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Lanthipeptides are ribosomally synthesized and post-translationally modified peptides characterized by lanthionine (Lan) and/or methyllanthionine (MeLan) residues. Four classes of enzymes have been identified to install these structures in a substrate peptide. Recently, a novel class of lanthipeptides was discovered that lack genes for known class I-IV lanthionine synthases in their biosynthetic gene cluster (BGC). In this study, the dehydration of Ser/Thr during the biosynthesis of the class V lanthipeptide cacaoidin was reconstituted

Systemic lupus erythematosus (SLE) is a chronic immune-inflammatory disease characterized by multiorgan affectation and lowered self-tolerance. Additionally, epigenetic changes have been described as playing a pivotal role in SLE. This work aims to assess the effects of oleacein (OLA), one of the main extra virgin olive oil secoiridoids, when used to supplement the diet of a murine pristane-induced SLE model. In the study, 12-week-old female BALB/c mice were injected with pristane and fed with an OLA-enriched diet (0.01 % (w/w)) for 24 weeks. The presence of immune complexes was evaluated by immunohistochemistry and immunofluorescence. Endothelial dysfunction was studied in thoracic aortas. Signaling pathways and oxidative-inflammatory-related mediators were evaluated by Western blotting. Moreover, we studied epigenetic changes such as DNA methyltransferase (DNMT-1) and micro(mi)RNAs expression in renal tissue. Nutritional treatment with OLA reduced the deposition of immune complexes, ameliorating kidney damage. These protective effects could be related to the modulation of mitogen-activated protein kinases, the Janus kinase/signal transducer and transcription activator of transcription, nuclear factor kappa, nuclear-factor-erythroid-2-related factor 2, inflammasome signaling pathways, and the regulation of miRNAs (miRNA-126, miRNA-146a, miRNA-24-3p, and miRNA-123) and DNMT-1 expression. Moreover, the OLA-enriched diet normalized endothelial nitric oxide synthase and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-1 overexpression. These preliminary results suggest that an OLA-supplemented diet could constitute a new alternative nutraceutical therapy in the management of SLE, supporting this compound as a novel epigenetic modulator of the immunoinflammatory response.

Subgroup analysis evaluates a health intervention in subpopulations according to a characteristic or factor. It can be useful for generating new hypotheses or conducting new studies. However, subgroup analysis presents several limitations and it should be considered cautiously. The development of new onco-hematological drugs is accelerating in recent years and the impact of subgroup analysis on clinical decision-making is increasing. The interpretation of subgroup analyses can be controversial in some cases, negatively affecting patients and healthcare systems. This work is a review of the clinical and pharmacoeconomic impact of subgroup analysis in onco-hematological patients. The study describes some illustrative examples of inadequate interpretations about subset analysis: combination of pembrolizumab plus chemotherapy in lung cancer, inhibitors of cyclin-dependent kinases in breast cancer, daratumumab-based regimens in newly diagnosed multiple myeloma, combination of nivolumab with ipilimumab in melanoma and docetaxel in prostate cancer. Subgroup analysis can have a significant impact on the data selection for the development of studies; efficacy, safety, and convenience of treatments in onco-hematological patients; efficiency of therapies in health systems; and therapeutic positioning of antineoplastic drugs. There is a strong need to establish homogeneous criteria for the assessment of subgroup analysis and to develop new tools for its consideration.

The "Structured HIstory of Medication use" (SHIM) questionnaire is a tool developed to obtain an accurate pre-admission overview of medications, involving a structured interview with patients, and has demonstrated its potential to prevent reconciliation errors. The objective of this study was to cross-culturally adapt the SHIM questionnaire to Spanish.Forward and blind-back translations followed by a synthesis and adaptation, with the participation of an expert panel, to guarantee the equivalence between the original questionnaire and the Spanish version. Subsequently, pilot testing of the Spanish version was carried out through cognitive interviews in a sample of polymedicated patients under follow-up by the Department of Internal Medicine.The Spanish version of the SHIM questionnaire (SHIM-e) was obtained. Scores for difficulty assigned by translators involved in forward and back translations were low. During the synthesis and adaptation phase, three discrepancies were resolved, and the expert panel decided to include some terms commonly used for clinical interviews in the Spanish version of the questionnaire. The pilot testing, which was performed in a sample of 10 polymedicated patients admitted to the Department of General and Digestive Surgery, showed 100% comprehensibility for all items, except for number 13, which was 90%.This work presents the first cross-cultural adaptation to Spanish of the SHIM questionnaire. The forward and blind-back translations presented low difficulty and the results of the pilot testing showed a high level of comprehensibility for the Spanish version of this tool.

