Exploring the impact of MiR-92a-3p on FOLFOX chemoresistance biomarker genes in colon cancer cell lines.

Introduction: One of the primary obstacles faced by individuals with advanced colorectal cancer (CRC) is the potential development of acquired chemoresistance as the disease advances. Studies have indicated a direct association between elevated levels of miR-92a-3p and the progression, metastasis, and chemoresistance observed in CRC. We proposed that miR-92a-3p impairs FOLFOX (fluorouracil/oxaliplatin) chemotherapy response by upregulating the expression of chemoresistance biomarker genes through the activation of ß-catenin and epithelial-mesenchymal transition (EMT). These FOLFOX biomarker genes include the pyrimidine biosynthesis pathway genes dihydropyrimidine dehydrogenase (DPYD), thymidylate synthase (TYMS), methylenetetrahydrofolate reductase (MTHFR), and the genes encoding the DNA repair complexes subunits ERCC1 and ERCC2, and XRCC1. Methods: To assess this, we transfected SW480 and SW620 colon cancer cell lines with miR-92a-3p mimics and then quantified the expression of DPYD, TYMS, MTHFR, ERCC1, ERCC2, and XRCC1, the expression of EMT markers and transcription factors, and activation of ß-catenin. Results and discussion: Our results reveal that miR-92a-3p does not affect the expression of DPYD, TYMS, MTHFR, and ERCC1. Furthermore, even though miR-92a-3p affects ERCC2, XRCC1, E-cadherin, and ß-catenin mRNA levels, it has no influence on their protein expression. Conclusion: We found that miR-92a-3p does not upregulate the expression of proteins of DNA-repair pathways and other genes involved in FOLFOX chemotherapy resistance.

Genetic Polymorphisms and Tumoral Mutational Profiles over Survival in Advanced Colorectal Cancer Patients: An Exploratory Study.

Colorectal cancer is a common disease, both in Chile and worldwide. The most widely used chemotherapy schemes are based on 5-fluorouracil (5FU) as the foundational drug (FOLFOX, CapeOX). Genetic polymorphisms have emerged as potential predictive biomarkers of response to chemotherapy, but conclusive evidence is lacking. This study aimed to investigate the role of genetic variants associated with 5FU-based chemotherapy on therapeutic response, considering their interaction with oncogene mutations (KRAS, NRAS, PI3KCA, AKT1, BRAF). In a retrospective cohort of 63 patients diagnosed with metastatic colorectal cancer, a multivariate analysis revealed that liver metastases, DPYD, ABCB1, and MTHFR polymorphisms are independent indicators of poor prognosis, irrespective of oncogene mutations. BRAF wild-type status and high-risk drug-metabolism polymorphisms correlated with a poor prognosis in this Chilean cohort. Additionally, findings from the genomics of drug sensitivity (GDSC) project demonstrated that cell lines with wild-type BRAF have higher IC50 values for 5-FU compared to BRAF-mutated cell lines. In conclusion, the genetic polymorphisms DPYDrs1801265, ABCB1rs1045642, and MTHFRrs180113 may serve as useful biomarkers for predicting a poor prognosis in patients undergoing 5-fluorouracil chemotherapy, regardless of oncogene mutations.

Clinical and pulmonary function analysis in long-COVID revealed that long-term pulmonary dysfunction is associated with vascular inflammation pathways and metabolic syndrome.

