Emerging lactic acid bacteria bacteriocins as anti-cancer and anti-tumor agents for human health.

Modern cancer diagnostics and treatment options have greatly improved survival rates; the illness remains a major cause of mortality worldwide. Current treatments for cancer, such as chemotherapy, are not cancer-specific and may cause harm to healthy cells; therefore, it is imperative that new drugs for cancer be developed that are both safe and effective. It has been found that lactic acid bacteria (LAB) have the potential to produce bacteriocins, which could potentially offer a promising alternative for cancer treatment. They have been shown in several studies to be effective against cancer cells while having no effect on healthy cells. More research is needed to fully understand the potential of LAB bacteriocins as anti-cancer medicines, to find the appropriate dose and delivery route, and to conduct clinical trials to evaluate the effectiveness and safety of the products in human patients, as is suggested by this work. Furthermore, LAB bacteriocins may evolve into a significant new class of anti-cancer drugs and food products. Patients with cancer may have a safe and effective alternative treatment option in the form of anti-cancer foods and drugs. Therefore, the aim of this study is to provide an in-depth analysis of the recent breakthroughs and potential future technical advancements of significant bacteriocins that are produced by LAB, how these bacteriocins function, and how these bacteriocins may be utilized as an anti-cancer agent. In addition, the current analysis emphasizes the significant constraints and boundaries that bacteriocins face when they are used as an anti-cancer factor.

Cardiac events occurring after allogeneic hematopoietic cell transplantation with post-transplant cyclophosphamide. Study conducted on behalf of the GETH-TC.

This multicenter study investigates the incidence and predictors of cardiac events (CE) following allo-HCT with PTCY in 453 AML patients. CE occurred in 57 (12.3%) patients within a median of 52 days (IQR: 13-289), with day 100 and 5-year cumulative incidences of 7.7% and 13.5%. Early (first 100 days) and late CE occurred at rates of 7.7% and 4.8%. The most prevalent CE were heart failure (n = 18, 31.6%), pericardial complications (n = 16, 28.1%), and arrhythmia (n = 14, 24.6%). The proportions of patients older than 55 years (64.9% vs. 46.1%, P = 0.010), with hypertension (36.8% vs. 18.4%, P = 0.001) and dyslipidemia (28.1% vs. 11.1%, P = 0.001) were higher in patients with CE. Patients undergoing haplo-HCT trend to have more CE (68.4% vs. 56.8%, P = 0.083). The multivariate regression analysis revealed that only hypertension (HR 1.88, P = 0.036) and dyslipidemia (HR 2.20, P = 0.018) were predictors for CE, with no differences according to donor type (haplo-HCT vs. others: HR 1.33, P = 0.323). Among the 57 patients with CE, the mortality rate was 12.2%. Notably, the diagnosis of CE negatively impacted NRM (HR 2.57, P = 0.011) and OS (HR 1.80, P = 0.009), underscoring necessity of aggressively treating cardiovascular risk factors, and implementing post-transplant cardiac monitoring protocols to prevent these complications.

Low dose lenalidomide versus placebo in non-transfusion dependent patients with low risk, del(5q) myelodysplastic syndromes (SintraREV): a randomised, double-blind, phase 3 trial.

