An international phase II trial and immune profiling of SBRT and atezolizumab in advanced pretreated colorectal cancer.

BACKGROUND: Immuno-radiotherapy may improve outcomes for patients with advanced solid tumors, although optimized combination modalities remain unclear. Here, we report the colorectal (CRC) cohort analysis from the SABR-PDL1 trial that evaluated the PD-L1 inhibitor atezolizumab in combination with stereotactic body radiation therapy (SBRT) in advanced cancer patients. METHODS: Eligible patients received atezolizumab 1200 mg every 3 weeks until progression or unmanageable toxicity, together with ablative SBRT delivered concurrently with the 2nd cycle (recommended dose of 45 Gy in 3 fractions, adapted upon normal tissue tolerance constraint). SBRT was delivered to at least one tumor site, with at least one additional measurable lesion being kept from the radiation field. The primary efficacy endpoint was one-year progression-free survival (PFS) rate from the start of atezolizumab. Sequential tumor biopsies were collected for deep multi-feature immune profiling. RESULTS: Sixty pretreated (median of 2 prior lines) advanced CRC patients (38 men [63%]; median age, 59 years [range, 20-81 years]; 77% with liver metastases) were enrolled in five centers (France: n = 4, Spain: n = 1) from 11/2016 to 04/2019. All but one (98%) received atezolizumab and 54/60 (90%) received SBRT. The most frequently irradiated site was lung (n = 30/54; 56.3%). Treatment-related G3 (no G4-5) toxicity was observed in 3 (5%) patients. Median OS and PFS were respectively 8.4 [95%CI:5.9-11.6] and 1.4 months [95%CI:1.2-2.6], including five (9%) patients with PFS > 1 year (median time to progression: 19.2 months, including 2/5 MMR-proficient). Best overall responses consisted of stable disease (n = 38; 64%), partial (n = 3; 5%) and complete response (n = 1; 2%). Immune-centric multiplex IHC and RNAseq showed that SBRT redirected immune cells towards tumor lesions, even in the case of radio-induced lymphopenia. Baseline tumor PD-L1 and IRF1 nuclear expression (both in CD3 + T cells and in CD68 + cells) were higher in responding patients. Upregulation of genes that encode for proteins known to increase T and B cell trafficking to tumors (CCL19, CXCL9), migration (MACF1) and tumor cell killing (GZMB) correlated with responses. CONCLUSIONS: This study provides new data on the feasibility, efficacy, and immune context of tumors that may help identifying advanced CRC patients most likely to respond to immuno-radiotherapy. TRIAL REGISTRATION: EudraCT N°: 2015-005464-42; Clinicaltrial.gov number: NCT02992912.

Assessing the impact of digital patient monitoring on health outcomes and healthcare resource usage in addition to the feasibility of its combination with at-home treatment, in participants receiving systemic anticancer treatment in clinical practice: protocol for an interventional, open-label, multicountry platform study (ORIGAMA).

INTRODUCTION: Digital patient monitoring (DPM) tools can enable more effective clinical care and improved patient outcomes in cancer. However, their broad adoption requires ease of use and demonstration of real-world clinical utility/impact. ORIGAMA (MO42720) is an interventional, open-label, multicountry platform study investigating the clinical utility of DPM tools and specific treatments. ORIGAMA will begin with two cohorts that aim to assess the impact of the atezolizumab-specific Roche DPM Module (hosted on the Kaiku Health DPM platform (Helsinki, Finland)) on health outcomes and healthcare resource usage, and its feasibility to support at-home treatment administration, in participants receiving systemic anticancer treatment. Other digital health solutions may be added to future cohorts. METHODS AND ANALYSIS: In Cohort A, participants with metastatic non-small cell lung cancer (NSCLC), extensive-stage SCLC or Child Pugh A unresectable hepatocellular carcinoma will be randomised to a locally approved anticancer regimen containing intravenous atezolizumab (TECENTRIQ, F. Hoffmann-La Roche Ltd/Genentech) and local standard-of-care support, with/without the Roche DPM Module. Cohort B will assess the feasibility of the Roche DPM Module in supporting administration of three cycles of subcutaneous atezolizumab (1875 mg; Day 1 of each 21-day cycle) in the hospital, followed by 13 cycles at home by a healthcare professional (ie, flexible care), in participants with programmed cell-death ligand 1-positive, early-stage NSCLC. The primary endpoints are the mean difference in change of the participant-reported Total Symptom Interference Score at Week 12 from baseline (Cohort A) and flexible care adoption rate at Cycle 6 (Cohort B). ETHICS AND DISSEMINATION: This study will be conducted according to the Declaration of Helsinki, and/or the applicable laws and regulations of the country in which the research is conducted, whichever affords the greater protection to the individual. The study received its first Ethics Committee approval in Spain in October 2022. Participants will provide written informed consent in a face-to-face setting. The results of this study will be presented at national and/or international congresses and disseminated via publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT05694013.