Introduction: Long-term pulmonary dysfunction (L-TPD) is one of the most critical manifestations of long-COVID. This lung affection has been associated with disease severity during the acute phase and the presence of previous comorbidities, however, the clinical manifestations, the concomitant consequences and the molecular pathways supporting this clinical condition remain unknown. The aim of this study was to identify and characterize L-TPD in patients with long-COVID and elucidate the main pathways and long-term consequences attributed to this condition by analyzing clinical parameters and functional tests supported by machine learning and serum proteome profiling. Methods: Patients with L-TPD were classified according to the results of their computer-tomography (CT) scan and diffusing capacity of the lungs for carbon monoxide adjusted for hemoglobin (DLCOc) tests at 4 and 12-months post-infection. Results: Regarding the acute phase, our data showed that L-TPD was favored in elderly patients with hypertension or insulin resistance, supported by pathways associated with vascular inflammation and chemotaxis of phagocytes, according to computer proteomics. Then, at 4-months post-infection, clinical and functional tests revealed that L-TPD patients exhibited a restrictive lung condition, impaired aerobic capacity and reduced muscular strength. At this time point, high circulating levels of platelets and CXCL9, and an inhibited FCgamma-receptor-mediated-phagocytosis due to reduced FcγRIII (CD16) expression in CD14+ monocytes was observed in patients with L-TPD. Finally, 1-year post infection, patients with L-TPD worsened metabolic syndrome and augmented body mass index in comparison with other patient groups. Discussion: Overall, our data demonstrated that CT scan and DLCOc identified patients with L-TPD after COVID-19. This condition was associated with vascular inflammation and impair phagocytosis of virus-antibody immune complexes by reduced FcγRIII expression. In addition, we conclude that COVID-19 survivors required a personalized follow-up and adequate intervention to reduce long-term sequelae and the appearance of further metabolic diseases.

Study of dose dependence on density in planar 3D-printed applicators for HDR Ir192 surface brachytherapy.

PURPOSE: This paper describes a method to evaluate the influence of 3D printed plesiotherapy applicators densities in the most clinically relevant dosimetric planes of these brachytherapy treatments. Studied densities range goes from that of water to that of air including the intermediate applicators densities made of acrylonitrile butadiene styrene and polylactic acid, materials used as Fused Deposition Modelling (FDM) filaments. METHODS AND MATERIALS: All applicators were manufactured by means of FDM 3D printing and a special empty applicator of ABS walls was designed to be filled with water or air. In each of these applicators, the values of the dose and gamma index at the surface and at the prescription depth were measured in clinical conditions, using EBT films. RESULTS: Analysis of results allow us to conclude that the influence of the applicators density on the dose value in the studied materials depends on the distance at which the dose is measured. Thus, at the prescription depth no influence is observed, however this influence becomes noticeable near the surface of the applicators with dose differences of more than 10% for densities close to 0.4 g/cm3. CONCLUSION: Therefore, the density of FDM manufactured applicators should be taken into account when calculating surface dose for low density applicators, as variations caused by density can have clinical implications because is the surface dose that is associated with the toxicity of brachytherapy skin treatments.

Pulmonary Inflammatory Response in Lethal COVID-19 Reveals Potential Therapeutic Targets and Drugs in Phases III/IV Clinical Trials.

Background: It is imperative to identify drugs that allow treating symptoms of severe COVID-19. Respiratory failure is the main cause of death in severe COVID-19 patients, and the host inflammatory response at the lungs remains poorly understood. Methods: Therefore, we retrieved data from post-mortem lungs from COVID-19 patients and performed in-depth in silico analyses of single-nucleus RNA sequencing data, inflammatory protein interactome network, and shortest pathways to physiological phenotypes to reveal potential therapeutic targets and drugs in advanced-stage COVID-19 clinical trials. Results: Herein, we analyzed transcriptomics data of 719 inflammatory response genes across 19 cell types (116,313 nuclei) from lung autopsies. The functional enrichment analysis of the 233 significantly expressed genes showed that the most relevant biological annotations were inflammatory response, innate immune response, cytokine production, interferon production, macrophage activation, blood coagulation, NLRP3 inflammasome complex, and the TLR, JAK-STAT, NF-κB, TNF, oncostatin M signaling pathways. Subsequently, we identified 34 essential inflammatory proteins with both high-confidence protein interactions and shortest pathways to inflammation, cell death, glycolysis, and angiogenesis. Conclusion: We propose three small molecules (baricitinib, eritoran, and montelukast) that can be considered for treating severe COVID-19 symptoms after being thoroughly evaluated in COVID-19 clinical trials.

