Late Neonatal Sepsis in Very-low-birth-weight Premature Newborns Is Associated With Alterations in Neurodevelopment at Twenty-five Months of Age.

AIM: To evaluate the impact of late-onset sepsis (LOS) on the neurodevelopment of very-low-birth-weight (VLBW) premature infants. METHODS: This is a retrospective cohort study of VLBW premature infants. The Mental Development Index (MDI) was determined for a population of 546 VLBW infants, at 14 and 25 months of age, and evaluated using the Bayley test. A history of meningitis or early neonatal sepsis was considered an exclusion criterion. The study parameters analyzed included perinatal variables, the development of neonatal comorbidities and a history of LOS. Multivariate linear regression and multinomial logistic regression analyses were performed. RESULTS: LOS was observed in 115 newborns, among whom microbiological testing showed that 65.0% presented Gram-positive bacteria, with Staphylococcus epidermidis being responsible for 55.4%. There was a significant association between the 25-month MDI and a history of LOS. This represents a decrease of 7.9 points in the MDI evaluation of newborns with a history of LOS. The latter history is also associated with the following neurodevelopmental alternations: mild motor disorders [odds ratio (OR): 2.75; 95% confidence intervals (CI): 1.07-7.05], moderate cognitive delay (OR: 3.07; 95% CI: 1.17-8.00) and cerebral palsy (OR: 2.41; 95% CI: 1.09-5.35). CONCLUSIONS: In our study cohort, LOS was associated with alterations in neurodevelopment, including reduced MDI, together with motor and cognitive disorders and cerebral palsy. To improve neurodevelopmental outcomes in this group of newborns, neonatal intensive care unit personnel should focus attention on preventing hospital-acquired infections.

Modulation of tumor microenvironment by targeting histone acetylation in bladder cancer.

Alterations in the epigenetic machinery in both tumor and immune cells contribute to bladder cancer (BC) development, constituting a promising target as an alternative therapeutic option. Here, we have explored the effects of a novel histone deacetylase (HDAC) inhibitor CM-1758, alone or in combination with immune checkpoint inhibitors (ICI) in BC. We determined the antitumor effects of CM-1758 in various BC cell lines together with the induction of broad transcriptional changes, with focus on the epigenetic regulation of PD-L1. Using an immunocompetent syngeneic mouse model of metastatic BC, we studied the effects of CM-1758 alone or in combination with anti-PD-L1 not only on tumor cells, but also in the tumor microenvironment. In vitro, we found that CM-1758 has cytotoxic and cytostatic effects either by inducing apoptosis or cell cycle arrest in BC cells at low micromolar levels. PD-L1 is epigenetically regulated by histone acetylation marks and is induced after treatment with CM-1758. We also observed that treatment with CM-1758 led to an important delay in tumor growth and a higher CD8 + T cell tumor infiltration. Moreover, anti-PD-L1 alone or in combination with CM-1758 reprogramed macrophage differentiation towards a M1-like polarization state and increased of pro-inflammatory cytokines systemically, yielding potential further antitumor effects. Our results suggest the possibility of combining HDAC inhibitors with immunotherapies for the management of advanced metastatic BC.

Immune Predictors of Response after Bacillus Calmette-Guérin Treatment in Non-Muscle-Invasive Bladder Cancer.

Bacillus Calmette-Guérin (BCG) has been the standard of care for the treatment of high-risk, non-muscle-invasive bladder cancer (NMIBC) for decades, but 49.6% of high-risk and very-high-risk patients will experience progression to muscle-invasive disease in five years. Furthermore, cytology and cystoscopy entail a high burden for both patients and health care systems due to the need for very long periods of follow-up. Subsequent adjuvant treatment using intravesical immunotherapy with BCG has been shown to be effective in reducing tumor recurrence and progression, but it is not free of severe adverse effects that ultimately diminish patients' quality of life. Because not all patients benefit from BCG treatment, it is of paramount importance to be able to identify responders and non-responders to BCG as soon as possible in order to offer the best available treatment and prevent unnecessary adverse events. The tumor microenvironment (TME), local immune response, and systemic immune response (both adaptive and innate) seem to play an important role in defining responders, although the way they interact remains unclear. A shift towards a proinflammatory immune response in TME is thought to be related to BCG effectiveness. The aim of this review is to collect the most relevant data available regarding BCG's mechanism of action, its role in modulating innate and adaptive immune responses and the secretion of certain cytokines, and their potential use as immunological markers of response; the aim is also to identify promising lines of investigation.

