Pannexin-1 expression in tumor cells correlates with colon cancer progression and survival.

AIMS: Pannexin-1 (PANX1) is a hemichannel that releases ATP upon opening, initiating inflammation, cell proliferation, and migration. However, the role of PANX1 channels in colon cancer remains poorly understood, thus constituting the focus of this study. MAIN METHODS: PANX1 mRNA expression was analyzed using multiple cancer databases. PANX1 protein expression and distribution were evaluated by immunohistochemistry on primary tumor tissue and non-tumor colonic mucosa from colon cancer patients. PANX1 inhibitors (probenecid or 10Panx) were used to assess colon cancer cell lines viability. To study the role of PANX1 in vivo, a subcutaneous xenograft model using HCT116 cells was performed in BALB/c NOD/SCID immunodeficient mice to evaluate tumor growth under PANX1 inhibition using probenecid. KEY FINDINGS: PANX1 mRNA was upregulated in colon cancer tissue compared to non-tumor colonic mucosa. Elevated PANX1 mRNA expression in tumors correlated with worse disease-free survival. PANX1 protein abundance was increased on tumor cells compared to epithelial cells in paired samples, in a cancer stage-dependent manner. In vitro and in vivo experiments indicated that blocking PANX1 reduced cell viability and tumor growth. SIGNIFICANCE: PANX1 can be used as a biomarker of colon cancer progression and blocking PANX1 channel opening could be used as a potential therapeutic strategy against this disease.

cGAS-STING signaling pathway in intestinal homeostasis and diseases.

The intestinal mucosa is constantly exposed to commensal microbes, opportunistic pathogens, toxins, luminal components and other environmental stimuli. The intestinal mucosa consists of multiple differentiated cellular and extracellular components that form a critical barrier, but is also equipped for efficient absorption of nutrients. Combination of genetic susceptibility and environmental factors are known as critical components involved in the pathogenesis of intestinal diseases. The innate immune system plays a critical role in the recognition and elimination of potential threats by detecting pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). This host defense is facilitated by pattern recognition receptors (PRRs), in which the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has gained attention due to its role in sensing host and foreign double-stranded DNA (dsDNA) as well as cyclic dinucleotides (CDNs) produced by bacteria. Upon binding with dsDNA, cGAS converts ATP and GTP to cyclic GMP-AMP (cGAMP), which binds to STING and activates TANK binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3), inducing type I interferon (IFN) and nuclear factor kappa B (NF-κB)-mediated pro-inflammatory cytokines, which have diverse effects on innate and adaptive immune cells and intestinal epithelial cells (IECs). However, opposite perspectives exist regarding the role of the cGAS-STING pathway in different intestinal diseases. Activation of cGAS-STING signaling is associated with worse clinical outcomes in inflammation-associated diseases, while it also plays a critical role in protection against tumorigenesis and certain infections. Therefore, understanding the context-dependent mechanisms of the cGAS-STING pathway in the physiopathology of the intestinal mucosa is crucial for developing therapeutic strategies targeting the cGAS-STING pathway. This review aims to provide insight into recent findings of the protective and detrimental roles of the cGAS-STING pathway in intestinal diseases.

Factors associated with the perception of inadequate sanitary control in 12 Latin American countries during the COVID-19 pandemic.

Introduction: Sanitary control mechanisms differ greatly from country to country. Therefore, it is important to know citizens' perception of different realities. We aimed to determine the factors associated with the perception of inadequate sanitary control in 12 Latin American countries during the COVID-19 pandemic. Methods: This is an analytical cross-sectional study. We asked about six perceptions in regard to different situations experienced by inhabitants of 12 Latin American countries during the pandemic. Frequencies according to country were described and associations vs. other important variables were obtained. Results: Out of 8,489 participants, 68% stated that there were moments of collective hysteria. Honduras was the country that most perceived inadequate control mechanisms established by the government. Multivariate analysis showed that there were statistically significant differences among many of the countries according to the six evaluated items. The higher the level of education, the greater the perception of poor control in five of the aspects. Additionally, men had a lower perception of inadequate control. The older the age, the lower the perception of inadequate control regarding whether there was collective hysteria and shortages of basic essentials. Those with COVID-19 had a lower perception of medicine shortages. Conclusion: The population of multiple realities in Latin America have perceived a bad management of the pandemic. Citizens' perception is an important indicator of the performance of each government during the COVID-19 pandemic. This study may provide valuable information on the relationship between the effectiveness of government sanitary control and people's mental health, which ultimately helps to create objective prevention programs against post-traumatic stress disorder, depression, fear of contagion, and collective hysteria. In addition, governments could use this information to design effective mitigation plans for future unavoidable pandemic events based on the six criteria discussed here.

