MicroRNA dysregulation and esophageal cancer development depend on the extent of zinc dietary deficiency

open9siopenFong, Louise Y.; Taccioli, Cristian; Jing, Ruiyan; Smalley, Karl J.; Alder, Hansjuerg; Jiang, Yubao; Fadda, Paolo; Farber, John L.; Croce, Carlo M.Fong, Louise Y.; Taccioli, Cristian; Jing, Ruiyan; Smalley, Karl J.; Alder, Hansjuerg; Jiang, Yubao; Fadda, Paolo; Farber, John L.; Croce, Carlo M

A Population of Short-duration Gamma-ray Bursts with Dwarf Host Galaxies

We present a population of 11 of the faintest ($> 25.5$ AB mag) short gamma-ray burst (GRB) host galaxies. We model their sparse available observations using the stellar population inference code Prospector-$\beta$ and develop a novel implementation to incorporate the galaxy mass-radius relation. Assuming these hosts are randomly drawn from the galaxy population and conditioning this draw on their observed flux and size in few photometric bands, we determine that these hosts have dwarf galaxy stellar masses of $7.0\lesssim\log(M_*/M_\odot)\lesssim9.1$. This is striking as only $14\%$ of short GRB hosts with previous inferred stellar masses had $M_* \lesssim 10^{9}\,M_{\odot}$. We further show these short GRBs have smaller physical and host-normalized offsets than the rest of the population, suggesting that the majority of their neutron star (NS) merger progenitors were retained within their hosts. The presumably shallow potentials of these hosts translate to small escape velocities of $\sim5.5-80$ km/s, indicative of either low post-supernova systemic velocities or short inspiral times. While short GRBs with identified dwarf host galaxies now comprise $\approx 14\%$ of the total Swift-detected population, a number are likely missing in the current population, as larger systemic velocities (observed from Galactic NS population) would result in highly offset short GRBs and less secure host associations. However, the revelation of a population of short GRBs retained in low-mass host galaxies offers a natural explanation for observed $r$-process enrichment via NS mergers in Local Group dwarf galaxies, and has implications for gravitational wave follow-up strategies.Comment: 22 pages, 9 figures, 2 tables, submitte

Does high sugar intake really alter the oral microbiota?: A systematic review

https://scienti.minciencias.gov.co/cvlac/visualizador/generarCurriculoCv.do?cod_rh=0001561382GIOMET0000-0002-5435-345

Repression of Esophageal Neoplasia and Inflammatory Signaling by Anti-miR-31 Delivery In Vivo.

BACKGROUND: Overexpression of microRNA-31 (miR-31) is implicated in the pathogenesis of esophageal squamous cell carcinoma (ESCC), a deadly disease associated with dietary zinc deficiency. Using a rat model that recapitulates features of human ESCC, the mechanism whereby Zn regulates miR-31 expression to promote ESCC is examined. METHODS: To inhibit in vivo esophageal miR-31 overexpression in Zn-deficient rats (n = 12-20 per group), locked nucleic acid-modified anti-miR-31 oligonucleotides were administered over five weeks. miR-31 expression was determined by northern blotting, quantitative polymerase chain reaction, and in situ hybridization. Physiological miR-31 targets were identified by microarray analysis and verified by luciferase reporter assay. Cellular proliferation, apoptosis, and expression of inflammation genes were determined by immunoblotting, caspase assays, and immunohistochemistry. The miR-31 promoter in Zn-deficient esophagus was identified by ChIP-seq using an antibody for histone mark H3K4me3. Data were analyzed with t test and analysis of variance. All statistical tests were two-sided. RESULTS: In vivo, anti-miR-31 reduced miR-31 overexpression (P = .002) and suppressed the esophageal preneoplasia in Zn-deficient rats. At the same time, the miR-31 target Stk40 was derepressed, thereby inhibiting the STK40-NF-κΒ-controlled inflammatory pathway, with resultant decreased cellular proliferation and activated apoptosis (caspase 3/7 activities, fold change = 10.7, P = .005). This same connection between miR-31 overexpression and STK40/NF-κΒ expression was also documented in human ESCC cell lines. In Zn-deficient esophagus, the miR-31 promoter region and NF-κΒ binding site were activated. Zn replenishment restored the regulation of this genomic region and a normal esophageal phenotype. CONCLUSIONS: The data define the in vivo signaling pathway underlying interaction of Zn deficiency and miR-31 overexpression in esophageal neoplasia and provide a mechanistic rationale for miR-31 as a therapeutic target for ESCC