There Is More than Multiple Choice: Crowd-Sourced Assessment Tips for Online, Hybrid, and Face-to-Face Environments.

Developing effective assessments of student learning is a challenging task for faculty and even more difficult for those in emerging disciplines that lack readily available resources and standards. With the power of technology-enhanced education and accessible digital learning platforms, instructors are also looking for assessments that work in an online format. This article will be useful for all teachers, but especially for entry-level instructors, in addition to more mature instructors who are looking to become more well versed in assessment, who seek a succinct summary of assessment types to springboard the integration of new forms of assessment of student learning into their courses. In this paper, ten assessment types, all appropriate for face-to-face, blended, and online modalities, are discussed. The assessments are mapped to a set of bioinformatics core competencies with examples of how they have been used to assess student learning. Although bioinformatics is used as the focus of the assessment types, the question types are relevant to many disciplines.

Preliminary Pharmacogenomic-Based Predictive Models of Tamoxifen Response in Hormone-dependent Chilean Breast Cancer Patients.

Tamoxifen (TAM), a selective oestrogen receptor modulator, is one of the most used treatments in oestrogen receptor-positive (ER+) early and metastatic breast cancer (BC) patients. The response to TAM has a high degree of inter-individual variability. This is mainly due to genetic variants in CYP2D6 gene, as well as other genes encoding proteins involved in the TAM pharmacokinetic and/or pharmacodynamic. Therefore, prediction of the TAM response using these genetic factors together with other non-genetic variables may be relevant to improve breast cancer treatment. Thus, in this work, we used genetic polymorphisms and clinical variables for TAM response modelling. One hundred sixty-two ER + BC patients with 2 years of TAM treatment were retrospectively recruited, and the genetic polymorphisms CYP2D6*4, CYP3A4*1B (CYP3A4*1.001), CYP3A5*3, UGT2B7*2, UGT2B15*2, SULT1A1*2, and ESRA V364E were analyzed by PCR-RFLP. Concomitantly, the therapeutic response was obtained from clinical records for association with genotypes using univariate and multivariate biostatistical models. Our results show that UGT2B15*1/*2 genotype protects against relapse (OR = 0.09; p = 0.02), CYP3A5*3/*3 genotype avoids endometrial hyperplasia (OR = 0.07; p = 0.01), SULT1A1*1/*2 genotype avoids vaginal bleeding (OR = 0.09; p = 0.03) and ESRA 364E/364E genotype increases the probability of vaginal bleeding (OR = 5.68; p = 0.02). Logistic regression models, including genomic and non-genomic variables, allowed us to obtain preliminary predictive models to explain relapse (p = 0.010), endometrial hyperplasia (p = 0.002) and vaginal bleeding (p = 0.014). Our results suggest that the response to TAM treatment in ER + BC patients might be associated with the presence of the studied genetic variants in UGT2B15, CYP3A5, SULT1A1 and ESRA genes. After clinical validation protocols, these models might be used to help to predict a percentage of BC relapse and adverse reactions, improving the individual response to TAM-based treatment.

Effect of CYP3A4, CYP3A5, MDR1 and POR Genetic Polymorphisms in Immunosuppressive Treatment in Chilean Kidney Transplanted Patients.

Cyclosporine (CsA) and tacrolimus (TAC) are immunosuppressant drugs characterized by a narrow therapeutic range and high pharmacokinetic variability. The effect of polymorphisms in genes related to the metabolism and transport of these drugs, namely CYP3A4, CYP3A5, MDR1 and POR genes, has been evaluated in diverse populations. However, the impact of these polymorphisms on drug disposition is not well established in Latin American populations. Using TaqMan® probes, we determined the allelic frequency of seven variants in CYP3A4, CYP3A5, MDR1 and POR in 139 Chilean renal transplant recipients, of which 89 were treated with CsA and 50 with TAC. We tested associations between variants and trough and/or 2-hour concentrations, normalized by dose (C0/D and C2/D) at specific time points post-transplant. We found that CYP3A5*3/*3 carriers required lower doses of TAC. In TAC treated patients, most CYP3A5*3/*3 carriers presented higher C0/D and a high proportion of patients with C0 levels outside the therapeutic range relative to other genotypes. These results reinforce the value of considering CYP3A5 genotypes alongside therapeutic drug monitoring for TAC treated Chilean kidney recipients.

