de sonda vesical y postoperado de cirugía abdominal, se asociaron significativamente (P<0,05) a infección por Pseudomonas aeruginosa multirresistente en pacientes con neumonía asociada a ventilación mecánica de la unidad de cuidados intensivos. El tiempo de exposición de sonda vesical es factor de riesgo para infección por Pseudomonas aeruginosa multirresistente (p<0.001). Conclusiones: El tiempo de uso de sonda vesical por más de 7 días sin recambio de sonda es un factor de riesgo para infección por Pseudomonas aeruginosa multirresistente en pacientes con neumonía asociada a ventilación mecánica.

ABSTRACT Objective: Determine the risk factors for multidrug-resistant Pseudomonas aeruginosa infection in patients with pneumonia associated with mechanical ventilation in the intensive care unit. Material and Methods: An observational, analytical, retrospective, case-control study was carried out in which 84 medical records of patients aged ≥ 18 years with a diagnosis of ventilator-associated pneumonia were selected by simple randomization at the Alta Complejidad Hospital Virgen de la Puerta (HACVP) and Hospital Belén de Trujillo (HBT) during the period from January-2014 to December-2019. In the data analysis, the Chi-square test was used to determine the statistical significance of association in the study variables. Results: Age, use of prior broad-spectrum antibiotic therapy, use of urinary catheter, time of urinary catheter use, and postoperative abdominal surgery were significantly associated (P <0,05) with multidrug-resistant Pseudomonas aeruginosa infection in patients with pneumonia associated with intensive care unit mechanical ventilation. Urinary catheter exposure time is a risk factor for multidrug-resistant Pseudomonas aeruginosa infection (p <0.001). Conclusions: The time of use of the urinary catheter for more than 7 days without change the catheter is a risk factor for infection by multidrug-resistant Pseudomonas aeruginosa in patients with pneumonia associated with mechanical ventilation.

Design of an algorithm for the diagnostic approach of patients with joint pain.

BACKGROUND: Rheumatic diseases are a reason for frequent consultation with primary care doctors. Unfortunately, there is a high percentage of misdiagnosis. OBJECTIVE: To design an algorithm to be used by primary care physicians to improve the diagnostic approach of the patient with joint pain, and thus improve the diagnostic capacity in four rheumatic diseases. METHODS: Based on the information obtained from a literature review, we identified the main symptoms, signs, and paraclinical tests related to the diagnosis of rheumatoid arthritis, spondyloarthritis with peripheral involvement, systemic lupus erythematosus with joint involvement, and osteoarthritis. We conducted 3 consultations with a group of expert rheumatologists, using the Delphi technique, to design a diagnostic algorithm that has as a starting point "joint pain" as a common symptom for the four diseases. RESULTS: Thirty-nine rheumatologists from 18 countries of Ibero-America participated in the Delphi exercise. In the first consultation, we presented 94 items to the experts (35 symptoms, 31 signs, and 28 paraclinical tests) candidates to be part of the algorithm; 74 items (25 symptoms, 27 signs, and 22 paraclinical tests) were chosen. In the second consultation, the decision nodes of the algorithm were chosen, and in the third, its final structure was defined. The Delphi exercise lasted 8 months; 100% of the experts participated in the three consultations. CONCLUSION: We present an algorithm designed through an international consensus of experts, in which Delphi methodology was used, to support primary care physicians in the clinical approach to patients with joint pain. Key Points • We developed an algorithm with the participation of rheumatologists from 18 countries of Ibero-America, which gives a global vision of the clinical context of the patient with joint pain. • We integrated four rheumatic diseases into one tool with one common symptom: joint pain. It is a novel tool, as it is the first algorithm that will support the primary care physician in the consideration of four different rheumatic diseases. • It will improve the correct diagnosis and reduce the number of paraclinical tests requested by primary care physicians, in the management of patients with joint pain. This point was verified in a recently published study in the journal Rheumatology International (reference number 31).