BACKGROUND: Lenalidomide is the standard of care for patients who are transfusion dependent with chromosome 5q deletion (del[5q]) myelodysplastic syndromes. In the SintraREV trial, we aimed to investigate whether an early intervention of low lenalidomide doses for 2 years could delay transfusion dependency in patients with anaemia who were not transfusion dependent. METHODS: This randomised, double-blind, phase 3 trial, was conducted at 22 sites (University Hospitals) in Spain, France, and Germany. Eligible patients were aged 18 years or older diagnosed with low-risk or intermediate-1-risk del(5q) myelodysplastic syndromes with non-transfusion-dependent anaemia (according to the IPSS), were erythropoietin-stimulating agents naive, and had an ECOG performance status of 2 or less. Patients were randomly assigned (2:1) by means of a telephone system to receive lenalidomide 5 mg daily in 28-day cycles versus placebo for 2 years. The primary endpoint was time to transfusion dependency based on blinded independent central review. Analysis were by intent-to-treat (ITT) and evaluable population. Safety analyses included all participants who received at least one dose of treatment. This trial is registered with ClinicalTrials.gov (NCT01243476) and EudraCT (2009-013619-36) and is complete. FINDINGS: Between Feb 15, 2010, and Feb 21, 2018, 61 patients were randomly assigned to receive lenalidomide (n=40; two did not receive treatment) or placebo (n=21). The median age was 72·2 (IQR 65·4-81·9) years, 50 (82%) patients were female, and 11 (18%) were male. The median follow-up time was 60·6 (IQR 32·1-73·9) months. Regarding primary endpoint, median time to transfusion dependency was not reached (95% CI not applicable) in the lenalidomide group versus 11·6 months (95% CI 0·00-30·11) in the placebo group (p=0·0027). Lenalidomide significantly reduced the risk of transfusion dependency by 69·8% (hazard ratio 0·302, 95% CI 0·132-0·692; p=0·0046). The most frequent treatment-related adverse event was neutropenia, occurring in 24 (63%) of 38 patients in the lenalidomide group (grade 3 and 4 in 17 [45%] patients and one [3%], respectively) and in four (19%) of 21 patients in the placebo group (grade 3 in one [5%] patient). Thrombocytopenia was detected in seven (18%) of 38 patients receiving lenalidomide (grade 3 in two [5%] patients). Regarding the non-haematological toxicity, skin disorders (rash nine [23%] of 38 patients) were the most frequently described toxicities among patients receiving lenalidomide, being grade 3 in one (3%) of 38 patients. 19 serious adverse events were reported in 13 patients, 18 in the lenalidomide group and one in the placebo group, five of which were potentially related to the study drug. No treatment-related deaths were identified. INTERPRETATION: An early approach with low doses of lenalidomide across two years delays the time to transfusion dependency and improves the rate and quality of the responses, with a manageable safety profile in patients who are non-transfusion dependent with del(5q) low-risk myelodysplastic syndromes. FUNDING: Bristol Myers Squibb.

Change in Body Mass Index in Youth in the First 5 Years After Type 1 Diabetes Mellitus Diagnosis.

OBJECTIVE: Examine body mass index (BMI) trajectories in American youth with type 1 diabetes (T1D) over the first 5 years following diagnosis. METHODS: Retrospective record review of BMI trajectories in youth with T1D diagnosed in 2015 to 2016. RESULTS: Near the time of diabetes diagnosis, 35.5% of youth had BMIs in the overweight/obesity range. These rates increased over time (P < .001), with 52.8% having overweight/obesity 5 years after diagnosis. Average age when BMI rose from healthy to overweight/obese or overweight to obese (rise group) was at 12.7 years, occurring 2.5 years after diagnosis. There were no differences between hemoglobin A1c, use of continuous glucose monitors, or use of insulin pumps between the rise group and those with healthy BMI throughout the study period. CONCLUSIONS: Alarmingly high rates of overweight/obesity in youth were observed within 5 years following T1D diagnosis. Awareness and further research are necessary to address this independent risk factor for morbidities.

Brain oscillations during emotion regulation and the two-dimensional model of adult attachment.

Emotion Regulation (ER) refers to the processes by which individuals influence their own emotions. It is a crucial aspect of human behavior, affecting everything from interpersonal relationships to mental health. The relationship between ER and Attachment Theory (AT) is pivotal. AT suggests that early bonds with primary caregivers influence future relationship expectations and behaviors. These initial experiences shape internal models of self and others, affecting how individuals regulate their emotions. Understanding the interplay between ER and AT is essential for comprehending the human affective system. In this study, we explored the neural underpinnings of ER, focusing on two distinct strategies: cognitive reappraisal and expressive suppression. Using electroencephalography (EEG), we examined changes in neural oscillations from 52 adults during an ER task. Specifically, we observed increased frontal theta activity (3-6 Hz) during reappraisal compared to suppression strategies. This frontal theta activity suggests enhanced cognitive control engagement. Conversely, during suppression, we noted a decrease in beta frequency (15-30 Hz) activity from central electrodes, indicative of differing neural processes. Further integrating psychological theories, we explored the relationship between these neural markers and dimensions of human attachment. Employing the Experiences in Close Relationships-12 scale (ECR-12), we identified a negative correlation between attachment anxiety and frontal theta activity. Lower levels of attachment anxiety were associated with increased theta activity, reflecting potentially more effective emotion regulation. Additionally, we found that higher theta activity corresponded with fewer difficulties in emotional control measured by the Difficulties in Emotion Regulation Scale (DERS). Regarding central beta activity, our findings revealed an interesting correlation with Emotional Inattention, a concept tied to Attachment Avoidance. This suggests that central beta activity may serve as a neural marker for specific attachment-related ER processing. These results highlight the distinct neural pathways involved in different ER strategies and their relationship with the AT and neural responses during emotional processing.

