New antimicrobials to target gut and food pathogens

There is a pressing need for the discovery of new antimicrobials to fight antibiotic resistant bacteria. The aim of this thesis was the discovery and characterisation of new bacteriocins from two sources, fermented foods and human faeces, testing the hypothesis that bacteria from the same niche will produce antimicrobials uniquely suited to act in this niche. Isolates from culture collections and new isolates from food and faecal samples were screened against a panel of pathogens responsible for food spoilage and human disease. Promising candidates were selected for genome sequencing, antimicrobial characterisation and biological study. The genome of Lactobacillus gasseri LM19 showed the presence of antimicrobial genes encoding, among others, a new bacteriocin, gassericin M. L. gasseri LM19 could survive and express its bacteriocin genes under colonic conditions. Its administration modulated the effects of Clostridium perfringens on the gut microbiota composition. Streptococcus agalactiae DPC7040 was previously shown to produce the natural variant nisin P. MALDI-ToF analysis confirmed that nisin P is three amino acids shorter than nisin A and that two lanthionine rings were absent in 50% of molecules. This structure impacted on its antimicrobial activity, which was weaker than that of nisin A and nisin H in faecal fermentations. Staphylococcus epidermidis strains isolated from faecal samples were compared with skin isolates with respect to genomic and phenotypic traits. It was concluded that S. epidermidis has no specific genomic features to colonise different body sites but is likely to adapt its metabolism to the different conditions. Potential novel antimicrobials were found in Lactobacillus amylovorus and Lactobacillus crispatus isolates, which showed probiotic properties and interesting phenotypic differences between strains. Together, this work further demonstrates that fermented food and gut environments are valuable sources of new isolates, the study of which can yield new antimicrobials and give insights into bacterial ecology and evolution

The relationship of acculturation and social support to birth outcomes of pregnant Mexican-American adolescents

The adolescent pregnancy rate in the U.S. continues to be an issue that concerns nursing and allied health related fields. There has been minimal research published regarding Mexican-American adolescent pregnancy outcomes. The purpose of this was to assess the relationship between social support and acculturation on pregnancy outcomes of Mexican- American adolescents. Statistical descriptive analysis analyzed the relationships between the demographic data, the Acculturation Rating Scale-II for Mexican-Americans, the Norbeck Social Support Questionnaire, and birth outcomes. Pearson\u27s product moment correlation analyzed the relationship between acculturation and social support on birth outcomes. Several positive correlations were found at the p ≤ 0.01 and p ≤ 0.05 significance levels. Significant positive correlations were found between the three social support categories, the acculturation levels, acculturation scale scores, gestational age, birth weight, maternal age and education levels. A weak positive correlation was found between the Mexican Orientation Score and gestational status

Instrumentos jurídicos de movilidad humana y la trata de personas en el Ecuador

El objetivo general de este estudio es el de fundamentar los instrumentos jurídicos de movilidad humana y la trata de personas en el Ecuador. El problema central se relaciona con el alto índice de trata de personas en el Ecuador durante el período 2010 al 2015 en diferentes lugares del territorio nacional, pero con gran incidencia en ciudades fronterizas, y la falta de una normativa clara dentro del Proyecto de Ley Orgánica de Movilidad Humana para el procedimiento a seguir en los casos de trata de personas dejando vulnerables a las víctimas de este crimen. Para el desarrollo de este trabajo se utilizó el método cualitativo tipo estudio de caso, mediante entrevistas a expertos y el análisis del «Protocolo para prevenir, reprimir y sancionar la trata de personas, especialmente mujeres y niños que complementa la convención de las Naciones Unidas contra la delincuencia organizada transnacional» para finalmente aportar con una normativa propuesta a ser incluida en el Proyecto de Ley Orgánica de Movilidad Humana

Randomized open-label controlled study of cancer vaccine OSE2101 versus chemotherapy in HLA-A2-positive patients with advanced non-small-cell lung cancer with resistance to immunotherapy: ATALANTE-1