[Effects of pharmaceutical counseling on the effectiveness of anticoagulation in patients with atrial fibrillation]. / Impacto de la atención farmacéutica en la calidad del tratamiento con acenocumarol en pacientes con fibrilación auricular.

BACKGROUND: Vitamin K antagonists such as acenocoumarol and warfarin are usually indicated for the treatment of Atrial Fibrillation (AF). The Therapeutic Range Time (TRT) is a quality of treatment indicator. Values greater than 65% are associated with significantly lower stroke and bleeding rates. Proper pharmaceutical care improves TRT. AIM: To evaluate the impact of pharmaceutical care in patients with AF treated with acenocoumarol. MATERIAL AND METHODS: We studied 41 patients using acenocoumarol for AF aged 71 ± 11 years (43% women). They received pharmaceutical counseling during 12 weeks. TRT was calculated retrospectively for the year before counseling and prospectively during the intervention period. RESULTS: After receiving pharmaceutical counseling TRT improved from 29% at baseline to 46% at the end of the intervention (p < 0.01). After pharmaceutical care, the adherence of patients to drug treatment improved from 27% at baseline to 85% at the end of the study. The user satisfaction survey of the pharmaceutical care received showed a high degree of patient satisfaction. CONCLUSIONS: Pharmaceutical care in patients with oral anticoagulant treatment improves TRT of anticoagulation. It is accepted and positively evaluated by patients.

A case-control study of a combination of single nucleotide polymorphisms and clinical parameters to predict clinically relevant toxicity associated with fluoropyrimidine and platinum-based chemotherapy in gastric cancer.

BACKGROUND: Fluoropyrimidine plus platinum chemotherapy remains the standard first line treatment for gastric cancer (GC). Guidelines exist for the clinical interpretation of four DPYD genotypes related to severe fluoropyrimidine toxicity within European populations. However, the frequency of these single nucleotide polymorphisms (SNPs) in the Latin American population is low (< 0.7%). No guidelines have been development for platinum. Herein, we present association between clinical factors and common SNPs in the development of grade 3-4 toxicity. METHODS: Retrospectively, 224 clinical records of GC patient were screened, of which 93 patients were incorporated into the study. Eleven SNPs with minor allelic frequency above 5% in GSTP1, ERCC2, ERCC1, TP53, UMPS, SHMT1, MTHFR, ABCC2 and DPYD were assessed. Association between patient clinical characteristics and toxicity was estimated using logistic regression models and classification algorithms. RESULTS: Reported grade ≤ 2 and 3-4 toxicities were 64.6% (61/93) and 34.4% (32/93) respectively. Selected DPYD SNPs were associated with higher toxicity (rs1801265; OR = 4.20; 95% CI = 1.70-10.95, p = 0.002), while others displayed a trend towards lower toxicity (rs1801159; OR = 0.45; 95% CI = 0.19-1.08; p = 0.071). Combination of paired SNPs demonstrated significant associations in DPYD (rs1801265), UMPS (rs1801019), ABCC2 (rs717620) and SHMT1 (rs1979277). Using multivariate logistic regression that combined age, sex, peri-operative chemotherapy, 5-FU regimen, the binary combination of the SNPs DPYD (rs1801265) + ABCC2 (rs717620), and DPYD (rs1801159) displayed the best predictive performance. A nomogram was constructed to assess the risk of developing overall toxicity. CONCLUSION: Pending further validation, this model could predict chemotherapy associated toxicity and improve GC patient quality of life.