Integration of metabolomics, transcriptomics, and microRNA expression profiling reveals a miR-143-HK2-glucose network underlying zinc-deficiency-associated esophageal neoplasia

Esophageal squamous cell carcinoma (ESCC) in humans is a deadly disease associated with dietary zinc (Zn)-deficiency. In the rat esophagus, Zn-deficiency induces cell proliferation, alters mRNA and microRNA gene expression, and promotes ESCC. We investigated whether Zn-deficiency alters cell metabolism by evaluating metabolomic profiles of esophageal epithelia from Zn-deficient and replenished rats vs sufficient rats, using untargeted gas chromatography time-of-flight mass spectrometry (n = 8/group). The Zn-deficient proliferative esophagus exhibits a distinct metabolic profile with glucose down 153-fold and lactic acid up 1.7-fold (P \u3c 0.0001), indicating aerobic glycolysis (the Warburg effect ), a hallmark of cancer cells. Zn-replenishment rapidly increases glucose content, restores deregulated metabolites to control levels, and reverses the hyperplastic phenotype. Integration of metabolomics and our reported transcriptomic data for this tissue unveils a link between glucose down-regulation and overexpression of HK2, an enzyme that catalyzes the first step of glycolysis and is overexpressed in cancer cells. Searching our published microRNA profile, we find that the tumor-suppressor miR-143, a negative regulator of HK2, is down-regulated in Zn-deficient esophagus. Using in situ hybridization and immunohistochemical analysis, the inverse correlation between miR-143 down-regulation and HK2 overexpression is documented in hyperplastic Zndeficient esophagus, archived ESCC-bearing Zn-deficient esophagus, and human ESCC tissues. Thus, to sustain uncontrolled cell proliferation, Zn-deficiency reprograms glucose metabolism by modulating expression of miR-143 and its target HK2. Our work provides new insight into critical roles of Zn in ESCC development and prevention. © Fong et al

Zinc deficiency activates S100A8 inflammation in the absence of COX-2 and promotes murine oral-esophageal tumor progression

Zinc (Zn)-deficiency (ZD) is implicated in the pathogenesis of human oral-esophageal cancers. Previously, we showed that in ZD mice genetic deletion of cyclooxygenase-2 (Cox-2) enhances N-nitrosomethylbenzylamine-induced forestomach carcinogenesis. By contrast, Cox-2 deletion offers protection in Zn-sufficient (ZS) mice. We hypothesize that ZD activates pathways insensitive to COX-2 inhibition, thereby promoting carcinogenesis. This hypothesis is tested in a Cox-2−/− mouse tongue cancer model that mimics pharmacologic blockade of COX-2 by firstly examining transcriptome profiles of forestomach mucosa from Cox-2−/− and wild-type mice on a ZD vs. ZS diet, and secondly investigating the roles of identified markers in mouse forestomach/tongue preneoplasia and carcinomas. In Cox-2−/− mice exposed to the tongue carcinogen 4-nitroquinoline 1-oxide, dietary ZD elicited tongue/esophagus/forestomach carcinomas that were prevented by ZS. The precancerous ZD:Cox-2−/−vs. ZS:Cox-2−/− forestomach had an inflammatory signature with upregulation of the proinflammation genes S100a8 and S100a9. Bioinformatics analysis revealed overrepresentation of inflammation processes comprising S100a8/a9 and an nuclear factor (NF)-κB network with connectivity to S100A8. Immunohistochemistry revealed co-overexpression of S100A8, its heterodimeric partner S100A9, the receptor for advanced glycation end-products (RAGE), NF-κB p65, and cyclin D1, in ZD:Cox-2−/− forestomach/tongue preneoplasia and carcinomas, evidence for the activation of a RAGE-S100A8/A9 inflammatory pathway. Accumulation of p53 in these carcinomas indicated activation of additional inflammatory pathways. Zn-replenishment in ZD:Cox-2−/−mice reversed the inflammation and inhibited carcinogenesis. Thus, ZD activates alternative inflammation-associated cancer pathways that fuel tumor progression and bypass the antitumor effect of Cox-2 ablation. These findings have important clinical implications, as combination cancer therapy that includes Zn may improve efficacy