CD44v6, STn & O-GD2: promising tumor associated antigens paving the way for new targeted cancer therapies.

Targeted therapies are the state of the art in oncology today, and every year new Tumor-associated antigens (TAAs) are developed for preclinical research and clinical trials, but few of them really change the therapeutic scenario. Difficulties, either to find antigens that are solely expressed in tumors or the generation of good binders to these antigens, represent a major bottleneck. Specialized cellular mechanisms, such as differential splicing and glycosylation processes, are a good source of neo-antigen expression. Changes in these processes generate surface proteins that, instead of showing decreased or increased antigen expression driven by enhanced mRNA processing, are aberrant in nature and therefore more specific targets to elicit a precise anti-tumor therapy. Here, we present promising TAAs demonstrated to be potential targets for cancer monitoring, targeted therapy and the generation of new immunotherapy tools, such as recombinant antibodies and chimeric antigen receptor (CAR) T cell (CAR-T) or Chimeric Antigen Receptor-Engineered Natural Killer (CAR-NK) for specific tumor killing, in a wide variety of tumor types. Specifically, this review is a detailed update on TAAs CD44v6, STn and O-GD2, describing their origin as well as their current and potential use as disease biomarker and therapeutic target in a diversity of tumor types.

Anti-inflammatory effects of α-humulene and ß-caryophyllene on pterygium fibroblasts.

AIM: To investigate the anti-inflammatory effects of the sesquiterpenes α-humulene and ß-caryophyllene on pterygium fibroblasts. METHODS: Primary cultures of pterygium fibroblasts were established. Third passage pterygium fibroblasts were exposed to α-humulene and ß-caryophyllene separately and together. The cell viability was assessed by 3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide (MTT) assay at 12, 24, 48, and 72h after exposure. The levels of the inflammatory cytokines interleukin (IL)-1ß, IL-6, IL-8, tumor necrosis factor (TNF)-α and IL-10 in the conditioned culture medium were assessed by enzyme-linked immunosorbent assay (ELISA) at 12, 24 and 48h after exposure. Data were statistically analyzed using Friedman repeated measures analysis of variances on ranks. RESULTS: The 25 µmol/L ß-caryophyllene induced significant decrease in the IL-6 production by pterygium fibroblasts 48h after the exposure (P=0.041). The levels of IL-1ß, IL-8, IL-10, and TNF-α were very low and had no statistically significant variations after exposure to α-humulene, ß-caryophyllene, or both compounds together. CONCLUSION: The exposure to 25 µmol/L of ß-caryophyllene significantly reduce the production of IL-6 by pterygium fibroblasts after 48h. This sesquiterpene may be a potential alternative adjuvant agent for the treatment of pterygium.

Health conditions of Hitnü indigenous people potentially exposed to crude oil in Arauca, Colombia / Condiciones de salud de los indígenas hitnü potencialmente expuestos a petróleo crudo (Arauca, Colombia)

Introduction: The Hitnü indigenous people live in precarious sanitary conditions, with food insecurity and being victims of sociopolitical violence in Arauca, Colombia. In addition, it is possible that they may be affected by exposure to hydrocarbons found in oil. Objective: To identify the health outcomes of morbidity and mortality profiles of the Hitnü people that could be associated with the exposure to crude oil. Materials and methods: A cross-sectional study was carried out with Hitnü indigenous people, during February and March, 2021, time of drought. A household questionnaire was applied, and one individual to collect data from the environment around the house, occupations and other activities, as well as data from sociodemographic, signs, symptoms, and findings of a medical examination. The potential association with hydrocarbons was explored considering three groups: inhabitants in Arauca city, Aspejaná reserve (not exposed), and San José del Lipa and La Vorágine reserves (exposed by the Ele river and tributaries). With free listings, causes of death were explored. The study incorporated a rigorous intercultural management in all its components. Results: A total of 576 indigenous people from 16 settlements participated. The water consumed could serve as means of exposure to hydrocarbons. Health problems were very varied, including infectious and chronic diseases, malnutrition, and trauma. The masses on the neck were associated with residing in the ancestral reserves (PR = 3.86; CI95% 1.77-8.39), territories with potential exposure to crude-oil. The most relevant causes of death were homicide, tumors, and tuberculosis. Conclusion: For its possible association with exposure to hydrocarbons, it is a priority to start the intercultural study of lymphadenopathies in indigenous communities potentially exposed to crude oil.