Testing for t(3;8) in MYC/BCL6-rearranged large B-cell lymphoma identifies a high-risk subgroup with inferior survival.

ABSTRACT: A reciprocal t(3;8) BCL6::MYC fusion is common in large B-cell lymphoma (LBCL) with MYC and BCL6 disruption. These pseudo-double-hit cases are not adverse, whereas t(3;8)-MYC/BCL6 lymphoma has an inferior prognosis relative to other MYC-rearranged LBCL.

Patient-Reported Outcome Measures in Atopic Dermatitis and Chronic Urticaria Are Underused in Clinical Practice.

BACKGROUND: Patient-reported outcome measures (PROMs) are validated and standardized tools that complement physician evaluations and guide treatment decisions. They are crucial for monitoring atopic dermatitis (AD) and chronic urticaria (CU) in clinical practice, but there are unmet needs and knowledge gaps regarding their use in clinical practice. OBJECCTIVE: We investigated the global real-world use of AD and CU PROMs in allergology and dermatology clinics as well as their associated local and regional networks. METHODS: Across 72 specialized allergy and dermatology centers and their local and regional networks, 2,534 physicians in 73 countries completed a 53-item questionnaire on the use of PROMs for AD and CU. RESULTS: Of 2,534 physicians, 1,308 were aware of PROMs. Of these, 14% and 15% used PROMs for AD and CU, respectively. Half of physicians who use PROMs do so only rarely or sometimes. Use of AD and CU PROM is associated with being female, younger, and a dermatologist. The Patient-Oriented Scoring Atopic Dermatitis Index and Urticaria Activity Score were the most common PROMs for AD and CU, respectively. Monitoring disease control and activity are the main drivers of the use of PROMs. Time constraints were the primary obstacle to using PROMs, followed by the impression that patients dislike PROMs. Users of AD and CU PROM would like training in selecting the proper PROM. CONCLUSIONS: Although PROMs offer several benefits, their use in routine practice is suboptimal, and physicians perceive barriers to their use. It is essential to attain higher levels of PROM implementation in accordance with national and international standards.

Importance of Certain Varieties of Cucurbits in Enhancing Health: A Review.

The Cucurbitaceae family is an extensive group of fruits and vegetables that exhibit common characteristics; for example, they are farmed on a global scale and exhibit a wide range of applications, including fresh consumption and use in various food and beverage products. As is frequent, many species or genera share a common name, and this can lead to some confusion when looking for information about a specific variety. In this review, we describe the findings about the biological activity, like antibacterial, antiviral, antidiabetic, and anticancer properties, of two genera of this family, Cucumis and Momordica, which have been characterized and evaluated in several research studies and regarding which information is readily accessible. Those activities rely on the various physicochemical qualities and nutritional content of each variety, including factors like ß-carotene and polyphenols, among others. The goal of this review is to provide a rapid search for each activity examined in the literature, enabling future research on their potential uses in functional foods and nutraceutical supplements.

Emotion regulation unveiled through the categorical lens of attachment.