Cancer vaccine; Immunotherapy resistance; Quality of lifeVacuna contra el cáncer; Resistencia a la inmunoterapia; Calidad de vidavacuna contra el càncer; Resistència a la immunoteràpia; Qualitat de vidaBackground Patients with advanced non-small-cell lung cancer (NSCLC) treated with immune checkpoint blockers (ICBs) ultimately progress either rapidly (primary resistance) or after durable benefit (secondary resistance). The cancer vaccine OSE2101 may invigorate antitumor-specific immune responses after ICB failure. The objective of ATALANTE-1 was to evaluate its efficacy and safety in these patients. Patients and methods ATALANTE-1 was a two-step open-label study to evaluate the efficacy and safety of OSE2101 compared to standard-of-care (SoC) chemotherapy (CT). Patients with human leukocyte antigen (HLA)-A2-positive advanced NSCLC without actionable alterations, failing sequential or concurrent CT and ICB were randomized (2 : 1) to OSE2101 or SoC (docetaxel or pemetrexed). Primary endpoint was overall survival (OS). Interim OS futility analysis was planned as per Fleming design. In April 2020 at the time of interim analysis, a decision was taken to prematurely stop the accrual due to coronavirus disease 2019 (COVID-19). Final analysis was carried out in all patients and in the subgroup of patients with ICB secondary resistance defined as failure after ICB monotherapy second line ≥12 weeks. Results Two hundred and nineteen patients were randomized (139 OSE2101, 80 SoC); 118 had secondary resistance to sequential ICB. Overall, median OS non-significantly favored OSE2101 over SoC {hazard ratio (HR) [95% confidence interval (CI)] 0.86 [0.62-1.19], P = 0.36}. In the secondary resistance subgroup, OSE2101 significantly improved median OS versus SoC [11.1 versus 7.5 months; HR (95% CI) 0.59 (0.38-0.91), P = 0.017], and significantly improved post-progression survival (HR 0.46, P = 0.004), time to Eastern Cooperative Oncology Group (ECOG) performance status deterioration (HR 0.43, P = 0.006) and Quality of Life Questionnaire Core 30 (QLQ-C30) global health status compared to SoC (P = 0.045). Six-month disease control rates and progression-free survival were similar between groups. Grade ≥3 adverse effects occurred in 11.4% of patients with OSE2101 and 35.1% in SoC (P = 0.002). Conclusions In HLA-A2-positive patients with advanced NSCLC and secondary resistance to immunotherapy, OSE2101 increased survival with better safety compared to CT. Further evaluation in this population is warranted.This work was supported by OSE Immunotherapeutics (no grant number)

First-line nivolumab plus ipilimumab for metastatic non-small cell lung cancer, including patients with ECOG performance status 2 and other special populations: CheckMate 817

Antigen CTLA-4; Immunoteràpia; Neoplàsies pulmonarsAntígeno CTLA-4; Inmunoterapia; Neoplasias PulmonaresCTLA-4 antigen; Immunotherapy; Lung NeoplasmsBackground CheckMate 817, a phase 3B study, evaluated flat-dose nivolumab plus weight-based ipilimumab in patients with metastatic non-small cell lung cancer (NSCLC). Here, in this research, we report on first-line treatment in patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1 (cohort A) and special populations (cohort A1: ECOG PS 2; or ECOG PS 0–1 with untreated brain metastases, renal impairment, hepatic impairment, or controlled HIV infection). Methods Cohorts A and A1 received nivolumab 240 mg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary endpoint was the incidence of grade 3–4 and grade 5 immune-mediated adverse events (IMAEs; adverse events (AEs) deemed potentially immune-related, occurring <100 days of last dose, and treated with immune-modulating medication (except endocrine events)) and treatment-related select AEs (treatment-related AEs with potential immunological etiology requiring frequent monitoring/intervention, reported between first dose and 30 days after the last dose) in cohort A; efficacy endpoints were secondary/exploratory. In cohort A1, safety/efficacy assessment was exploratory. Results The most common grade 3–4 IMAEs were pneumonitis (5.1%), diarrhea/colitis (4.9%), and hepatitis (4.6%) in cohort A (N=391) and diarrhea/colitis (3.5%), hepatitis (3.5%), and rash (3.0%) in cohort A1 (N=198). The most common grade 3–4 treatment-related select AEs were hepatic (5.9%), gastrointestinal (4.9%), and pulmonary (4.6%) events in cohort A and gastrointestinal (4.0%), skin (3.5%), and endocrine (3.0%) events in cohort A1. No grade 5 IMAEs or treatment-related select AEs occurred. Treatment-related deaths occurred in 4 (1.0%) and 3 (1.5%) patients in cohorts A and A1, respectively. Three-year overall survival (OS) rates were 33.7% and 20.5%, respectively. Conclusions Flat-dose nivolumab plus weight-based ipilimumab was associated with manageable safety and durable efficacy in cohort A, consistent with data from phase 3 metastatic NSCLC studies. Special populations of cohort A1 including patients with ECOG PS 2 or ECOG PS 0–1 with untreated brain metastases had manageable treatment-related toxicity and clinically meaningful 3-year OS rate.This work was supported by Bristol Myers Squibb (Princeton, New Jersey, USA)

Programa de educación para la salud dirigido a familiares de pacientes con trastornos depresivos.