Resumen Antecedentes y objetivo El cuestionario “Structured HIstory of Medication use” (SHIM) es una herramienta disenada para obtener una vision completa de la medicacion del paciente antes del ingreso mediante una entrevista estructurada, y ha demostrado su potencial para prevenir errores de conciliacion. El objetivo de este estudio fue adaptar transculturalmente el cuestionario SHIM al espanol. Pacientes y metodos Traduccion directa e inversa seguidas de una sintesis y adaptacion, que conto con la participacion de un panel de expertos, para garantizar la equivalencia entre el cuestionario original y su version espanola. Posteriormente se realizo un analisis de la comprensibilidad de la version espanola del cuestionario mediante entrevistas cognitivas en una muestra de pacientes polimedicados en seguimiento por el Servicio de Medicina Interna. Resultados Se obtuvo la version espanola del cuestionario SHIM (SHIM-e). El grado de dificultad asignado por los traductores a la traduccion directa e inversa fue bajo. Durante la fase de sintesis y adaptacion se resolvieron tres discrepancias y se decidio emplear, en la version del cuestionario adaptada al espanol, algunos terminos de uso comun en la entrevista clinica. El analisis de la comprensibilidad, realizado en una muestra de 10 pacientes polimedicados e ingresados en la Unidad de Cirugia General y de Aparato Digestivo, mostro una comprensibilidad del 100% para todos los items, excepto para el numero 13 que fue del 90%. Conclusiones Este trabajo presenta la primera adaptacion transcultural al espanol del cuestionario SHIM. Los procesos de traduccion directa e inversa han presentado una dificultad baja y los resultados de las entrevistas cognitivas muestran un nivel alto de comprensibilidad para la version espanola de esta herramienta.

Introduction There is subgroup analysis suggesting a lack of benefit of daratumumab use in multiple myeloma (MM) and hepatic disease (HD). The objectives of this study were to conduct a systematic review and interpretation of daratumumab-based regimen efficacy in transplant-ineligible patients with untreated MM and HD. Methods A systematic search in Pubmed® database about randomized clinical trials (RCTs) with subgroup analysis regarding hepatic function for overall survival (OS) or progression-free survival (PFS) were developed. Two methodologies were applied. One of them considered statistical interaction, prespecification, biological support and consistency of subgroup results. Second methodology was two-part validated tool: preliminary questions to reject subset analysis without minimal relevance, and a checklist relating a recommendation for applicability in clinical practice. Results It was included three records. About first methodology, statistical interaction among subgroups was found for PFS in one RCT. Subsets were prespecified in all RCTs. Biological support of efficacy differences could be reasonable. Inconsistent results were found. Second methology directly rejected applicability of subset analysis in two records. Checklist recommended “null” application of results in the remaining RCT. Conclusions No consistent heterogeneity for daratumumab-based regimen efficacy was observed among subgroups regarding hepatic function in transplant-ineligible patients with untreated MM. Patients with normal hepatic function and HD could benefit from these treatments.

Background Use of docetaxel in low- and high-burden metastatic hormone-sensitive prostate cancer presents considerable controversy. There is literature suggesting lack of benefit for low-volume of metastases. Objective The study aims to develop a systematic review and methodological assessment of subset analysis about use of docetaxel in metastatic hormone-sensitive prostate cancer regarding volume of metastatic disease. Methods A systematic review in the Pubmed® database was conducted up to 25 September 2020. A reference tracking was also developed. Randomised clinical trials with subgroup analysis according volume of metastatic disease for overall survival were selected. Two methodologies were used. One of them considered statistical interaction of subsets ( p(i) Results A total of 31 results were found in systematic reviews in the Pubmed® database. One result was identified in the reference tracking. Of the total of 32 results, four randomised clinical trials were included in the study. About first methodology, statistical interaction among subgroups was obtained in one randomised clinical trial. Subgroup analysis was pre-specified in two randomised clinical trials. Biological plausibility was reasonable. No external consistency among results of subgroup analyses in randomised clinical trials was observed. Preliminary questions of second methodology rejected applicability of subgroup analysis in three randomised clinical trials. A ‘null’ recommendation for applicability of subset results was obtained in the remaining randomised clinical trial. Conclusions Patients with low- and high-burden metastatic hormone-sensitive prostate cancer would benefit from docetaxel therapy. No consistent differences for overall survival were observed in subgroup analyses regarding volume of metastatic disease.

