Mutational Profiles Reveal an Aberrant TGF-β-CEA Regulated Pathway in Colon Adenomas.

Mutational processes and signatures that drive early tumorigenesis are centrally important for early cancer prevention. Yet, to date, biomarkers and risk factors for polyps (adenomas) that inordinately and rapidly develop into colon cancer remain poorly defined. Here, we describe surprisingly high mutational profiles through whole-genome sequence (WGS) analysis in 2 of 4 pairs of benign colorectal adenoma tissue samples. Unsupervised hierarchical clustered transcriptomic analysis of a further 7 pairs of adenomas reveals distinct mutational signatures regardless of adenoma size. Transitional single nucleotide substitutions of C:G\u3eT:A predominate in the adenoma mutational spectrum. Strikingly, we observe mutations in the TGF-β pathway and CEA-associated genes in 4 out of 11 adenomas, overlapping with the Wnt pathway. Immunohistochemical labeling reveals a nearly 5-fold increase in CEA levels in 23% of adenoma samples with a concomitant loss of TGF-β signaling. We also define a functional role by which the CEA B3 domain interacts with TGFBR1, potentially inactivating the tumor suppressor function of TGF-β signaling. Our study uncovers diverse mutational processes underlying the transition from early adenoma to cancer. This has broad implications for biomarker-driven targeting of CEA/TGF-β in high-risk adenomas and may lead to early detection of aggressive adenoma to CRC progression

Vitamin D Deficiency Promotes Liver Tumor Growth in Transforming Growth Factor-β/Smad3-Deficient Mice Through Wnt and Toll-like Receptor 7 Pathway Modulation.

Disruption of the TGF-β pathway is associated with liver fibrosis and suppression of liver tumorigenesis, conditions associated with low Vitamin D (VD) levels. However, potential contributions of VD to liver tumor progression in the context of TGF-β signaling remain unexplored. Our analyses of VD deprivation (VDD) in in vivo models of liver tumor formation revealed striking three-fold increases in tumor burden in Smad3(+/-) mice, with a three-fold increase in TLR7 expression compared to controls. ChIP and transcriptional assays confirm Smad3 binding at two TLR7 promoter SBE sites. Molecular interactions between TGF-β pathway and VDD were validated clinically, where an absence of VD supplementation was associated with low TGF-β pathway member expression levels and β-catenin activation in fibrotic/cirrhotic human liver tissues. Subsequent supplementing VD led to restoration of TGF-β member expression with lower β-catenin levels. Bioinformatics analysis provides positive supportive correlation between somatic mutations for VD-related genes and the TGF-β pathway. We conclude that VDD promotes tumor growth in the context of Smad3 disruption, potentially through regulation of TLR7 expression and β-catenin activation. VD could therefore be a strong candidate for liver cancer prevention in the context of aberrant Smad3 signaling

Alcohol, Stem Cells and Cancer.

Dosage, gender, and genetic susceptibility to the effects of alcohol remained only partially elucidated. In this review, we summarize the current knowledge of the mechanisms underlying the role of alcohol in liver and gastrointestinal cancers. In addition, two recent pathways- DNA repair and TGF-β signaling which provide new insights into alcohol in the regulation of cancers and stem cells are also discussed here

A Pan-cancer analysis reveals high-frequency genetic alterations in mediators of signaling by the tgf-β superfamily

We present an integromic analysis of gene alterations that modulate transforming growth factor β (TGF-β)-Smad-mediated signaling in 9,125 tumor samples across 33 cancer types in The Cancer Genome Atlas (TCGA). Focusing on genes that encode mediators and regulators of TGF-β signaling, we found at least one genomic alteration (mutation, homozygous deletion, or amplification) in 39% of samples, with highest frequencies in gastrointestinal cancers. We identified mutation hotspots in genes that encode TGF-β ligands (BMP5), receptors (TGFBR2, AVCR2A, and BMPR2), and Smads (SMAD2 and SMAD4). Alterations in the TGF-β superfamily correlated positively with expression of metastasis-associated genes and with decreased survival. Correlation analyses showed the contributions of mutation, amplification, deletion, DNA methylation, and miRNA expression to transcriptional activity of TGF-β signaling in each cancer type. This study provides a broad molecular perspective relevant for future functional and therapeutic studies of the diverse cancer pathways mediated by the TGF-β superfamily

Identification of Potential Meniere’s Disease Targets in the Adult Stria Vascularis

The stria vascularis generates the endocochlear potential and is involved in processes that underlie ionic homeostasis in the cochlear endolymph, both which play essential roles in hearing. The histological hallmark of Meniere’s disease (MD) is endolymphatic hydrops, which refers to the bulging or expansion of the scala media, which is the endolymph-containing compartment of the cochlea. This histologic hallmark suggests that processes that disrupt ion homeostasis or potentially endocochlear potential may underlie MD. While treatments exist for vestibular symptoms related to MD, effective therapies for hearing fluctuation and hearing loss seen in MD remain elusive. Understanding the potential cell types involved in MD may inform the creation of disease mouse models and provide insight into underlying mechanisms and potential therapeutic targets. For these reasons, we compare published datasets related to MD in humans with our previously published adult mouse stria vascularis single-cell and single-nucleus RNA-Seq datasets to implicate potentially involved stria vascularis (SV) cell types in MD. Finally, we provide support for these implicated cell types by demonstrating co-expression of select candidate genes for MD within SV cell types.Intramural Research Program of the NIH, NIDCD DC000088European Commission PI17-1644FIBAO PE-0356-201