Human-like hyperplastic prostate with low ZIP1 induced solely by Zn deficiency in rats

Prostate cancer is a leading cause of cancer death in men over 50 years of age, and there is a characteristic marked decrease in Zn content in the malignant prostate cells. The cause and consequences of this loss have thus far been unknown. We found that in middle-aged rats a Zn-deficient diet reduces prostatic Zn levels (P = 0.025), increases cellular proliferation, and induces an inflammatory phenotype with COX-2 overexpression. This hyperplastic/inflammatory prostate has a human prostate cancer-like microRNA profile, with up-regulation of the Zn-homeostasis-regulating miR-183-96-182 cluster (fold change = 1.41-2.38; P = 0.029-0.0003) and down-regulation of the Zn importer ZIP1 (target of miR-182), leading to a reduction of prostatic Zn. This inverse relationship between miR-182 and ZIP1 also occurs in human prostate cancer tissue, which is known for Zn loss. The discovery that the Zn-depleted middle-aged rat prostate has a metabolic phenotype resembling that of human prostate cancer, with a 10-fold down-regulation of citric acid (P = 0.0003), links citrate reduction directly to prostatic Zn loss, providing the underlying mechanism linking dietary Zn deficiency with miR-183-96-182 overexpression, ZIP1 down-regulation, prostatic Zn loss, and the resultant citrate down-regulation, changes mimicking features of human prostate cancer. Thus, dietary Zn deficiency during rat middle age produces changes that mimic those of human prostate carcinoma and may increase the risk for prostate cancer, supporting the need for assessment of Zn supplementation in its prevention

Hereditariedade dos componentes das medidas cefalométricas odi, apdi e Triângulo Mcnamara em pacientes com má oclusão esquelética classe ii e classe iii, frequentando a clínica dentária da Universidad Cooperativa de Colombia