Pentaminomycins F-H (1-3), a group of three new hydroxyarginine-containing cyclic pentapeptides, were isolated from cultures of a Streptomyces cacaoi subsp. cacaoi strain along with the known pentaminomycins A-E. The structures of the new peptides were determined by a combination of mass spectrometry, NMR, and Marfey's analyses. Pentaminomycins F (1) and G (2) were shown to contain the rare amino acid 3-(2-pyridyl)-alanine. This finding represents the first reported examples of nonribosomal peptides containing this residue. The ldlld chiral sequence found for the three compounds was in agreement with that reported for previously isolated pentaminomycins and consistent with the epimerization domains present in the putative nonribosomal peptide synthetase (NRPS) biosynthetic gene cluster.

Se trata de un recurso de Realidad Virtual que sitúa al estudiante en los laboratorios de prácticas de la Facultad de Farmacia de la Universidad de Sevilla. El recurso permite al alumnado realizar de forma virtual una serie de ensayos básicos para la determinación cualitativa de los principios activos de una droga de origen vegetal; así como el estudio de la actividad farmacológica de un extracto elaborado a partir de dicha droga. En concreto, los ensayos se centrarán en Atropa Belladonna L. y sus principios activos, atropina y escopolamina. El recurso se compone de una serie de textos, vídeos didácticos y cuestiones teórico-prácticas que proporcionan soporte al estudiante para avanzar en los diferentes escenarios. Dichos elementos serán liberados mediante la interacción del estudiante con los elementos del laboratorio. Este recurso es una herramienta de gran utilidad para que los alumnos apliquen, de una forma sencilla y con un ejemplo práctico, sus conocimientos adquiridos durante su interacción con el contenido de dichas asignaturas, así como combinarlos con aquellos adquiridos en otras asignaturas como, por ejemplo, la asignatura de Farmacognosia del Grado de Farmacia. Es de destacar que este recurso también es de gran valor como herramienta docente no presencial, ya que permitirá adaptar la docencia práctica a laboratorios virtuales. De esta manera, hace accesible la práctica de laboratorio al alumnado que no pudiera acudir físicamente al laboratorio. La necesidad de este tipo de herramientas virtuales ha quedado evidente con la pandemia del SARS-CoV-2 que se está viviendo desde principios del 2020.

Lantibiotics are ribosomally synthesized and post-translationally modified peptides (RiPPs) characterized by the presence of lanthionine or methyllanthionine rings and their antimicrobial activity. Cacaoidin, a novel glycosylated lantibiotic, was isolated from a Streptomyces cacaoi strain and fully characterized by NMR, mass spectrometry, chemical derivatization approaches and genome analysis. The new molecule combines outstanding structural features, such as a high number of d-amino acids, an uncommon glycosylated tyrosine residue and an unprecedented N,N-dimethyl lanthionine. This latter feature places cacaoidin within a new RiPP family located between lanthipeptides and linaridins, here termed lanthidins. Cacaoidin displayed potent antibacterial activity against Gram-positive pathogens including Clostridium difficile. The biosynthetic gene cluster showed low homology with those of other known lanthipeptides or linaridins, suggesting a new RiPP biosynthetic pathway.

d-Pinitol (3-O-methyl-d-chiro-inositol) is a cyclitol nearly ubiquitous in the Leguminosae and Pinaceae families. It plays an important role in plants as physiological cellular modulator and chemical defense against unfavorable environmental conditions, such as water deficit and high level of salinity. Plants rich in d-pinitol are being used in traditional medicine as empirical treatment for diabetes, inflammation, cancer or infections. This review summarizes the extensive literature published about d-pinitol biosynthesis, plant distribution, biological activities and pharmacological studies, including in vitro, in vivo, and clinical trials.