BACKGROUND: Emotion regulation, the process by which individuals manage and modify their emotional experiences, expressions, and responses to adaptively navigate and cope with various situations, plays a crucial role in daily life. Our study investigates the variations in emotion regulation strategies among individuals with different attachment styles (AS). Specifically, we examine how individuals with secure, anxious, avoidant, and fearful attachment styles effectively utilize cognitive reappraisal and expressive suppression to regulate their emotions. METHODS: A total of n = 98 adults were instructed to attend, reappraise, or suppress their emotions while viewing negative and neutral images from the International Affective Picture System (IAPS) in an experimental emotion regulation task. After completing the task, participants rated the valence and arousal elicited by the images. Attachment styles were measured using the ECR-12 questionnaire and then categorized into four AS. RESULTS: Our study revealed that individuals with secure AS (n = 39) effectively reduced displeasure through cognitive reappraisal but experienced levels of displeasure with expressive suppression. Anxious AS (n = 16) individuals successfully reduced displeasure using cognitive reappraisal but struggled to regulate arousal and effectively use expressive suppression. Avoidant AS (n = 24) individuals could reduce displeasure with both strategies but experienced high arousal during suppression attempts. Fearful AS (n = 19) individuals effectively regulated both displeasure and arousal using either strategy. However, Secure AS individuals showed superior reappraisal efficacy, significantly reducing arousal levels compared to the Fearful AS group. Both Secure and Avoidant AS groups experienced higher valence during reappraisal relative to a baseline, indicating a decrease in displeasure. CONCLUSIONS: Individuals with different AS exhibit variations in the effectiveness of their use of emotion regulation strategies. Our findings reinforce the significance of AS in shaping emotion regulation processes and emphasize the need for tailored approaches to support individuals with different attachment orientations.

An attachment-based pilot program to promote adolescent adjustment to parental divorce.

The study aimed to assess the impact of an attachment-based intervention on adolescent adaptation to parental divorce. The Adolescent Adjustment Pilot Program to Parental Divorce (AAPPD) employed an experimental group format, targeting improvements in various adaptation indicators (life satisfaction, positive affect, and negative affect). The sample comprised 30 Chilean adolescents aged 12 to 16 (M = 13.6, SD = 1.35), with 60% females and 40% males. After the intervention, the adolescents showed a decrease in negative affect at 6 and 12 months. However, no differences were identified in other dimensions of subjective well-being considered as indicators of divorce adaptation. The findings prompt discussion on theoretical and clinical implications.

Borolatonin limits cognitive deficit and neuron loss while increasing proBDNF in ovariectomised rats.

BACKGROUND: Borolatonin is a potential therapeutic agent for some neuronal diseases such as Alzheimer's disease (AD). Its administration exerts ameliorative effects such as those induced by the equimolar administration of melatonin in behavioral tests on male rats and in neuronal immunohistochemistry assays. OBJECTIVE: In this study, motivated by sex differences in neurobiology and the incidence of AD, the ability of borolatonin to induce changes in female rats was assessed. METHODS: Effects of borolatonin were measured by the evaluation of both behavioral and immunohistopathologic approaches; additionally, its ability to limit amyloid toxicity was determined in vitro. RESULTS: Surprisingly, behavioral changes were similar to those reported in male rats, but not those evaluated by immunoassays regarding neuronal survival; while pro-brain-derived neurotrophic factor (BDNF) immunoreactivity and the limitation of toxicity by amyloid in vitro were observed for the first time. CONCLUSION: Borolatonin administration induced changes in female rats. Differences induced by the administration of borolatonin or melatonin could be related to the differences in the production of steroid hormones in sex dependence. Further studies are required to clarify the possible mechanism and origin of differences in disturbed memory caused by the gonadectomy procedure between male and female rats.

The Value of Implementing a Digital Approach in the Obstructive Sleep Apnoea Patient Pathway: A Spanish Example.