Malocclusion is a pathological entity associated with abnormalities in craniofacial growth and development in which genetic and environmental factors are involved. The role of heritability has been widely investigated in craniometric and cephalometric studies of facial similarities, where it has been shown that the facial shape is the result of the genotype of the person, that is why, the facial appearance presents a familial hereditary tendency. Objective: To determine the heritability of the components of the composite cephalometric measurements: ODI and APDI and McNamara's Triangle in patients with class II and class III of skeletal malocclusion, who went to the Orthodontic clinic of the UCC-Campus Pasto. Methodology: A quantitative, observational and descriptive cross-sectional approach is developed by using a total sample of 60 pairs of siblings. The percentage of heritability is obtained by using the Haseman Elston linear regression test, where a value higher than 80% is considered highly heritable and values ​​of P <0.05 are considered significant. Results: The components that presented the highest heritability were: the cephalometric measurement shared between the ODI and APDI components, the Plano de Frankfort-Plano Palatino angle, with a 100%, and the linear measurement Condilion-Gnation, with a 98%. Conclusions: Mandibular size is influenced by highly heritable factors, but the mandibular position, represented by Facial Plane - Frankfort Plane and ENA-Me, has low heritability, it means that is highly adaptable. Cephalometric measurements such as Plane-Facial Plane-AB and Plane-Mandibular Plane-AB, are the result of a relationship between the maxillary and the mandible, presenting a low heritability, which suggests that they are influenced by external factors inherent to each person.La maloclusión es una entidad patológica asociada con anomalías en crecimiento y desarrollo craneofacial en donde intervienen factores genéticos y ambientales. El papel de la heredabilidad ha sido ampliamente investigado en estudios craneométricos y cefalométricos de similitudes faciales, donde se ha evidenciado que la forma facial, es resultado del genotipo del individuo, por consiguiente, la apariencia facial presenta una tendencia hereditaria familiar. Objetivo: Determinar la heredabilidad de los componentes de las medidas cefalométricas compuestas: ODI y APDI y del Triángulo de McNamara en pacientes con maloclusión esquelética clase II y clase III, que asisten a la clínica de Ortodoncia de la UCC- Campus Pasto.Metodología: Enfoque cuantitativo, Observacional, descriptivo de corte transversal, que utiliza una muestra total de 60 pares de hermanos. El porcentaje de heredabilidad fue calculado mediante la prueba de regresión lineal Haseman Elston, donde un valor mayor a 80% se considera altamente heredable y valores de  P<0.05 se consideraron significativos. Resultados: Los componentes que presentaron mayor heredabilidad fueron; la medida cefalométrica compartida entre los componentes de ODI y APDI, el ángulo  Plano de Frankfort-Plano Palatino, con el 100% y la medida lineal  Condilion-Gnation con un 98%. Conclusiones: El tamaño mandibular está influenciado por factores altamente heredables, pero la posición mandibular, representada por Plano facial - Plano de Frankfort y ENA-Me presentan una baja heredabilidad, es decir altamente adaptables. Las medidas cefalométricas como Plano facial-Plano AB y Plano Mandibular -Plano AB, son el resultado de una relación entre el maxilar y la mandíbula, presentando una baja heredabilidad, lo que sugiere que están influenciadas por factores externos inherentes a cada sujeto.  A má oclusão é uma entidade patológica associada a anormalidades no crescimento e desenvolvimento cra-niofacial em que intervêm fatores genéticos e ambientais. O papel da herdabilidade tem sido amplamente investigado em estudos craniométricos e cefalométricos de semelhanças faciais, onde foi demonstrado que a forma facial é resultado do genótipo do indivíduo, portanto, a aparência facial tem uma tendência hereditária familiar. Objetivo: Determinar a herdabilidade dos componentes das medidas cefalométricas compostas: ODI e APDI e Triângulo de McNamara em pacientes com má oclusão esquelética classe II e classe III, que frequentam a clínica de Ortodontia do UCC-Campus Pasto. Metodologia: Abordagem quantitativa, observacional, descritiva transversal, que utiliza uma amostra total de 60 pares de irmãos. A porcentagem de herdabilidade foi calculada usando o teste de regressão linear de Haseman Elston, onde um valor maior que 80% é considerado altamente hereditário e valores de P<0,05 foram considerados significativos. Resultados: Os componentes que apresentaram maior herdabilidade foram; a medida cefalométrica compar-tilhada entre os componentes ODI e APDI, o ângulo Plano-Palatino de Frankfort, com 100% e a medida linear Condilion-Gnation com 98%. Conclusões: O tamanho mandibular é influenciado por fatores altamente hereditários, mas a posição mandibu-lar, representada pelo Plano Facial - Plano de Frankfurt e ENA-Me tem baixa herdabilidade, ou seja, altamente adaptável. Medidas cefalométricas como Plano Facial-Plano AB e Plano Mandibular-Plano AB, são resultado de uma relação entre a maxila e a mandíbula, apresentando baixa herdabilidade, o que sugere que sejam influenciadas por fatores externos inerentes a cada sujeito

Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas

This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smokin