Phenylglycines are building blocks of many non-ribosomally synthesized peptides. The dihydroxyphenylglycine-containing cyclodepsipeptide cochinmicin I exhibits endothelin receptor antagonist activity. Therefore, it represents an interesting and synthetically challenging molecule because of the racemization-prone nature of dihydroxyphenylglycine. We present the total synthesis of cochinmicin I and the non-natural derivative cochinmicin VI and describe the identification and assignment of the cochinmicin (

The antioxidant and anti-inflammatory responses of (−)-methyl-oleocanthal (met-OLE), a new metabolite of the extra virgin olive oil (EVOO) phenolic oleocanthal (OLE), were explored in lipopolysaccharide (LPS)-induced murine peritoneal macrophages. Possible signaling pathways and epigenetic modulation of histones were studied. Met-OLE inhibited LPS-induced intracellular reactive oxygen species (ROS) and nitrite (NO) production and decreased the overexpression of the pro-inflammatory enzymes COX-2, mPGES-1 and iNOS in murine macrophages. In addition, met-OLE was able to significantly decrease the activation of p38, JNK, and ERK mitogen-activated protein kinases (MAPKs) and blocked canonical and non-canonical inflammasome signaling pathways. On the contrary, met-OLE upregulated haem oxigenase 1 (HO-1) and nuclear factor (erythroid-derived 2)-like 2 (Nrf-2) expression in treated cells. Finally, met-OLE pretreated spleen cells counteracted LPS induction, preventing H3K18 acetylation or H3K9 and H3K27 demethylation. Overall, these results provide novel mechanistic insights into the beneficial effects of met-OLE regarding the regulation of the immune–inflammatory response through epigenetic changes in histone markers. This revealing evidence suggests that the methylated metabolite of OLE may contribute significantly to the beneficial effects that are associated with the secoiridoid-related compound and the usual consumption of EVOO. España Ministerio de Economía y Competitividad grant number AG-2017-89342-P Junta de Andalucía funded by CTS-259, FQM-182

Systemic lupus erythematosus (SLE) is a multiorgan disorder with a deregulated immune-inflammatory response. Nutritional therapy has been considered a promising approach to SLE management. Oleocanthal (OLE), the main extra virgin olive oil (EVOO)-derived secoiridoid, has shown to regulate the immune-inflammatory response in various disease contexts; however, its possible beneficial effects on SLE remain unclear. This study sought to evaluate the effects of OLE enriched diet on renal damage and aortic endothelial dysfunction in murine pristane-induced SLE, focusing on the action mechanisms and signaling pathways involved. BALB/c mice were injected with pristane and fed with OLE supplemented diet (0.01 % (w/w)) for six months. Levels of cytokines were measured by ELISA in lipopolysaccharide (LPS)-stimulated peritoneal macrophages and splenocytes. Presence of immunoglobulin G (IgG) and IgM immune complexes were examined by immunofluorescence and immunohistochemistry. Thoracic aortas were used to evaluate endothelial dysfunction. Western blotting was employed to detect signaling pathways and oxidative-inflammatory-related mediators. Dietary OLE supplementation reduced Th1/Th17 pro-inflammatory cytokines production and alleviated renal damage by decreasing immunoglobulin complexes deposition, and inflammation-mediating enzymes expression. The mechanisms underlying these protective effects could be related to the regulation of nuclear factor erythroid 2-related factor 2/Haem oxygenase 1 (Nrf-2/HO-1), mitogen-activated protein kinases (MAPKs), signal transducer and transcription activator of transcription (STAT-3), inflammasome and, nuclear factor kappa B (NF-κB) signaling pathways. Also, dietary OLE improved aortic endothelial dysfunction and vascular reactivity, normalizing endothelial nitric oxide synthase (eNOS) uncoupling, and NADPH oxidase-1 (NOX-1) overexpression. This study shows the immunomodulatory effects of OLE in an in vivo model of SLE by improving renal damage and regulating aortic endothelial dysfunction. These preliminary results provide OLE as a new therapeutic strategy in SLE management.

The present study was designed to investigate the potential anti-inflammatory, antioxidant and immunomodulatory activities of three new derivatives from OL in lipopolysaccharide (LPS)-induced mouse peritoneal macrophages in comparison with natural OL. Nitrites levels were analyzed by Griess method and intracellular reactive oxygen species (ROS) by fluorescence analysis. The levels of cytokines were evaluated by ELISA. The protein expression of cyclo-oxigenase (COX)-2), inducible nitric oxide synthase (iNOS), janus kinase/signal transducer activator of transcription (JAK/STAT) pathway (pSTAT3), haem-oxigenase 1 (HO-1), nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and MAPKS activation were determined by Western blot. The mechanisms underlying these protective effects could be related to the activation of Nrf2/HO-1 pathway and inhibition of both JAK-STAT and MAPKs signalling pathways. We conclude that OL and new OL acylated-derivatives exhibited immunomodulatory effects and thus, may offer a new promising therapeutic strategy in the management of immune mediated-inflammatory diseases.