Introducción. El pueblo hitnü vive en condiciones sanitarias precarias, con inseguridad alimentaria y víctima de la violencia sociopolítica en Arauca (Colombia). Además, se sospecha que pueden estar afectados por la exposición a los hidrocarburos del petróleo. Objetivo. Identificar los eventos de salud del perfil de morbilidad y mortalidad de los indígenas hitnü que podrían asociarse con la exposición a petróleo crudo. Materiales y métodos. Se realizó un estudio transversal con indígenas hitnü, durante febrero y marzo de 2021, época de sequía. Se aplicó un cuestionario de hogares y uno individual para recolectar datos del ambiente peridomiciliario, ocupaciones y otras actividades, así como datos sociodemográficos, signos, síntomas y hallazgos de un examen médico. La potencial asociación con los hidrocarburos se exploró considerando tres grupos, según su localización: cabecera de Arauca, resguardo Aspejená (no expuestos) y resguardos de San José del Lipa y La Vorágine (expuestos por su cercanía al río Ele y afluentes). Con listados libres, se exploraron las causas de muerte. El estudio incorporó un riguroso manejo intercultural en todos sus componentes. Resultados. Participaron 576 indígenas de 16 asentamientos. El agua consumida pudo servir como medio de exposición a los hidrocarburos. Los problemas de salud fueron muy variados e incluían enfermedades infecciosas y crónicas, malnutrición y trauma. Las masas en el cuello se asociaron con residir en los resguardos ancestrales (RP=3,86; IC95% 1,77-8,39), territorios potencialmente expuestos al petróleo. Las causas de muerte más relevantes fueron el homicidio, los tumores y la tuberculosis. Conclusión: Por su posible asociación con los hidrocarburos, es prioritario el estudio intercultural de linfoadenopatías entre indígenas potencialmente expuestos al petróleo.

Condiciones de salud de los indígenas hitnü potencialmente expuestos a petróleo crudo (Arauca, Colombia) / Health conditions of Hitnü indigenous people potentially exposed to crude oil in Arauca, Colombia

Introducción. El pueblo hitnü vive en condiciones sanitarias precarias, con inseguridad alimentaria y víctima de la violencia sociopolítica en Arauca (Colombia). Además, se sospecha que pueden estar afectados por la exposición a los hidrocarburos del petróleo. Objetivo. Identificar los eventos de salud del perfil de morbilidad y mortalidad de los indígenas hitnü que podrían asociarse con la exposición a petróleo crudo. Materiales y métodos. Se realizó un estudio transversal con indígenas hitnü, durante febrero y marzo de 2021, época de sequía. Se aplicó un cuestionario de hogares y uno individual para recolectar datos del ambiente peridomiciliario, ocupaciones y otras actividades, así como datos sociodemográficos, signos, síntomas y hallazgos de un examen médico. La potencial asociación con los hidrocarburos se exploró considerando tres grupos, según su localización: cabecera de Arauca, resguardo Aspejená (no expuestos) y resguardos de San José del Lipa y La Vorágine (expuestos por su cercanía al río Ele y afluentes). Con listados libres, se exploraron las causas de muerte. El estudio incorporó un riguroso manejo intercultural en todos sus componentes. Resultados. Participaron 576 indígenas de 16 asentamientos. El agua consumida pudo servir como medio de exposición a los hidrocarburos. Los problemas de salud fueron muy variados e incluían enfermedades infecciosas y crónicas, malnutrición y trauma. Las masas en el cuello se asociaron con residir en los resguardos ancestrales (RP=3,86; IC95% 1,77-8,39), territorios potencialmente expuestos al petróleo. Las causas de muerte más relevantes fueron el homicidio, los tumores y la tuberculosis. Conclusión. Por su posible asociación con los hidrocarburos, es prioritario el estudio intercultural de linfoadenopatías entre indígenas potencialmente expuestos al petróleo.