Retrospective pharmacogenetic analysis of a pediatric patient under anticoagulant treatment: Clinical case / Análisis farmacogenético retrospectivo de una paciente pediátrica en tratamiento anticoagulante: caso clínico.

We present the clinical case of a 10-year-old patient diagnosed with dilated cardiomyopathy who registered INR values above 10 upon receiving standard doses of acenocoumarol, as well as other values reported as uncoagulable, forcing the discontinuation and restart of treatment more than once. Expected and stable INR levels were achieved after more than 30 days of treatment, surprisingly with half the recommended dose for a patient of her age and weight. We decided to conduct a retrospective pharmacogenomic analysis including nucleotide genetic polymorphisms (SNPs) with different degrees of association with the dose/response to antivitamin K (AVK) drugs: rs2108622 (gene CYP4F2), rs9923231, rs7294 (gene VKORC1), rs1799853, and rs1057910 (CYP2C9 gene) using TaqMan® RT-PCR. The patient was homozygous for rs9923231 (VKORC1) and heterozygous for rs2108622 (CYP4F2),a genetic profile strongly associated with a requirement of lower AVK doses as shown by national and international evidence. In conclusion, the pharmacogenetic analysis confirmed that this patient's genetic conditions, involving low expression of the VKA therapeutic target, required a lower dose than that established in clinical protocols as recommended by the Food and Drug Administration (FDA) and the PharmGKB® for coumarin drugs. A previous genotypic analysis of the patient would have allowed reaching the therapeutic range sooner, thus avoiding potential bleeding risks. This shows the importance of pharmacogenetic analyses for highly variable treatments with a narrow therapeutic range.

Se presenta el caso clínico de una paciente de 10 años diagnosticada con miocardiopatía dilatada, quien registró valores en el índice internacional normalizado (International Normalized Ratio, INR) superiores a 10 con la dosis estándar de acenocumarol, además de otros valores que indicaban el estado incoagulable, lo que obligó a suspender y reiniciar el tratamiento en varias ocasiones. Después de más de 30 días de tratamiento, sorprendentemente se lograron los niveles esperados y estables en el INR con la mitad de a dosis recomendada para una paciente de su edad y peso. Se decidió hacer un análisis farmacogenético retrospectivo del caso mediante RT-PCR con sondas TaqMan™ que incluyó cinco polimorfismos de un solo nucleótido y distinto grado de asociación con la dosis-respuesta a los fármacos antivitamínicos K (AVK): rs2108622 (gen CYP4F2), rs9923231, rs7294 (gen VKORC1), rs1799853 y rs1057910 (gen CYP2C9). La paciente resultó ser homocigota para el rs9923231 (VKORC1) y heterocigota para el rs2108622 (CYP4F2). Se ha evidenciado a nivel nacional e internacional que este perfil genético está fuertemente asociado con una necesidad de dosis menores de antivitamínicos K. En conclusión, el análisis farmacogenético confirmó que la condición genética de la paciente, la cual conlleva una baja expresión de la enzima VKORC1 (blanco terapéutico de los antivitamínicos K), hacía predecible la necesidad de una dosis menor a la establecida según los protocolos clínicos recomendados por la Food and Drug Administration (FDA) y PharmGKB™ para los fármacos cumarínicos.

Análisis farmacogenético retrospectivo de una paciente pediátrica en tratamiento anticoagulante: caso clínico / Retrospective pharmacogenetic analysis of a pediatric patient under anticoagulant treatment: Clinical case