Cacaoidin is produced by the strain Streptomyces cacaoi CA-170360 and represents the first member of the new lanthidin (class V lanthipeptides) RiPP family. In this work, we describe the complete identification, cloning and heterologous expression of the cacaoidin biosynthetic gene cluster, which shows unique RiPP genes whose functions were not predicted by any bioinformatic tool. We also describe that the cacaoidin pathway is restricted to strains of the subspecies Streptomyces cacaoi subsp. cacaoi found in public genome databases, where we have also identified the presence of other putative class V lanthipeptide pathways. This is the first report on the heterologous production of a class V lanthipeptide.

Se trata de un recurso de realidad virtual que sitúa al estudiante en un laboratorio de cultivo celular. El recurso permite al estudiante conocer los instrumentos y equipos básicos que componen un laboratorio de cultivo celular, así como realizar de forma virtual un experimento modelo para evaluar la actividad antiinflamatoria de un nuevo fármaco en estudio preclínico. El recurso consta se compone de una serie de videos y cuestiones teórico-prácticas que permiten al estudiante ir avanzando por diferentes escenarios para comprender y profundizar en conceptos básicos sobre la Farmacología Experimental, centrados en el cultivo celular como herramienta de ensayo preclínico. El recurso consta de dos escenarios, uno dentro del laboratorio de cultivo celular y el otro en un laboratorio general para finalizar el experimento. Concretamente, al inicio del recurso, el alumnado puede conocer e informarse sobre los diferentes elementos del laboratorio de cultivo celular con sólo colocar el puntero del ratón sobre los objetos que se visualizan en el laboratorio y cliqueando sobre ellos. Una vez reconocidos todos los elementos del laboratorio, se inicia la práctica a través del cliqueo del cuaderno de prácticas que se encuentra en la mesa del laboratorio de cultivos. Esta herramienta docente está formada por 18 pasos en total, donde el alumnado debe ir visualizando los vídeos y contestando a las diferentes preguntas y actividades para poder avanzar en las prácticas y conseguir así completar el informe con los resultados obtenidos en el ensayo. Las respuestas correctas puntúan positivamente, quedando registradas en un contador de color verde, y permiten avanzar en el recurso. Por el contrario, las respuestas incorrectas puntúan negativamente, registrándose en un contador de color rojo, e impiden el avance al siguiente paso. En este último caso, el alumnado puede volver a consultar los elementos de dicho paso para corregir su selección y, de esa forma, poder seguir avanzando en el recurso. También existe un contador que registra el tiempo empleado en total. Al finalizar la práctica, el alumnado deberá realizar una “captura” de pantalla con los resultados obtenidos (contador de respuestas correctas, contador de respuestas incorrectas y contador del tiempo) y adjuntar dicha captura con el informe de resultados en pdf que deberá rellenar y enviar al profesorado. Es altamente aconsejable trabajar el recurso con un ordenador de sobremesa/portátil, ya que permite cargar de forma más rápida y eficiente los elementos. Aunque es posible su visualización y realización desde dispositivos móviles, la potencia técnica de los mismos podría dificultar su realización al no cargar correctamente los elementos.

Background and importance Addition of docetaxel to hormonal treatment in low and high burden metastatic hormone sensitive prostate cancer (mHSPC) has raised important issues. There are studies suggesting increased overall survival (OS) in high burden disease and lack of benefit for low volume of metastases. Aim and objectives To perform a systematic search and methodological evaluation of subgroup analyses about the use of docetaxel in mHSPC according to volume of metastatic disease (VMD). Material and methods A systematic search in Pubmed was conducted up to 25 September 2020. The following search strategy was used in the ‘Clinical Queries/Narrow’ tool: (Therapy/Narrow[filter]) AND (docetaxel AND prostate cancer AND hormone sensitive). Randomised clinical trials (RCTs) with subgroup analysis regarding VMD for OS were included. The rest of the review results were excluded. Two methodologies were used. One evaluated the heterogeneity of the subgroups (p Results There were 31 results in the search and the following were excluded: 9 were not RCTs, 13 did not evaluate the effect of docetaxel, 4 had no subset analysis for VMD and 1 did not assess OS. Therefore, four RCTs were included. According to the first methodology, heterogeneity among subgroups was observed in one RCT. Subset analysis was prespecified in two RCTs. Biological support was found in the subgroup analyses of all RCTs. No consistency among results of these subgroup analyses were observed. Preliminary questions of the second methodology discarded applicability of subset analysis in three RCTs. In the remaining RCT, a ‘null’ recommendation was obtained for applicability of subgroup results because of inconsistency. Conclusion and relevance Regarding the use of docetaxel in mHSPC, no consistent differences for OS were found in subset analysis according to VMD. Patients with low and high burden mHSPC benefited from docetaxel therapy. This is the first study with a systematic review and methodology of subgroup analyses in mHSPC according to VMD. References and/or acknowledgements Sun X, et al. How to use a subgroup analysis: users’ guide to the medical literature. JAMA 2014;311:405–11. Gil-Sierra MD, et al. Checklist for clinical applicability of subgroup analysis. J Clin Pharm Ther 2020;45:530–8. Conflict of interest No conflict of interest