Introduction: Continuous positive airway pressure (CPAP) is the gold standard therapy for obstructive sleep apnoea (OSA). However, non-adherence is common and costly. The COVID-19 pandemic required the use of novel solutions to ensure service provision and quality of care. This retrospective analysis determined the impact and value of a digital versus standard pathway for the management of OSA in Spain. Methods: A time-driven activity-based costing approach was applied to OSA management over 1 year using a standard or digital pathway. The standard pathway included face-to-face appointments at the time of diagnosis, then after 1-3 months and every 6 months thereafter. The digital pathway had fewer face-to-face appointments and utilised telemonitoring. A cost analysis was performed to determine the per-patient cost per healthcare professional (HCP) for a digital pathway for therapy implementation and follow-up compared with the standard pathway. Results: Compared with the standard pathway, the digital pathway decreased the waiting list time from 18 to 2 months, the overall pathway time from 12 to 6 months, HCP cost per patient from €95 to €85, and number of hospital appointments per patient from 6 to 3.1. Furthermore, CPAP device usage improved from 5.7 to 6.3 h/night and the proportion of individuals defined as adherent increased from 79% to 91%. Conclusions: Implementation of digital processes using available technology reduced HCP time and costs, and improved adherence to CPAP in people with OSA. Greater utilisation of a digital pathway could improve access to therapy, allow personalised patient management, and facilitate better clinical outcomes.

Introducción: La presión positiva continua en la vía aérea (CPAP) es el tratamiento de referencia para la apnea obstructiva del sueño (AOS). Sin embargo, su incumplimiento es frecuente y costoso. La pandemia de COVID-19 requirió el uso de soluciones novedosas para garantizar la prestación de servicios y la calidad de la atención. Este análisis retrospectivo determinó el impacto y el valor de un pathway digital frente a un pathway estándar para el manejo de la AOS en España. Métodos: Se aplicó el Time-DrivenActivityBasedCosting al tratamiento de la AOS durante 1 año utilizando el pathway estándar o digital. El pathway estándar incluía citas presenciales en el momento del diagnóstico, después de 1 a 3 meses y posteriormente cada 6 meses. el pathway digital tenía menos citas presenciales y utilizaba la telemonitorización. Se realizó un análisis de costes para determinar el coste por paciente y profesional sanitario (HCP) del pathway digital para la implementación y el seguimiento de la terapia en comparación con el pathway estándar. Resultados: En comparación con el pathway estándar, el pathway digital redujo el tiempo de la lista de espera de 18 a 2 meses, el tiempo total del pathway del paciente de 12 a 6 meses, el coste del HCP por paciente de 95 a 85 euros, y el número de citas hospitalarias por paciente de 6 a 3,1. Además, el uso del dispositivo de CPAP mejoró de 5,7 a 6,3 h/noche y la proporción de pacientes definidos como adherentes aumentó del 79% al 91%. Conclusiones: La implementación de procesos digitales utilizando la tecnología disponible redujo el tiempo y los costes del HCP y mejoró la adherencia a la CPAP en personas con AOS. Una mayor utilización de un pathway digital podría mejorar el acceso a la terapia, permitir una gestión personalizada del paciente y facilitar mejores resultados clínicos.

Cellular and Molecular Mechanisms of Mast Cells in Atherosclerotic Plaque Progression and Destabilization.

Mast cells (MCs) are commonly recognized for their crucial involvement in the pathogenesis of allergic diseases, but over time, it has come to light that they also play a role in the pathophysiology of non-allergic disorders including atherosclerosis. The involvement of MCs in the pathology of atherosclerosis is supported by their accumulation in atherosclerotic plaques upon their progression and the association of intraplaque MC numbers with acute cardiovascular events. MCs that accumulate within the atherosclerotic plaque release a cocktail of mediators through which they contribute to neovascularization, plaque progression, instability, erosion, rupture, and thrombosis. At a molecular level, MC-released proteases, especially cathepsin G, degrade low-density lipoproteins (LDL) and mediate LDL fusion and binding of LDL to proteoglycans (PGs). Through a complicated network of chemokines including CXCL1, MCs promote the recruitment of among others CXCR2+ neutrophils, therefore, aggravating the inflammation of the plaque environment. Additionally, MCs produce extracellular traps which worsen inflammation and contribute to atherothrombosis. Altogether, evidence suggests that MCs actively, via several underlying mechanisms, contribute to atherosclerotic plaque destabilization and acute cardiovascular syndromes, thus, making the study of interventions to modulate MC activation an interesting target for cardiovascular medicine.

Validation of remote anthropometric measurements in a rural randomized pediatric clinical trial in primary care settings.