The Zebrafish Embryo as a Model to Test Protective Effects of Food Antioxidant Compounds.

The antioxidant activity of food compounds is one of the properties generating the most interest, due to its health benefits and correlation with the prevention of chronic disease. This activity is usually measured using in vitro assays, which cannot predict in vivo effects or mechanisms of action. The objective of this study was to evaluate the in vivo protective effects of six phenolic compounds (naringenin, apigenin, rutin, oleuropein, chlorogenic acid, and curcumin) and three carotenoids (lycopene B, ß-carotene, and astaxanthin) naturally present in foods using a zebrafish embryo model. The zebrafish embryo was pretreated with each of the nine antioxidant compounds and then exposed to tert-butyl hydroperoxide (tBOOH), a known inducer of oxidative stress in zebrafish. Significant differences were determined by comparing the concentration-response of the tBOOH induced lethality and dysmorphogenesis against the pretreated embryos with the antioxidant compounds. A protective effect of each compound, except ß-carotene, against oxidative-stress-induced lethality was found. Furthermore, apigenin, rutin, and curcumin also showed protective effects against dysmorphogenesis. On the other hand, ß-carotene exhibited increased lethality and dysmorphogenesis compared to the tBOOH treatment alone.

Genética del hipotiroidismo congénito / The genetics of congenital hypothyroidism

Se realizó una revisión narrativa sobre la genética del hipotiroidismo congénito (HC). Se utilizaron las bases de datos Medline/PubMed, LILACS-BIREME y SciELO. Se identificaron los estudios originales publicados entre 2000 y agosto de 2020. Las palabras clave utilizadas durante la búsqueda fueron las siguientes: "hipotiroidismo congénito (congenital hypothyroidism)", "genética (genetic)", "polimorfismos de nucleótido único (SNP) (single polymorphisms nucleotid)". Se revisaron 58 estudios originales que informan las bases moleculares del HC. Se ha definido el concepto básico del HC, así como las bases moleculares que están asociados con la aparición de dicho trastorno. La revisión de la literatura ha permitido identificar al menos 12 genes que codifican las proteínas, las cuales, al producirse mutaciones, están implicadas en el HC. De los 12 genes informados que desempeñan un papel importante en el HC, errores en 6 genes se han vinculado con el HC con disgenesia tiroidea, lo cual implica alteraciones en la morfogénesis de la glándula tiroides, mientras que mutaciones en otros 6 genes se han asociado con dishormonogénesis, que genera un bloqueo total o parcial de los procesos bioquímicos implicados en la síntesis y secreción de hormonas tiroideas. La prevalencia en Sudamérica varía aproximadamente desde 1 por cada 1170 hasta 1 por cada 8285 neonatos. El estudio de la genética molecular pone de manifiesto que, en el futuro, aportará datos importantes en cuanto a la identificación de nuevas mutaciones y asociaciones con fenotipos clínicos que podrían relacionarse con el HC, para, de esta manera, potenciar el diagnóstico y tratamiento