Background and importance A greater benefit was suggested with early treatment with remdesivir against COVID-19. Aim and objectives To develop a systematic review and methodological interpretation of subgroup analyses according to timing of use of remdesivir in COVID-19. Material and methods A bibliographic review in MEDLINE was conducted up to 10 October 2020. The ‘Clinical Queries/Narrow’ tool was used with the search strategy: ((Therapy/Narrow[filter]) AND (remdesivir AND COVID)). Randomised clinical trials (RCTs) with subset analysis about early and late use of remdesivir (≤10 vs >10 days from symptom onset, or ≤9 vs >9 days) were selected. The rest of the studies were excluded. All endpoints with subgroup analysis regarding timing of remdesivir use were assessed. Two methodologies were applied. The first considered statistical interaction among subsets, prespecification, biological plausibility and consistency of the subgroup analyses of similar RCTs.1 The second methodology was a validated tool with preliminary questions to discard subset analysis without minimal relevance, and a checklist.2 This checklist assigned a score related to a recommendation for applicability of subgroup analysis in clinical practice. Results 20 results were found after review; 16 studies were excluded because they were not RCTs and 1 study had no efficacy evaluation of remdesivir. Therefore, three RCTs were selected. Endpoints considered were: time to clinical improvement, mortality, viral load, and clinical status at days 11 and 15. According to the first methodology, no statistical interaction was observed in the outcomes of the RCTs. Prespecification was established in time to clinical improvement, and clinical status at day 15 of an RCT. Biological plausibility was described in the subset analysis of each endpoint of the RCTs. No consistency of subgroup analyses were found. The second methodology discarded the applicability of the subset analysis through preliminary questions in two RCTs because of the absence of minimal relevance. For the third RCT, ‘null’ recommendation (score −3 points) of clinical applicability was reached for clinical status at day 11. Conclusion and relevance No differences were found between early and late use of remdesivir in COVID-19. We developed the first study with a systematic review and methodology about subgroup analysis of timing of use of remdesivir. References and/or acknowledgements Sun X, et al. How to use a subgroup analysis: users’ guide to the medical literature. JAMA 2014;311:405–11. Gil-Sierra MD, et al. Checklist for clinical applicability of subgroup analysis. J Clin Pharm Ther 2020;45:530–8. Conflict of interest No conflict of interest

Background and importance There are studies (subgroup analyses) suggesting a lack of benefit for daratumumab drug combinations in patients with untreated multiple myeloma (MM) and hepatic impairment (HI). Aim and objectives To conduct a systematic search and methodological interpretation of subset analysis about the use of daratumumab based treatments in patients with untreated MM and HI. Material and methods A bibliographic review in Pubmed was performed up to 11 October 2020. A review strategy was used in the ‘Clinical Queries/Narrow’ tool: (Therapy/Narrow[filter]) AND (daratumumab AND myeloma). Randomised clinical trials (RCTs) with subset analyses according to baseline hepatic function for overall survival (OS) or progression free survival (PFS) in untreated MM were selected. The rest of the search results were excluded. Two methodologies were applied. One considered statistical interaction among subsets (p Results A total of 25 results were found in the search and the following were excluded: 10 were not RCTs, 9 studies had a different clinical context, 2 evaluated different drugs and 1 had no subset analysis. Therefore, three RCTs were included. According to the first methodology, statistical interaction among subsets was observed for PFS in one RCT. Subgroup analysis was prespecified in each endpoint of all RCTs. Biological support could be reasoned for outcomes of subgroup analyses in all RCTs. However, no consistency of these subset analyses was found. The second methodology (validated tool) discarded applicability of subgroup analysis in two RCTs. In the remaining RCT, checklist recommended a ‘null’ application of subgroup analysis for PFS because of inconsistency of results. Conclusion and relevance No differences in OS or PFS according to baseline hepatic function should be considered for daratumumab based combinations in patients with untreated MM. Patients with normal hepatic function and HI could benefit from treatment. Application of subgroup analysis should be considered with caution. References and/or acknowledgements Sun X, et al. How to use a subgroup analysis: users’ guide to the medical literature. JAMA 2014;311:405–11 Gil-Sierra MD, et al. Checklist for clinical applicability of subgroup analysis. J Clin Pharm Ther 2020;45:530–8. Conflict of interest Corporate sponsored research or other substantive relationships MDG-S: membership of an advisory board (consultation fees) and lecture for Janssen Pharmaceutica (reimbursement for attending symposia). The other authors have no conflicts of interest to declare