Rural children are more at risk for childhood obesity but may have difficulty participating in pediatric weight management clinical trials if in-person visits are required. Remote assessment of height and weight observed via videoconferencing may provide a solution by improving the accuracy of self-reported data. This study aims to validate a low-cost, scalable video-assisted protocol for remote height and weight measurements in children and caregivers. Families were provided with low-cost digital scales and tape measures and a standardized protocol for remote measurements. Thirty-three caregiver and child (6-11 years old) dyads completed remote (at home) height and weight measurements while being observed by research staff via videoconferencing, as well as in-person measurements with research staff. We compared the overall and absolute mean differences in child and caregiver weight, height, body mass index (BMI), and child BMI adjusted Z-score (BMIaz) between remote and in-person measurements using paired samples t-tests and one sample t-tests, respectively. Bland-Altman plots were used to estimate the limits of agreement (LOA) and assess systematic bias. Simple regression models were used to examine associations between measurement discrepancies and sociodemographic factors and number of days between measurements. Overall mean differences in child and caregiver weight, height, BMI, and child BMIaz were not significantly different between remote and in-person measurements. LOAs were - 2.1 and 1.7 kg for child weight, - 5.2 and 4.0 cm for child height, - 1.5 and 1.7 kg/m2 for child BMI, - 0.4 and 0.5 SD for child BMIaz, - 3.0 and 2.8 kg for caregiver weight, - 2.9 and 3.9 cm for caregiver height, and - 2.1 and 1.6 kg/m2 for caregiver BMI. Absolute mean differences were significantly different between the two approaches for all measurements. Child and caregiver age were each significantly associated with differences between remote and in-person caregiver height measurements; there were no significant associations with other measurement discrepancies. Remotely observed weight and height measurements using non-research grade equipment may be a feasible and valid approach for pediatric clinical trials in rural communities. However, researchers should carefully evaluate their measurement precision requirements and intervention effect size to determine whether remote height and weight measurements suit their studies.Trial registration: ClinicalTrials.gov NCT04142034 (29/10/2019).

C-TYPE LECTIN-2D RECEPTOR CONTRIBUTES TO HISTONE-INDUCED VASCULAR BARRIER DYSFUNCTION DURING BURN INJURY.

ABSTRACT: Severe burns are associated with massive tissue destruction and cell death where nucleus histones and other damage-associated molecular patterns are released into the circulation and contribute to the pathogenesis of multiple-organ dysfunction. Currently, there is limited information regarding the pathophysiology of extracellular histones after burns, and the mechanisms underlying histone-induced vascular injury are not fully understood. In this study, by comparing the blood samples from healthy donors and burn patients, we confirmed that burn injury promoted the release of extracellular histones into the circulation, evidenced by increased plasma levels of histones correlating with injury severity. The direct effects of extracellular histones on human endothelial monolayers were examined, and the results showed that histones caused cell-cell adherens junction discontinuity and barrier dysfunction in a dose-related manner. Like burn patients, mice subjected to a scald burn covering 25% total body surface area also displayed significantly increased plasma histones. Intravital microscopic analysis of mouse mesenteric microcirculation indicated that treatment with a histone antibody greatly attenuated burn-induced plasma leakage in postcapillary venules, supporting the pathogenic role of extracellular histones in the development of microvascular barrier dysfunction during burns. At the molecular level, intrigued by the recent discovery of C-type lectin domain family 2 member D (Clec2d) as a novel receptor of histones, we tested its potential involvement in the histone interaction with endothelial cells. Indeed, we identified abundant expression of Clec2d in vascular endothelial cells. Further proximity ligation assay demonstrated a close association between extracellular histones and endothelial expressing Clec2d. Functionally, in vivo administration of an anti-Clec2d antibody attenuated burn-induced plasma leakage across mesenteric microvessels. Consistently, Clec2d knockdown in endothelial cells partially inhibited histone-induced endothelial barrier dysfunction. Together, our data suggest that burn injury-induced increases in circulating histones contribute to microvascular leakage and endothelial barrier dysfunction via a mechanism involving the endothelial Clec2d receptor.