A narrative review was conducted on the genetics of congenital hypothyroidism. The Medline/PubMed, LILACS-BIREME, and SciELO databases were used. Original studies published between 2000 and August 2020 were identified. The keywords used during the search were as follows: "congenital hypothyroidism", "genetics", "polymorphisms SNPs". Fifty-eight original studies reviewing the molecular basis of congenital hypothyroidism were reviewed. The basic concept of congenital hypothyroidism has been defined as well as the molecular bases that are associated with the development of this disorder. The literature review has identified at least 12 genes encoding proteins that, when mutations occur, are involved in congenital hypothyroidism. Of the 12 genes reported to play an important role in congenital hypothyroidism, errors in 6 genes have been associated with congenital hypothyroidism with thyroid dysgenesis, which implies alterations in the morphogenesis of the thyroid gland. On the other hand, mutations in 6 other genes have been associated with dyshormonogenesis that generates a total or partial blockage of the biochemical processes involved in the synthesis and secretion of thyroid hormones. The prevalence in South America is reported to vary from approximately 1 per 1000 to 1 per 8000 newborns. The study of molecular genetics shows that in the future it will contribute to the identification of new mutations and associations with clinical phenotypes that could be related to congenital hypothyroidism, thus enhancing diagnosis and treatment

Migración de neutrófilos en larvas de pez cebra expuestos a extractos de sofrito de tomate / Neutrophils migration in zebrafish larvae exposed to tomato sofrito extracts

Este trabajo se fundamenta en la evaluación de la actividad antiinflamatoria de extractos de sofrito de tomate, así como de compuestos estándares de la dieta mediterránea, usando un modelo experimental optimizado basado en larvas de pez cebra. La migración de neutrófilos en larvas de pez cebra de 96 horas post fertilización se indujo mediante una lesión y se potenció añadiéndole lipopolisacárido, dicha migración se visualizó y cuantificó mediante análisis de imagen. El efecto antiinflamatorio del extracto de tomate y de los compuestos utilizados fue correlacionado porcentualmente por la disminución de la migración de los neutrófilos. Los resultados muestran que el extracto de tomate presentó una reducción en la migración de neutrófilos de 40 % respecto al grupo control. Por otra parte, el ácido clorogénico y la cianidina presentes en el sofrito de tomate utilizados como estándares presentaron una disminución de la migración de neutrófilos de un 66,7 % y 62,5 % respectivamente. Estos porcentajes son comparables a los resultados observados en ensayos con drogas antiinflamatorias como la indometacina y piroxicam. Los resultados muestran que el extracto de sofrito de tomate presenta posible actividad antinflamatoria demostrada por la reducción de la migración de neutrófilos, además el modelo se mostró sensible y válido para ser aplicado en matrices alimentarias complejas(AU)

The main of this study was to evaluate the anti-inflammatory activity of tomato sofrito extracts, as well as standard compounds present in the Mediterranean diet, using an optimized experimental model based on zebrafish larvae. Neutrophil migration in zebrafish larvae 96 hours post fertilization was induced by a cut in the caudal fin and enhanced by adding lipopolysaccharide and was visualized and quantified by image analysis. The anti-inflammatory effect of tomato extract and the compounds used was correlated by the percentage decrease in the migration of neutrophils. The results showed that, tomato extract showed a reduction in neutrophil migration of 40% compared to the control group. Moreover, chlorogenic acid and cyanidin present in tomato sofrito sauce showed a decrease in neutrophil migration of 66.7% and 62.5% respectively. These percentages are comparable to the results observed in trials with anti-inflammatory drugs such as indomethacin and piroxicam. The results show that tomato sofrito extract has possible anti-inflammatory activity demonstrated by the reduction of neutrophil migration, furthermore the model was sensitive and valid to be applied in complex food matrices(AU)

[A case report of hand, foot, and mouth disease with necrotizing mucocutaneous lesions]. / Reporte de caso de enfermedad mano-pie-boca con lesiones mucocutáneas que evolucionan a necrosis.

In most cases, the cause of hand, foot, and mouth disease (HFMD) is coxsackievirus A type 16. The infection can also be caused by other strains of coxsackievirus, spreading mainly by the oral-fecal route, while it is less likely to be transmitted through secretions. HFMD occurs mainly in summer and is more common in children under ten. Skin lesions develop during the disease but rarely become necrotic. When present, they are a severe complication requiring hospitalization. This paper reports the case of a patient with HFMD who developed necrotic mucocutaneous lesions that responded favorably to intravenous acyclovir, fluids, and electrolyte support therapy.