The strain Streptomyces cacaoi CA-170360 produces the cyclic pentapeptides pentaminomycins A&ndash, H and BE-18257 A&ndash, C, two families of cyclopeptides synthesized by two non-ribosomal peptide synthetases encoded in tandem within the same biosynthetic gene cluster. In this work, we have cloned and confirmed the heterologous expression of this biosynthetic gene cluster, demonstrating that each of the non-ribosomal peptide synthetases present in the cluster is involved in the biosynthesis of each group of cyclopeptides. In addition, we discuss the involvement of a stand-alone enzyme belonging to the Penicillin Binding Protein family in the release and macrocyclization of the peptides.

© 2021 by the authors., Oleuropein (OL), an olive tree secoiridoid and its peracetylated derivate (Per-OL) have exhibited several beneficial effects on LPS-stimulated macrophages and murine experimental systemic lupus erythematosus (SLE). This study was designed to evaluate dietary Per-OL in comparison with OL supplementation effects on collagen-induced arthritis (CIA) murine model. Three-weeks-old DBA-1/J male mice were fed from weaning with a standard commercial diet or experimental enriched-diets in 0.05 % (w/w) OL, 0.05% and 0.025% Per-OL. After six weeks of pre-treatment, arthritis was induced by bovine collagen type II by tail base injection (day 0) and on day 21, mice received a booster injection. Mice were sacrificed 42 days after the first immunization. Both Per-OL and OL diets significantly prevented histological damage and arthritic score development, although no statistically significant differences were observed between both compounds. Also, serum collagen oligomeric matrix protein (COMP), metalloprotease (MMP)-3 and pro-inflammatory cytokines levels were ameliorated in paws from secoiridoids fed animals. Mitogen-activated protein kinases (MAPK)s and nuclear transcription factor-kappa-B (NF-κB) activations were drastically down-regulated whereas nuclear factor E2-related factor 2 (Nrf2) and heme-oxygenase-1 (HO-1) protein expressions were up-regulated in those mice fed with OL and Per-OL diets. We conclude that both Per-OL and its parent compound, OL, supplements might provide a basis for developing a new dietary strategy for the prevention of rheumatoid arthritis., The authors gratefully acknowledge the financial support by a research grant (Reference: AG2017-89342-P) from the Ministerio de Economía y Competitividad of Spain, the assistance of Centre for Technology and Innovation Research at the University of Seville (CITIUS), Dirección General de Investigación of Spain (CTQ2016-78703-P), Junta de Andalucía (CTS259 and FQM134) as well as, the European Regional Development Fund (FEDER) for financial support. M.L.C. acknowledges support from Junta de Andalucía and Fondo Social Europeo. T.M. thanks support from a Postgraduate Program of PIF fellowship and financial sponsorship from VI Plan Propio de Investigación y Transferencia at the University of Seville.

The strain Streptomyces cacaoi CA-170360 produces the cyclic pentapeptides pentaminomycins A–H and BE-18257 A–C, two families of cyclopeptides synthesized by two non-ribosomal peptide synthetases encoded in tandem within the same biosynthetic gene cluster. In this work, we have cloned and confirmed the heterologous expression of this biosynthetic gene cluster, demonstrating that each of the non-ribosomal peptide synthetases present in the cluster is involved in the biosynthesis of each group of cyclopeptides. In addition, we discuss the involvement of a stand-alone enzyme belonging to the Penicillin Binding Protein family in the release and macrocyclization of the peptides.