La depresión es el trastorno mental más frecuente y relevante en Atención Primaria. Ahora bien, el impacto de la depresión no solo se limita al enfermo, obligando a considerar el cuidado centrado en la familia como parte integrante de la práctica de enfermería. A través de la educación para la salud se ha podido comprobar una disminución de la carga familiar y una mejor evolución en el curso del trastorno del paciente. El objetivo principal de este trabajo ha sido elaborar un programa de educación para la salud para familiares de pacientes con trastorno depresivo, dirigido por enfermería desde Atención Primaria. Se ha realizado una revisión bibliográfica de las principales bases de datos (Dialnet, Science Direct, Scielo y Pubmed) y de guías y publicaciones de las principales instituciones mundiales. Además se ha recogido información tras la asistencia a una conferencia que tuvo lugar en el Centro de Investigación Biomédica Aragonés, en el marco de Jornadas Pacientes y Salud, con el nombre “Depresión. La importancia de la familia”. El profesional de enfermería debe poseer en el área de Atención Primaria un espacio fundamental para orientar a la familia en el proceso de recuperación del enfermo. La escucha y el acompañamiento de la familia en su proceso de cuidador facilita el tratamiento, la evolución y la prevención de las recaídas en el enfermo depresivo, a la vez que aumenta la calidad de vida y disminuye el sufrimiento de los cuidadores familiares

Gut microbiota as a source of novel antimicrobials

peer reviewedBacteria, Archaea, Eukarya and viruses coexist in the human gut, and this coexistence is functionally balanced by symbiotic or antagonistic relationships. Antagonism is often characterized by the production of antimicrobials against other organisms occupying the same environmental niche. Indeed, close co-evolution in the gut has led to the development of specialized antimicrobials, which is attracting increased attention as these may serve as novel alternatives to antibiotics and thereby help to address the global problem of antimicrobial resistance. The gastrointestinal (GI) tract is especially suitable for finding novel antimicrobials due to the vast array of microbes that inhabit it, and a considerable number of antimicrobial producers of both wide and narrow spectrum have been described. In this review, we summarize some of the antimicrobial compounds that are produced by bacteria isolated from the gut environment, with a special focus on bacteriocins. We also evaluate the potential therapeutic application of these compounds to maintain homeostasis in the gut and the biocontrol of pathogenic bacteria.Teagas

Digital Display Precision Predictor: the prototype of a global biomarker model to guide treatments with targeted therapy and predict progression-free survival

Biologia computacional i bioinformàtica; Oncologia; Marcadors predictiusBiología computacional y bioinformática; Oncología; Marcadores predictivosComputational biology and bioinformatics; Oncology; Predictive markersThe expanding targeted therapy landscape requires combinatorial biomarkers for patient stratification and treatment selection. This requires simultaneous exploration of multiple genes of relevant networks to account for the complexity of mechanisms that govern drug sensitivity and predict clinical outcomes. We present the algorithm, Digital Display Precision Predictor (DDPP), aiming to identify transcriptomic predictors of treatment outcome. For example, 17 and 13 key genes were derived from the literature by their association with MTOR and angiogenesis pathways, respectively, and their expression in tumor versus normal tissues was associated with the progression-free survival (PFS) of patients treated with everolimus or axitinib (respectively) using DDPP. A specific eight-gene set best correlated with PFS in six patients treated with everolimus: AKT2, TSC1, FKB-12, TSC2, RPTOR, RHEB, PIK3CA, and PIK3CB (r = 0.99, p = 5.67E−05). A two-gene set best correlated with PFS in five patients treated with axitinib: KIT and KITLG (r = 0.99, p = 4.68E−04). Leave-one-out experiments demonstrated significant concordance between observed and DDPP-predicted PFS (r = 0.9, p = 0.015) for patients treated with everolimus. Notwithstanding the small cohort and pending further prospective validation, the prototype of DDPP offers the potential to transform patients’ treatment selection with a tumor- and treatment-agnostic predictor of outcomes (duration of PFS)

Antifungal Peptides as Therapeutic Agents

peer-reviewedFungi have been used since ancient times in food and beverage-making processes and, more recently, have been harnessed for the production of antibiotics and in processes of relevance to the bioeconomy. Moreover, they are starting to gain attention as a key component of the human microbiome. However, fungi are also responsible for human infections. The incidence of community-acquired and nosocomial fungal infections has increased considerably in recent decades. Antibiotic resistance development, the increasing number of immunodeficiency- and/or immunosuppression-related diseases and limited therapeutic options available are triggering the search for novel alternatives. These new antifungals should be less toxic for the host, with targeted or broader antimicrobial spectra (for diseases of known and unknown etiology, respectively) and modes of actions that limit the potential for the emergence of resistance among pathogenic fungi. Given these criteria, antimicrobial peptides with antifungal properties, i.e., antifungal peptides (AFPs), have emerged as powerful candidates due to their efficacy and high selectivity. In this review, we provide an overview of the bioactivity and classification of AFPs (natural and synthetic) as well as their mode of action and advantages over current antifungal drugs. Additionally, natural, heterologous and synthetic production of AFPs with a view to greater levels of exploitation is discussed. Finally, we evaluate the current and potential applications of these peptides, along with the future challenges relating to antifungal treatments