Regulation of the Intestinal Extra-Adrenal Steroidogenic Pathway Component LRH-1 by Glucocorticoids in Ulcerative Colitis.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) and can be treated with glucocorticoids (GC), although some patients are unresponsive to this therapy. The transcription factor LRH-1/NR5A2 is critical to intestinal cortisol production (intestinal steroidogenesis), being reduced in UC patients. However, the relationship between LRH-1 expression and distribution with altered corticosteroid responses is unknown. To address this, we categorized UC patients by their steroid response. Here, we found that steroid-dependent and refractory patients presented reduced glucocorticoid receptor (GR)-mediated intestinal steroidogenesis compared to healthy individuals and responder patients, possibly related to increased colonic mucosa GR isoform beta (GRß) content and cytoplasmic LRH-1 levels in epithelial and lamina propria cells. Interestingly, an intestinal epithelium-specific GR-induced knockout (GRiKO) dextran sodium sulfate (DSS)-colitis mice model presented decreased epithelial LRH-1 expression, whilst it increased in the lamina propria compared to DSS-treated control mice. Mechanistically, GR directly induced NR5A2 gene expression in CCD841CoN cells and human colonic organoids. Furthermore, GR bound to two glucocorticoid-response elements within the NR5A2 promoter in dexamethasone-stimulated CCD841CoN cells. We conclude that GR contributes to intestinal steroidogenesis by inducing LRH-1 in epithelial cells, suggesting LRH-1 as a potential marker for glucocorticoid-impaired response in UC. However, further studies with a larger patient cohort will be necessary to confirm role of LRH-1 as a therapeutic biomarker.

Immune System, Microbiota, and Microbial Metabolites: The Unresolved Triad in Colorectal Cancer Microenvironment.

Colorectal cancer (CRC) is one of the most common cancers worldwide. As with other cancers, CRC is a multifactorial disease due to the combined effect of genetic and environmental factors. Most cases are sporadic, but a small proportion is hereditary, estimated at around 5-10%. In both, the tumor interacts with heterogeneous cell populations, such as endothelial, stromal, and immune cells, secreting different signals (cytokines, chemokines or growth factors) to generate a favorable tumor microenvironment for cancer cell invasion and metastasis. There is ample evidence that inflammatory processes have a role in carcinogenesis and tumor progression in CCR. Different profiles of cell activation of the tumor microenvironment can promote pro or anti-tumor pathways; hence they are studied as a key target for the control of cancer progression. Additionally, the intestinal mucosa is in close contact with a microorganism community, including bacteria, bacteriophages, viruses, archaea, and fungi composing the gut microbiota. Aberrant composition of this microbiota, together with alteration in the diet-derived microbial metabolites content (such as butyrate and polyamines) and environmental compounds has been related to CRC. Some bacteria, such as pks+ Escherichia coli or Fusobacterium nucleatum, are involved in colorectal carcinogenesis through different pathomechanisms including the induction of genetic mutations in epithelial cells and modulation of tumor microenvironment. Epithelial and immune cells from intestinal mucosa have Pattern-recognition receptors and G-protein coupled receptors (receptor of butyrate), suggesting that their activation can be regulated by intestinal microbiota and metabolites. In this review, we discuss how dynamics in the gut microbiota, their metabolites, and tumor microenvironment interplays in sporadic and hereditary CRC, modulating tumor progression.

Repercusión académica de la COVID-19 en universitarios peruanos / Academic impact of COVID-19 on Peruvian university students

Introducción: La pandemia del coronavirus ha generado que muchos estudiantes teman perder el ciclo. Objetivo: Validar una escala que mida la percepción de posibles repercusiones académicas en estudiantes universitarios en el Perú. Metodología: Se realizó un proceso de validación de un test que mide la percepción acerca de las posibles repercusiones académicas en estudiantes universitarios. La validación se realizó mediante búsqueda de literatura científica, construcción del primer bosquejo, validación del test por expertos (59 expertos: epidemiólogos, investigadores, médicos), análisis factorial exploratorio y estadístico. Resultados: Respecto a la relevancia se observa que el ítem 7 es más esencial o importante que los demás (V = 1,00; IC 95 por ciento: 0,73-0,96). El ítem 8 (M = 3,80; /= 1,152) presenta la mayor media y, la más baja, el ítem 6 (M = 3,03; DE = 1,342). La pertinencia del AFE se justifica con el índice KMO (0,85) y la prueba de Bartlett (12577,0; gl = 28; p = / 0,001) siendo aceptables y significativos. Se obtuvo un coeficiente α de Cronbach de 0,899 con un intervalo de confianza del 95 por ciento de 0,882-0,898; indicando que la consistencia del instrumento es buena. Conclusiones: Se validó una escala de factor único que mide la percepción que tienen los estudiantes universitarios acerca de las posibles repercusiones de la pandemia del coronavirus en sus estudios. Es necesario evaluar cada realidad y el instrumento puede servir como una escala base para ello(AU)