After the success of the first and second editions of the "INTERNATIONAL WORKSHOP INFLAMMATION AND IMMUNITY: FROM BENCH TO CLINIC" held in 2017 and 2019, respectively, we celebrate this third edition. This scientific seminar aims to meet basic and clinical researchers, together with industry and administration representatives, to explore and discuss inflammation and immunity in health and in pathological processes. Our aim is to promote a debate on research in these fields and to stimulate the translation of research findings into novel therapeutic applications. It will be an opportunity to forge new scientific collaborations within our environment and to favour the bases for future activities and joint projects. We are delighted to announce that the workshop is going virtual and invite you to join us online. The virtual sessions will include live-streamed talks from invited speakers with live Q&A sessions after each talk.

Pentaminomycins F-H, a group of three new hydroxyarginine-containing cyclic pentapeptides, were isolated from cultures of a Streptomyces cacaoi subsp. cacaoi strain along with the known pentaminomycins A-E. The structures of the new peptides were determined by a combination of mass spectrometry and NMR and Marfey's analyses. Among them, pentaminomycins F and G were shown to contain in their structures the rare amino acid 3-(2-pyridyl)-alanine. This finding represents the first reported example of non-ribosomal peptides containing this residue. The LDLLD chiral sequence found for the three compounds was in agreement with that reported for previously isolated pentaminomycins and consistent with the epimerization domains present in the putative non-robosomal peptide synthetase (NRPS) biosynthetic gene cluster.

1.AbstractThe strainStreptomyces cacaoiCA-170360 produces the cyclic pentapeptides pentaminomycins A-E and BE-18257 A-C, two families of cyclopeptides synthesized by two nonribosomal peptide synthetases encoded in tandem within the same biosynthetic gene cluster. In this work, we have cloned and confirmed the heterologous expression of this biosynthetic gene cluster, demonstrating that each of the nonribosomal peptide synthetases present in the cluster is involved in the biosynthesis of each group of cyclopeptides. In addition, we discuss the involvement of a stand-alone enzyme belonging to the Penicillin Binding Protein family in the release and macrocyclization of the peptides.

Background Recent systematic reviews and meta-analyses suggest that medication reconciliation (MR) is effective in decreasing the risk of medication discrepancies. Nevertheless, the association between MR and subsequent improved healthcare outcomes is not well established. Objectives This systematic review of reviews set out to identify published systematic reviews on the impact of MR programs on health outcomes and to describe key components of the intervention, the health outcomes assessed and any associations between MR and health outcomes. Methods PubMed, EMBASE, Cochrane Library, Cumulative Index to Nursing and Allied Health Literature (CINAHL) and SCOPUS were searched from inception to May 2019. Systematic reviews of all study designs, populations, intervention providers and settings that measured patient-related outcomes or healthcare utilization were considered. Methodological quality was assessed using A Measurement Tool to Assess Systematic Reviews 2 (AMSTAR 2). Two investigators performed study selection, quality assessment and data collection independently. Results Five systematic reviews met the inclusion criteria: 2 were rated as low quality and 3 as critically low quality. Reviews included primary studies in different settings (hospitals, the community and residential aged care facilities) that reported the impact of MR on mortality, length of stay, Emergency Department (ED) visits, readmissions, physician visits and healthcare utilization. Only one review reported results on mortality. However, healthcare utilization, which usually included ED visits and readmissions, was communicated in all reviews. Meta-analyses were conducted in all reviews except one. Medication reconciliation was not consistently found to be associated with improvements in health outcomes. Conclusions Few systematic reviews support the value of MR in achieving good patient-related outcomes and healthcare utilization improvements. The quality of the systematic reviews was low and the primary studies included commonly involved additional activities related to MR. There was no clear evidence in favor of intervention in mortality, length of stay, ED visits, unplanned readmissions, physician visits and healthcare utilization.

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease without an effective and safe treatment. Besides, macrophages are the major components of the innate immune system and play a critical role in the inflammation process in SLE. Secoiridoids from olive tree are phenolic compounds which have shown important pharmacological effects. Particularly, oleuropein (OL) has shown antioxidant, anti-inflammatory and immunomodulatory properties suggesting a potential application in a large number of inflammatory and reactive oxygen species (ROS)-mediated diseases. In addition, different studies have shown the importance of acyl derivatives of natural phenols due to their better hydrophilic/lipophilic balance.