Introduction. The Hitnü indigenous people live in precarious sanitary conditions, with food insecurity and being victims of sociopolitical violence in Arauca, Colombia. In addition, it is possible that they may be affected by exposure to hydrocarbons found in oil. Objective. To identify the health outcomes of morbidity and mortality profiles of the Hitnü people that could be associated with the exposure to crude oil. Materials and methods. A cross-sectional study was carried out with Hitnü indigenous people, during February and March, 2021, time of drought. A household questionnaire was applied, and one individual to collect data from the environment around the house, occupations and other activities, as well as data from sociodemographic, signs, symptoms, and findings of a medical examination. The potential association with hydrocarbons was explored considering three groups: inhabitants in Arauca city, Aspejaná reserve (not exposed), and San José del Lipa and La Vorágine reserves (exposed by the Ele river and tributaries). With free listings, causes of death were explored. The study incorporated a rigorous intercultural management in all its components. Results. A total of 576 indigenous people from 16 settlements participated. The water consumed could serve as means of exposure to hydrocarbons. Health problems were very varied, including infectious and chronic diseases, malnutrition, and trauma. The masses on the neck were associated with residing in the ancestral reserves (PR = 3.86; CI95% 1.77-8.39), territories with potential exposure to crude-oil. The most relevant causes of death were homicide, tumors, and tuberculosis. Conclusion. For its possible association with exposure to hydrocarbons, it is a priority to start the intercultural study of lymphadenopathies in indigenous communities potentially exposed to crude oil.

Toward Tumor Fight and Tumor Microenvironment Remodeling: PBA Induces Cell Cycle Arrest and Reduces Tumor Hybrid Cells' Pluripotency in Bladder Cancer.

Bladder cancer (BC) is the second most frequent cancer of the genitourinary system. The most successful therapy since the 1970s has consisted of intravesical instillations of Bacillus Calmette-Guérin (BCG) in which the tumor microenvironment (TME), including macrophages, plays an important role. However, some patients cannot be treated with this therapy due to comorbidities and severe inflammatory side effects. The overexpression of histone deacetylases (HDACs) in BC has been correlated with macrophage polarization together with higher tumor grades and poor prognosis. Herein we demonstrated that phenylbutyrate acid (PBA), a HDAC inhibitor, acts as an antitumoral compound and immunomodulator. In BC cell lines, PBA induced significant cell cycle arrest in G1, reduced stemness markers and increased PD-L1 expression with a corresponding reduction in histone 3 and 4 acetylation patterns. Concerning its role as an immunomodulator, we found that PBA reduced macrophage IL-6 and IL-10 production as well as CD14 downregulation and the upregulation of both PD-L1 and IL-1ß. Along this line, PBA showed a reduction in IL-4-induced M2 polarization in human macrophages. In co-cultures of BC cell lines with human macrophages, a double-positive myeloid-tumoral hybrid population (CD11b+EPCAM+) was detected after 48 h, which indicates BC cell-macrophage fusions known as tumor hybrid cells (THC). These THC were characterized by high PD-L1 and stemness markers (SOX2, NANOG, miR-302) as compared with non-fused (CD11b-EPCAM+) cancer cells. Eventually, PBA reduced stemness markers along with BMP4 and IL-10. Our data indicate that PBA could have beneficial properties for BC management, affecting not only tumor cells but also the TME.

Genomic Landscape of Vinflunine Response in Metastatic Urothelial Cancer.

BACKGROUND AND AIMS: Metastatic urothelial carcinoma (mUC) remains an incurable disease with limited treatment options after platinum-based chemotherapy and immune checkpoint blockade (ICB). Vinflunine has shown a modest increase in overall survival and remains a therapeutic option for chemo- and immunotherapy refractory tumours. However, biomarkers that could identify responding patients to vinflunine and possible alternative therapies after failure to treatment are still missing. In this study, we aimed to identify potential genomic biomarkers of vinflunine response in mUC patient samples and potential management alternatives. METHODS: Formalin-fixed paraffin-embedded samples of mUC patients (n = 23) from three university hospitals in Spain were used for genomic targeted-sequencing and transcriptome (using the Immune Profile panel by NanoString) analyses. Patients who received vinflunine after platinum-based chemotherapy failure were classified in non-responders (NR: progressive disease ≤ 3 months; n= 11) or responders (R: response ≥ 6 months; n = 12). RESULTS: Genomic characterization revealed that the most common alteration, TP53 mutations, had comparable frequency in R (6/12; 50%) and NR (4/11; 36%). Non-synonymous mutations in KTM2C (4/12; 33.3%), PIK3CA (3/12; 25%) and ARID2 (3/12; 25%) were predominantly associated with response. No significant difference was observed in tumour mutational burden (TMB) between R and NR patients. The NR tumours showed increased expression of diverse immune-related genes and pathways, including various interferon gamma-related genes. We also identified increased MAGEA4 expression as a potential biomarker of non-responding tumours to vinflunine treatment. CONCLUSIONS: Our data may help to identify potential genomic biomarkers of response to vinflunine. Moreover, tumours refractory to vinflunine showed immune signatures potentially associated with response to ICB. Extensive validation studies, including longitudinal series, are needed to corroborate these findings.