Se presenta el caso clínico de una paciente de 10 años diagnosticada con miocardiopatía dilatada, quien registró valores en el índice internacional normalizado (International Normalized Ratio, INR) superiores a 10 con la dosis estándar de acenocumarol, además de otros valores que indicaban el estado incoagulable, lo que obligó a suspender y reiniciar el tratamiento en varias ocasiones. Después de más de 30 días de tratamiento, sorprendentemente se lograron los niveles esperados y estables en el INR con la mitad de la dosis recomendada para una paciente de su edad y peso.Se decidió hacer un análisis farmacogenético retrospectivo del caso mediante RT-PCR con sondas TaqMan™ que incluyó cinco polimorfismos de un solo nucleótido y distinto grado de asociación con la dosis-respuesta a los fármacos antivitamínicos K (AVK): rs2108622 (gen CYP4F2), rs9923231, rs7294 (gen VKORC1), rs1799853 y rs1057910 (gen CYP2C9). La paciente resultó ser homocigota para el rs9923231 (VKORC1) y heterocigota para el rs2108622 (CYP4F2). Se ha evidenciado a nivel nacional e internacional que este perfil genético está fuertemente asociado con una necesidad de dosis menores de antivitamínicos K.En conclusión, el análisis farmacogenético confirmó que la condición genética de la paciente, la cual conlleva una baja expresión de la enzima VKORC1 (blanco terapéutico de los antivitamínicos K), hacía predecible la necesidad de una dosis menor a la establecida según los protocolos clínicos recomendados por la Food and Drug Administration (FDA) y PharmGKB™ para los fármacos cumarínicos. El análisis genotípico previo de la paciente hubiese permitido alcanzar el rango terapéutico más prontamente, evitando potenciales riesgos de hemorragia, lo que demuestra la importancia de los análisis farmacogenéticos en tratamientos de gran variabilidad y estrecho rango terapéutico.

Abstract We present the clinical case of a 10-year-old patient diagnosed with dilated cardiomyopathy who registered INR values above 10 upon receiving standard doses of acenocoumarol, as well as other values reported as uncoagulable, forcing the discontinuation and restart of treatment more than once. Expected and stable INR levels were achieved after more than 30 days of treatment, surprisingly with half the recommended dose for a patient of her age and weight. We decided to conduct a retrospective pharmacogenomic analysis including nucleotide genetic polymorphisms (SNPs) with different degrees of association with the dose/response to antivitamin K (AVK) drugs: rs2108622 (gene CYP4F2), rs9923231, rs7294 (gene VKORC1), rs1799853, and rs1057910 (CYP2C9 gene) using TaqMan® RT-PCR. The patient was homozygous for rs9923231 (VKORC1) and heterozygous for rs2108622 (CYP4F2), a genetic profile strongly associated with a requirement of lower AVK doses as shown by national and international evidence. In conclusion, the pharmacogenetic analysis confirmed that this patient's genetic conditions, involving low expression of the VKA therapeutic target, required a lower dose than that established in clinical protocols as recommended by the Food and Drug Administration (FDA) and the PharmGKB® for coumarin drugs. A previous genotypic analysis of the patient would have allowed reaching the therapeutic range sooner, thus avoiding potential bleeding risks. This shows the importance of pharmacogenetic analyses for highly variable treatments with a narrow therapeutic range.

Análisis y consideraciones técnicas acerca de dispositivos intrauterinos de levonorgestrel para la evaluación de productos similares y genéricos / Analysis and technical considerations about levonorgestrel intrauterine devices for the evaluation of generic and similar products

Los dispositivos intrauterinos hormonales de levonorgestrel son métodos anticonceptivos seguros y eficaces. Al igual que los medicamentos convencionales, una vez expirada la patente, las autoridades regulatorias de salud pueden aprobar el registro de productos similares. El objetivo de ello es disminuir los costos, considerando el elevado precio del producto original. Este tipo de productos están regulados y se aplican requisitos generales similares a los medicamentos tradicionales para demostración de seguridad y eficacia. Las propiedades mecánicas únicas del producto de referencia plantean un gran desafío a los productos similares. El presente artículo analiza de manera comparativa las características de los diversos sistemas intrauterinos hormonales de levonorgestrel, disponibles en el mercado. La autoridad sanitaria y los diversos centros clínicos deben considerar que en este tipo de productos no hay, hasta la fecha en el mundo, genéricos intercambiables y que por lo tanto, se debe decidir la intercambiabilidad de éstos sobre la base de estudios de bioequivalencia in vivo, luego de la demostración de equivalencia farmacéutica in vitro, tal y como sugiere la FDA, o en su defecto deberían ser registrados como productos nuevos, con estudios clínicos apropiados que demuestren seguridad y eficacia.