Introduction: As a result of the coronavirus pandemic, many students are worried that they may lose their academic term. Objective: Validate a scale to measure the perception of possible academic impacts among Peruvian university students. Method: A validation process was conducted of a test measuring the perception of university students about possible academic impacts. The validation was based on a scientific bibliography search, development of a preliminary overview, validation of the test by 59 experts: epidemiologists, researchers and physicians, exploratory factor analysis, and statistical analysis. Results: In terms of relevance, item 7 was found to be more essential or important than the others (V = 1.00; CI 95 percent: 0.73-0.96). Item 8 (M = 3.80; /= 1.152) exhibits the highest mean, and item 6 the lowest (M = 3.03; SD = 1.342). AFE relevance is justified by the KMO index (0.85) and Bartlett's test (12577.0; gl = 28; p = / 0.001), both of which were found to be acceptable and significant. A Cronbach's α coefficient of 0.899 was obtained, with a confidence interval of 95 percent, SD 0.882-0.898, indicating a good consistency level. Conclusions: A single factor scale was validated which measures the perception of university students about the possible impacts of the coronavirus pandemic on their studies. It is necessary to evaluate each reality, and the tool may serve as a base scale for that purpose(AU)

Reconstituting Drosophila Centromere Identity in Human Cells.

The centromere is an essential chromosomal region required for accurate chromosome segregation. Most eukaryotic centromeres are defined epigenetically by the histone H3 variant, centromere protein (CENP)-A, yet how its self-propagation is achieved remains poorly understood. Here, we develop a heterologous system to reconstitute epigenetic inheritance of centromeric chromatin by ectopically targeting the Drosophila centromere proteins dCENP-A, dCENP-C, and CAL1 to LacO arrays in human cells. Dissecting the function of these three components uncovers the key role of self-association of dCENP-C and CAL1 for their mutual interaction and dCENP-A deposition. Importantly, we identify CAL1 to be required for dCENP-C loading onto chromatin in cooperation with dCENP-A nucleosomes, thus closing the epigenetic loop to ensure dCENP-C and dCENP-A replenishment during the cell division cycle. Finally, we show that all three factors are sufficient for dCENP-A propagation and propose a model for the epigenetic inheritance of Drosophila centromere identity.

Corrigendum: Interleukin 33/ST2 Axis Components Are Associated to Desmoplasia, a Metastasis-Related Factor in Colorectal Cancer.

[This corrects the article DOI: 10.3389/fimmu.2019.01394.].

Interleukin 33/ST2 Axis Components Are Associated to Desmoplasia, a Metastasis-Related Factor in Colorectal Cancer.

In colorectal cancer (CRC), cancer-associated fibroblasts (CAFs) are the most abundant component from the tumor microenvironment (TM). CAFs facilitate tumor progression by inducing angiogenesis, immune suppression and invasion, thus altering the organization/composition of the extracellular matrix (i.e., desmoplasia) and/or activating epithelial-mesenchymal transition (EMT). Soluble factors from the TM can also contribute to cell invasion through secretion of cytokines and recently, IL-33/ST2 pathway has gained huge interest as a protumor alarmin, promoting progression to metastasis by inducing changes in TM. Hence, we analyzed IL-33 and ST2 content in tumor and healthy tissue lysates and plasma from CRC patients. Tissue localization and distribution of these molecules was evaluated by immunohistochemistry (using localization reference markers α-smooth muscle actin or α-SMA and E-cadherin), and clinical/histopathological information was obtained from CRC patients. In vitro experiments were conducted in primary cultures of CAFs and normal fibroblasts (NFs) isolated from tumor and healthy tissue taken from CRC patients. Additionally, migration and proliferation analysis were performed in HT29 and HCT116 cell lines. It was found that IL-33 content increases in left-sided CRC patients with lymphatic metastasis, with localization in tumor epithelia associated with abundant desmoplasia. Although ST2 content showed similarities between tumor and healthy tissue, a decreased immunoreactivity was observed in left-sided tumor stroma, associated to metastasis related factors (advanced stages, abundant desmoplasia, and presence of tumor budding). A principal component analysis (including stromal and epithelial IL-33/ST2 and α-SMA immunoreactivity with extent of desmoplasia) allowed us to distinguish clusters of low, intermediate and abundant desmoplasia, with potential to develop a diagnostic signature with benefits for further therapeutic targets. IL-33 transcript levels from CAFs directly correlated with CRC cell line migration induced by CAFs conditioned media, with rhIL-33 inducing a mesenchymal phenotype in HT29 cells. These results indicate a role of IL-33/ST2 in tumor microenvironment, specifically in the interaction between CAFs and epithelial tumor cells, thus contributing to invasion and metastasis in left-sided CRC, most likely by activating desmoplasia.