La enfermedad de mano-pie-boca es una patología originada en la mayoría de los casos por el virus coxsackie A tipo 16, aunque también puede ser ocasionada por otras cepas de la familia de los coxsackievirus. Dicho virus se propaga principalmente por vía fecal oral y, en menor proporción, por secreciones. Se presenta principalmente en verano, siendo frecuente en niños menores de 10 años. Dentro de dicha enfermedad las lesiones mucocutáneas que evolucionen en necrosis son poco frecuentes, constituyéndose en una complicación severa que requiere hospitalización. En el presente artículo se reporta un caso con diagnóstico de enfermedad mano-pie-boca, que evolucionó hacia lesiones mucocutáneas necróticas, mostrando una respuesta favorable a una terapia de soporte de aciclovir, líquidos y electrolitos.

Histone H1 depletion triggers an interferon response in cancer cells via activation of heterochromatic repeats.

Histone H1 has seven variants in human somatic cells and contributes to chromatin compaction and transcriptional regulation. Knock-down (KD) of each H1 variant in breast cancer cells results in altered gene expression and proliferation differently in a variant specific manner with H1.2 and H1.4 KDs being most deleterious. Here we show combined depletion of H1.2 and H1.4 has a strong deleterious effect resulting in a strong interferon (IFN) response, as evidenced by an up-regulation of many IFN-stimulated genes (ISGs) not seen in individual nor in other combinations of H1 variant KDs. Although H1 participates to repress ISG promoters, IFN activation upon H1.2 and H1.4 KD is mainly generated through the activation of the IFN response by cytosolic nucleic acid receptors and IFN synthesis, and without changes in histone modifications at induced ISG promoters. H1.2 and H1.4 co-KD also promotes the appearance of accessibility sites genome wide and, particularly, at satellites and other repeats. The IFN response may be triggered by the expression of noncoding RNA generated from heterochromatic repeats or endogenous retroviruses upon H1 KD. In conclusion, redundant H1-mediated silencing of heterochromatin is important to maintain cell homeostasis and to avoid an unspecific IFN response.

Genome distribution of replication-independent histone H1 variants shows H1.0 associated with nucleolar domains and H1X associated with RNA polymerase II-enriched regions.

Unlike core histones, the linker histone H1 family is more evolutionarily diverse, and many organisms have multiple H1 variants or subtypes. In mammals, the H1 family includes seven somatic H1 variants; H1.1 to H1.5 are expressed in a replication-dependent manner, whereas H1.0 and H1X are replication-independent. Using ChIP-sequencing data and cell fractionation, we have compared the genomic distribution of H1.0 and H1X in human breast cancer cells, in which we previously observed differential distribution of H1.2 compared with the other subtypes. We have found H1.0 to be enriched at nucleolus-associated DNA repeats and chromatin domains, whereas H1X is associated with coding regions, RNA polymerase II-enriched regions, and hypomethylated CpG islands. Further, H1X accumulates within constitutive or included exons and retained introns and toward the 3' end of expressed genes. Inducible H1X knockdown does not affect cell proliferation but dysregulates a subset of genes related to cell movement and transport. In H1X-depleted cells, the promoters of up-regulated genes are not occupied specifically by this variant, have a lower than average H1 content, and, unexpectedly, do not form an H1 valley upon induction. We conclude that H1 variants are not distributed evenly across the genome and may participate with some specificity in chromatin domain organization or gene regulation.

Dynamics and dispensability of variant-specific histone H1 Lys-26/Ser-27 and Thr-165 post-translational modifications.

In mammals, the linker histone H1, involved in DNA packaging into chromatin, is represented by a family of variants. H1 tails undergo post-translational modifications (PTMs) that can be detected by mass spectrometry. We developed antibodies to analyze several of these as yet unexplored PTMs including the combination of H1.4 K26 acetylation or trimethylation and S27 phosphorylation. H1.2-T165 phosphorylation was detected at S and G2/M phases of the cell cycle and was dispensable for chromatin binding and cell proliferation; while the H1.4-K26 residue was essential for proper cell cycle progression. We conclude that histone H1 PTMs are dynamic over the cell cycle and that the recognition of modified lysines may be affected by phosphorylation of adjacent residues.