Levonorgestrel hormonal intrauterine systems are safe and effective contraceptive methods. Like conventional drugs, once the patent expires, health regulatory authorities can approve the registration of similar products. The objective of this is to reduce costs, considering the high price of the original product. These types of products are regulated as drugs and similar general requirements apply to traditional drugs for demonstration of safety and efficacy. The unique mechanical properties of the reference product pose a great challenge to similar products. This article comparatively analyzes the characteristics of the various levonorgestrel hormonal intrauterine systems available on the market. Therefore, the health authority and clinical centers must consider that up to date, there are no interchangeable generics in this type of products worldwide. Thus, their interchangeability must be decided on the basis of in vivo bioequivalence studies after the demonstration of in vitro pharmaceutical equivalence, as suggested by the FDA. Without that, they should be registered as new products, with appropriate clinical studies that demonstrate safety and efficacy.

Resolvin D1 reduces expression and secretion of cytokines and monocyte adhesion triggered by Angiotensin II, in rat cardiac fibroblasts.

Cardiac fibroblasts (CF) play an important role in the healing process and in pathological remodeling of cardiac tissue. As sentinel cells in the heart, they respond to inflammatory stimuli, expressing cytokines and cell adhesion proteins, which ultimately lead to increased recruitment of monocytes and enhancement of the inflammatory response. Angiotensin II (Ang II) triggers an inflammatory response, leading to cardiac tissue remodeling. On the other hand, RvD1 has been shown to contribute to the resolution of inflammation; however, its role in Ang II-treated CF has not been addressed until now. The present research aimed to study the effect of RvD1 on cytokine levels, cell adhesion proteins expression in a model of Ang II-triggered inflammatory response. CF from adult Sprague Dawley rats were used to study mRNA and protein levels of MCP-1, IL-6, TNF-a, IL-10, ICAM-1 and VCAM-1; and adhesion of spleen mononuclear cells to CF after Ang II stimulation. Our results show that Ang II increased IL-6, MCP-1 and TNF-a mRNA levels, but only increased IL-6 and MCP-1 protein levels. These effects were blocked by Losartan, but not by PD123369. Moreover, RvD1 was able to prevent all Ang II effects in CF. Additionally, RvD1 reduced the intracellular Ca2+ increase triggered by Ang II, indicating that RvD1 acts in an early manner to block Ang II signaling. Conclusion: our findings confirm the pro-resolutive effects of inflammation by RvD1, which at the cardiovascular level, could contribute to repair damaged cardiac tissue.

Pharmacogenetic Associations Between Atazanavir/UGT1A1*28 and Efavirenz/rs3745274 (CYP2B6) Account for Specific Adverse Reactions in Chilean Patients Undergoing Antiretroviral Therapy.