Corrigendum: Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases.

[This corrects the article DOI: 10.3389/fimmu.2019.00277.].

Short Chain Fatty Acids (SCFAs)-Mediated Gut Epithelial and Immune Regulation and Its Relevance for Inflammatory Bowel Diseases.

Ulcerative colitis (UC) and Crohn's disease (CD), collectively known as Inflammatory Bowel Diseases (IBD), are caused by a complex interplay between genetic, immunologic, microbial and environmental factors. Dysbiosis of the gut microbiome is increasingly considered to be causatively related to IBD and is strongly affected by components of a Western life style. Bacteria that ferment fibers and produce short chain fatty acids (SCFAs) are typically reduced in mucosa and feces of patients with IBD, as compared to healthy individuals. SCFAs, such as acetate, propionate and butyrate, are important metabolites in maintaining intestinal homeostasis. Several studies have indeed shown that fecal SCFAs levels are reduced in active IBD. SCFAs are an important fuel for intestinal epithelial cells and are known to strengthen the gut barrier function. Recent findings, however, show that SCFAs, and in particular butyrate, also have important immunomodulatory functions. Absorption of SCFAs is facilitated by substrate transporters like MCT1 and SMCT1 to promote cellular metabolism. Moreover, SCFAs may signal through cell surface G-protein coupled receptors (GPCRs), like GPR41, GPR43, and GPR109A, to activate signaling cascades that control immune functions. Transgenic mouse models support the key role of these GPCRs in controlling intestinal inflammation. Here, we present an overview of microbial SCFAs production and their effects on the intestinal mucosa with specific emphasis on their relevance for IBD. Moreover, we discuss the therapeutic potential of SCFAs for IBD, either applied directly or by stimulating SCFAs-producing bacteria through pre- or probiotic approaches.

Dimorphic DNA methylation during temperature-dependent sex determination in the sea turtle Lepidochelys olivacea.

Sex determination in vertebrates depends on the expression of a conserved network of genes. Sea turtles such as Lepidochelys olivacea have temperature-dependent sex determination. The present work analyses some of the epigenetic processes involved in this. We describe sexual dimorphism in global DNA methylation patterns between ovaries and testes of L. olivacea and show that the differences may arise from a combination of DNA methylation and demethylation events that occur during sex determination. Irrespective of incubation temperature, 5-hydroxymethylcytosine was abundant in the bipotential gonad; however, following sex determination, this modification was no longer found in pre-Sertoli cells in the testes. These changes correlate with the establishment of the sexually dimorphic DNA methylation patterns, down regulation of Sox9 gene expression in ovaries and irreversible gonadal commitment towards a male or female differentiation pathway. Thus, DNA methylation changes may be necessary for the stabilization of the gene expression networks that drive the differentiation of the bipotential gonad to form either an ovary or a testis in L. olivacea and probably among other species that manifest temperature-dependent sex determination.

Impacto de intervención temprana a cuidadores de pacientes secuelados de un accidente cerebrovascular: estudio piloto / Impact of early intervention for stroke caregivers: a pilot study

Introducción: Los cuidadores de personas secueladas de un Accidente Cerebro Vascular (ACV), perciben que durante los primeros meses carecen de la información necesaria sobre el proceso de su familiar, afectando sobre su estado afectivo y percepción de estrés. Objetivo: Evaluar la intervención realizada a cuidadores de pacientes secuelados de un ACV como factor protector en el estado afectivo y de carga en los cuidadores. Sujetos y métodos: Se reclutaron cuidadores directos, de personas con secuelas de ACV, según Escala de Rankin durante el período hospitalario. Se realizo un taller teórico práctico, consistentes en 4 sesiones; 3 durante el periodo hospitalario del usuario y 1 dentro del primer mes posterior al alta, los temas tratados eran organización y distribución de la rutina, integración de rutinas de tiempo libre y relajación y manejo del paciente en el hogar. Se evalúo a los cuidadores con escalas diagnósticas de carga emocional (Zarit, Indice de Esfuerzo del Cuidador) y ansiedad (Goldberg). Resultados: Luego del taller hubo una reducción significativa de 20 por ciento en el número de cuidadores con depresión (p=0,036) y 37 por ciento en el número de cuidadores con ansiedad (p=0,034.). Asimismo hubo una disminución significativa en el puntaje de sobrecarga emocional del cuidador medido mediante la escala de Zarit (p = 0,044). Conclusiones: La intervención evaluada en el presente estudio piloto parece ser una medida que contribuye en disminuir la sobrecarga emocional y ansiedad del cuidador.