Repurposable Drugs That Interact with Steroid Responsive Gene Targets for Inner Ear Disease

Corticosteroids, oral or transtympanic, remain the mainstay for inner ear diseases characterized by hearing fluctuation or sudden changes in hearing, including sudden sensorineural hearing loss (SSNHL), Meniere’s disease (MD), and autoimmune inner ear disease (AIED). Despite their use across these diseases, the rate of complete recovery remains low, and results across the literature demonstrates significant heterogeneity with respect to the effect of corticosteroids, suggesting a need to identify more efficacious treatment options. Previously, our group has cross-referenced steroid-responsive genes in the cochlea with published single-cell and single-nucleus transcriptome datasets to demonstrate that steroid-responsive differentially regulated genes are expressed in spiral ganglion neurons (SGN) and stria vascularis (SV) cell types. These differentially regulated genes represent potential druggable gene targets. We utilized multiple gene target databases (DrugBank, Pharos, and LINCS) to identify orally administered, FDA approved medications that potentially target these genes. We identified 42 candidate drugs that have been shown to interact with these genes, with an emphasis on safety profile, and tolerability. This study utilizes multiple databases to identify drugs that can target a number of druggable genes in otologic disorders that are commonly treated with steroids, providing a basis for establishing novel repurposing treatment trials

Experimental study of petrophysical properties of a tight formation by considering the clay minerals and flow sensitivities

Quantitative X-ray diffraction analysis of rock, X-ray diffraction analysis of clay minerals types and components, Field Emission Scanning Electron Microscope (FESEM) and sensitivity flow experiments methods were used toresearch the effects of clay minerals on the porosity and permeability of Ordos Basin’s tight Chang 7 reservoir (Zhenbei area). These methods were also used to analyze the type, degree, and factors affecting reservoir sensitivity. The research showed that the reservoir possessed poor water, salt, and alkali sensitivity, poor to strong acid sensitivity and none to poor velocity sensitivity. Acid sensitivity among them had comparatively large differences, mainly because acid sensitivity was not only affected by chlorite but also by components of carbonate minerals. Stress sensitivity experiment results showed that the maximum degree of permeability damage in the rocks of this reservoir was median to very strong; irreversible damage level was weak to strong. Consequently, the experimental studies are favorable to not only determine the factor dominating the petrophysical properties of the tight formation, but also to optimize the follow-up development strategies, e.g. injection schedule and hydraulic fracturing implement.   Estudio Experimental de las propiedades petrofísicas de una formación compacta al considerar las arcillas minerales y las respuestas de flujo   Resumen Este trabajo utilizó análisis cuantitativos de rocas por difracción de rayos X, análisis de los tipos y componentes de arcillas minerales por difracción de rayos X, análisis con el microscopio electrónico de efecto de campo (FESEM, del inglés Field Emission Scanning Electron Microscope) y ensayos de respuesta de flujo para investigar los efectos de las arcillas minerales en la porosidad y permeabilidad del depósito Chang 7, en la cuenca del Ordos (región Zhenbei). Estos métodos también se utilizaron para analizar el tipo, el grado y los factores que afectan la respuesta del depósito. La investigación demuestra que el depósito posee poca agua, sal y respuesta alcalina, baja a fuerte respuesta de acidez, y ninguna a baja respuesta de velocidad. Entre estas características, la respuesta de acidez presentó grandes diferencias comparativas debido a que está afectada tanto por el clorito como por los componentes de minerales carbonatos. Los resultados de los ensayos de respuesta de tensión muestran que el máximo grado de daño por permeabilidad en las rocas del depósito es de mediano a muy fuerte; el nivel de daño irreversible va de débil hasta fuerte. Por lo tanto lo estudios experimentales son favorables no solo para determinar el factor dominante en las propiedades petrofísicas de la formación compacta sino también para optimizar las futuras estrategias de desarrollo, como una programación de las tareas de inyección y la implementación de la fractura hidráulica

Identification of Potential Meniere's Disease Targets in the Adult Stria Vascularis

The stria vascularis generates the endocochlear potential and is involved in processes that underlie ionic homeostasis in the cochlear endolymph, both which play essential roles in hearing. The histological hallmark of Meniere's disease (MD) is endolymphatic hydrops, which refers to the bulging or expansion of the scala media, which is the endolymph-containing compartment of the cochlea. This histologic hallmark suggests that processes that disrupt ion homeostasis or potentially endocochlear potential may underlie MD. While treatments exist for vestibular symptoms related to MD, effective therapies for hearing fluctuation and hearing loss seen in MD remain elusive. Understanding the potential cell types involved in MD may inform the creation of disease mouse models and provide insight into underlying mechanisms and potential therapeutic targets. For these reasons, we compare published datasets related to MD in humans with our previously published adult mouse stria vascularis single-cell and single-nucleus RNA-Seq datasets to implicate potentially involved stria vascularis (SV) cell types in MD. Finally, we provide support for these implicated cell types by demonstrating co-expression of select candidate genes for MD within SV cell types.This research was supported (in part) by the Intramural Research Program of the NIH, NIDCD to MH (DC000088). JL-E was funded by European Regional Development Funds to Instituto de Salud Carlos III by PI17-1644 Grant and FIBAO PE-0356- 2018 Grant.Ye