Background: Efavirenz (EFV), a non-nucleoside reverse transcriptase inhibitor, and atazanavir (ATV), a protease inhibitor, are drugs widely used in antiretroviral therapy (ART) for people living with HIV. These drugs have shown high interindividual variability in adverse drug reactions (ADRs). UGT1A1*28 and CYP2B6 c.516G>T have been proposed to be related with higher toxicity by ATV and EFV, respectively. Objective: To study the association between genetic polymorphisms and ADRs related to EFV or ATV in patients living with HIV treated at a public hospital in Chile. Methods: Epidemiologic, case-control, retrospective, observational study in 67 adult patients under EFV or ATV treatment was conducted, in the San Juan de Dios Hospital. Data were obtained from patients' medical records. Genotype analyses were performed using rtPCR for rs887829 (indirect identification of UGT1A1*28 allele) and rs3745274 (CYP2B6 c.516G>T), with TaqMan® probes. The association analyses were performed with univariate logistic regression between genetic variants using three inheritance models (codominant, recessive, and dominant). Results: In ATV-treated patients, hyperbilirubinemia (total bilirubin >1.2 mg/dl) had the main incidence (61.11%), and moderate and severe hyperbilirubinemia (total bilirubin >1.9 mg/dl) were statistically associated with UGT1A1*28 in recessive and codominant inheritance models (OR = 16.33, p = 0.028 and OR = 10.82, p = 0.036, respectively). On the other hand, in EFV-treated patients adverse reactions associated with CNS toxicity reached 34.21%. In this respect, nightmares showed significant association with CYP2B6 c.516G>T, in codominant and recessive inheritance models (OR = 12.00, p = 0.031 and OR = 7.14, p = 0.042, respectively). Grouped CNS ADRs (nightmares, insomnia, anxiety, and suicide attempt) also showed a statistically significant association with CYP2B6 c.516G > T in the codominant and recessive models (OR = 30.00, p = 0.011 and OR = 14.99, p = 0.021, respectively). Conclusion: Our findings suggest that after treatment with ATV or EFV, UGT1A1*28 and CYP2B6 c.516G>T influence the appearance of moderate-to-severe hyperbilirubinemia and CNS toxicity, respectively. However, larger prospective studies will be necessary to validate these associations in our population. Without a doubt, improving adherence in patients living with HIV is a critical issue to the success of therapy. Hence, validating and applying international pharmacogenetic recommendations in Latin American countries would improve the precision of ART: a fundamental aspect to achieve the 95-95-95 treatment target proposed by UNAIDS.

Smartphone screen testing, a novel pre-diagnostic method to identify SARS-CoV-2 infectious individuals.

The COVID-19 pandemic will likely take years to control globally, and constant epidemic surveillance will be required to limit the spread of SARS-CoV-2, especially considering the emergence of new variants that could hamper the effect of vaccination efforts. We developed a simple and robust - Phone Screen Testing (PoST) - method to detect SARS-CoV-2-positive individuals by RT-PCR testing of smartphone screen swab samples. We show that 81.3-100% of individuals with high-viral-load SARS-CoV-2 nasopharyngeal-positive samples also test positive for PoST, suggesting this method is effective in identifying COVID-19 contagious individuals. Furthermore, we successfully identified polymorphisms associated with SARS-CoV-2 Alpha, Beta, and Gamma variants, in SARS-CoV-2-positive PoST samples. Overall, we report that PoST is a new non-invasive, cost-effective, and easy-to-implement smartphone-based smart alternative for SARS-CoV-2 testing, which could help to contain COVID-19 outbreaks and identification of variants of concern in the years to come.

Impacto de la atención farmacéutica en la calidad del tratamiento con acenocumarol en pacientes con fibrilación auricular / Effects of pharmaceutical counseling on the effectiveness of anticoagulation in patients with atrial fibrillation

Background: Vitamin K antagonists such as acenocoumarol and warfarin are usually indicated for the treatment of Atrial Fibrillation (AF). The Therapeutic Range Time (TRT) is a quality of treatment indicator. Values greater than 65% are associated with significantly lower stroke and bleeding rates. Proper pharmaceutical care improves TRT. Aim: To evaluate the impact of pharmaceutical care in patients with AF treated with acenocoumarol. Material and Methods: We studied 41 patients using acenocoumarol for AF aged 71 ± 11 years (43% women). They received pharmaceutical counseling during 12 weeks. TRT was calculated retrospectively for the year before counseling and prospectively during the intervention period. Results: After receiving pharmaceutical counseling TRT improved from 29% at baseline to 46% at the end of the intervention (p < 0.01). After pharmaceutical care, the adherence of patients to drug treatment improved from 27% at baseline to 85% at the end of the study. The user satisfaction survey of the pharmaceutical care received showed a high degree of patient satisfaction. Conclusions: Pharmaceutical care in patients with oral anticoagulant treatment improves TRT of anticoagulation. It is accepted and positively evaluated by patients.