Background: Caregivers of ischemic stoke damaged patients feels during the first months after the event a lack of information on how to help their relative, affecting the sense of stress and anxiety. We made an intervention to caregivers of the stroke unit of the University of Chile Hospital, in 2008.Objective: Determine whether the intervention to caregivers of stroke damaged patients is a protective factor in their emotional state and stress on caregivers. Subjects and methods: Direct healthy caregivers were recruited with a severe impaired family member within the hospitalization period. Intervention was conducted in 4 sessions, 3 during the hospital period and 1 in his home within the first month after discharge, where the issues discussed with caregiver was self-care and patient management. To measure the intervention we evaluated before the workshop and 2 months after the last session with some standardized tests (Zarit, Caregiver Stress Index) and anxiety (Goldberg). Results: After the intervention there was a significant 20 percent reduction in the number of caregivers with depression (p=0.036) and 37percent in the number of caregivers with anxiety (p=0.034.). There was also a significant decrease in the score of caregiver's emotional overload measured by the Zarit scale (p=0.044). Conclusions: The intervention evaluated in this pilot study appears to be an effective measure in reducing the emotional overload and anxiety of the caregiver, with an evident improvement in their mood.

Na(+)- and H(+)-dependent motility in the coral pathogen Vibrio shilonii.

In this work, we analyzed motility and the flagellar systems of the marine bacterium Vibrio shilonii. We show that this bacterium produces lateral flagella when seeded on soft agar plates at concentrations of 0.5% or 0.6%. However, at agar concentrations of 0.7%, cells become round and lose their flagella. The sodium channel blocker amiloride inhibits swimming of V. shilonii with the sheathed polar flagellum, but not swarming with lateral flagella. We also isolated and characterized the filament­hook­basal body of the polar flagellum. The proteins in this structure were analyzed by MS. Eight internal sequences matched with known flagellar proteins. The comparison of these sequences with the protein database from the complete genome of V. shilonii allows us to conclude that some components of the polar flagellum are encoded in two different clusters of flagellar genes, suggesting that this bacterium has a complex flagellar system, more complex possibly than other Vibrio species reported so far.

[Use of algarrobo (Prosopis chilensis (Mol) Stuntz) flour as protein and dietary fiber source in cookies and fried chips manufacture]. / Uso de harina de cotiledón de algarrobo (Prosopis chilensis (Mol) Stuntz) como fuente de proteina y fibra dietética en la elaboración de galletas y hojuelas fritas.

Limiting amino acids of the protein from chilean "algarrobo" are isoleucine, theronine and methionine/cyteine. Cereals and legume blends allow to improve the amino acid balance, since legume have more lysine, and cereals are richer in sulphur amino acids. Due to the nutritional interest of "algarrobo" cotyledons, the use of "algarrobo cotyledon" flour (ACF) in sweet and salty snack manufacture was evaluated. Cookies and fried salty chips with 0%, 10% and 20% ACF were prepared. Flours were analyzed for color, particle size, moisture, proximate composition, available lysine, and soluble, insoluble and total dietary fiber. Cookies and chips were analyzed for the same characteristics (except for particle size); besides there were determined water activity, weight and size of the units, and also, the caloric value was computed. Sensory quality and acceptance of both products were evaluated. It is noticeable the high amount of protein, lipids, ash, crude fiber (63.6; 10.2; 4.3 and 4.2 g/100 g dmb, respectively), available lysine (62.4 mg/g protein) and total dietary fiber (24.2 g/100 g dmb) of ACF. Both, cookies and chips with ACF, showed a significant increase in the amount of protein, lipids, ash, crude fiber and, available lysine (from 15.5 to 19,3 and from 20.3 a 29.6 mg lisina/g protein, respectively), and total dietary fiber (from 1.39 to 2.80 and from 1.60 a 5.60 g/100 g dmb, respectively). All of the cookies trials were well accepted ("I like it very much"); chips with 10% of AFC showed the highest acceptance ("I like it"). It can be concluded that the use of ACF in cookies and chips manufacture increases the contribution of available lysine; their protein and dietary fiber content, improving the soluble/insoluble fiber ratio, without affect neither their physical nor their sensory acceptance.