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The impact of tumour associated stroma on cancer metastasis is an emerging field. However, cancer associated genes in peritumoral adipose tissue (pAT) in human colon cancer have not been explored. The aim of this study was to identify differentially expressed genes (DEGs) associated with cancer pathways in mesenteric pAT compared with adjacent adipose tissue. In total, nine patients with colon cancer pathological stage T2/T4 were employed in this study. DEGs were identified in 6 patients employing Nanostring PanCancer Pathway Panel and pathway enrichment analyses were performed. Differential expression of the 5 most up-regulated and 2 down regulated genes was validated with qRT-PCR. Results showed collagen type I alpha 1 chain (COL1A1) p = 0.007; secreted frizzled related protein (SFRP2) p = 0.057; fibroblast growth factor 7 (FGF7) not significant (ns); phospholipase A2, group IIA (PLA2G2A) ns; nerve growth factor receptor (NGFR) ns; lymphoid enhancer binding factor 1 (LEF1) p = 0.03; cadherin 1, Type 1, E-cadherin (epithelial) (CDH1) 0.09. Results have highlighted down-regulation of the Wingless/Integrated (Wnt) pathway in mesenteric pAT compared to distal adipose tissue. Highly upregulated genes in mesenteric pAT were involved in extracellular matrix (ECM)-receptor interactions and focal adhesion. Highly down regulated genes were involved in the cell cycle. Immunohistochemistry revealed differential distribution of COL1A1 showing maximum levels in tumour tissue and gradually decreasing in distant adipose tissue. COL1A1 and down regulation of Wnt pathway may have a role in local invasion and distant metastasis. COL1A1 may represent a stromal prognostic biomarker and therapeutic target in colon cancer.

IntroductionDysfunctional adipose tissue has emerged as a key contributor to colorectal cancer. However, the role of peritumoral adipose tissue (pAT) in colon cancer has not been widely investigated. Aim of this study is to identify differentially expressed genes (DEGs) associated with cancer pathways in peritumoral adipose tissue compared with adjacent normal adipose tissue in human colon cancer.MethodsFresh peritumoral and distal adipose tissue samples were collected from 6 patients undergoing surgery for colon cancer stage T3/T4. DEGs were identified employing Nanostring PanCancer Pathway Panel including 770 cancer-associated genes. Criteria for differential expression included p-value <0.05, fold-change greater than 2-fold and average normalised expression greater than 3. Five upregulated DEGs with the highest logarithmic fold change and 2 down regulated genes were validated using quantitative real-time polymerase chain reaction (RT-PCR). Protein expression of significantly DEG was evaluated with immunohistochemistry (IHC) in tumour tissue, peritumour adipose tissue and distal adipose tissue slides.ResultsA total of 64/770 DEGs were identified in peritumoral adipose tissue compared to distal adipose tissue. Up-regulated genes (28.1%) included COL1A1, SFRP2, FGF7, PLA2G2A, NGFR and SFRP2. Down regulated genes (71.9%) included LEF1 and CDH1. Differential expression was validated with qRT-PCR (COL1A1 p=0.007; SFRP2 p=0.057; FGF7 ns; PLA2G2A ns; NGFR ns; LeF1 p=0.03; CDH1 p=0.09). IHC revealed differential distribution of COL1A1 showing maximum expression in tumor tissue decreasing at more distant sites.ConclusionOur results have shown altered cancer associated pathways in peritumour stromal compartment, including down-regulation of Wingless/Integrated (WNT) pathway. Furthermore, we have identified significant up regulation of COL1A1 in peritumour adipose tissue compared to distal adipose tissue. COL1A1 may have a role in local invasion and distant metastasis, possibly mediated by SFRP2, a known pro-collagen c proteinase enhancer and WNT antagonist. SFRP2 and COL1A1 may represent potential stromal therapeutic targets in colon cancer.

Two types of adipose tissue exist: white (WAT) and brown (BAT). WAT stores energy while BAT consumes fatty acids and produces heat by non-shivering thermogenesis through Uncoupling Protein 1 (UCP1). BAT and WAT cooperate in maintaining energy homeostasis balance. Understanding their physiology is important for the development of treatments against diseases where this equilibrium is compromised, such as obesity and associated metabolic disorders. MicroRNAs (miRNAs) are potent gene regulators and an increasing body of evidence suggests their involvement in adipogenesis and adipose metabolism. MiRNAs can also be secreted into the extracellular environment and be taken up by distal cells, mediating cell-to-cell communication. However, very little is known about adipose tissue-derived circulating miRNAs. Through miRNA PCR array analysis we identified several miRNAs that are differentially secreted among undifferentiated and differentiated brown and white adipocytes, such as miR-196a, 378a-3p and miR-138-5p. Bioinformatics target prediction revealed that these miRNAs are potentially involved in important processes regulating the functioning of adipose tissue and its cross-talk with distal cells. Among the predicted targets of miR-196a, we identified ADAM10 (A Disintegrin And Metalloproteinase Domain-containing protein 10). This protein is responsible for the proteolytic release of several cell-surface proteins involved in numerous biological processes such as inflammation and its role could be of relevant importance in the physiopathology of the adipose tissues.

Adipogenesis is a highly organised series of events that facilitates the healthy expansion of adipose tissue, beginning during embryogenesis and continuing throughout life. White adipogenesis protects against lipotoxicity, influencing insulin resistance and obesity-related comorbidities. Brown adipogenesis enhances energy expenditure, thereby counteracting weight gain, lipotoxicity and insulin resistance. Recently, there has been a significant increase in interest regarding adipocyte differentiation, mainly focusing on the interplay between microRNAs (miRNAs) and the transcriptional cascade that governs adipogenesis and metabolic dysfunction. This study aimed to identify miRNAs regulating white and brown adipocyte differentiation and define miRNA action in a stem cell model of adipogenesis. Small RNAseq analysis of primary mouse brown and white adipocytes (WAs) identified miR-10b to be upregulated in mature brown adipocytes (BAs). We generated two model systems: 1) immortalized brown pre-adipocytes treated with miRNA inhibitors and 2) CRISPR/Cas9 KO of miR-10b in E14 mouse embryonic stem cells (mESCs). Both cell models were differentiated into mature adipocytes. To unravel the pathways that are affected by miR-10b depletion, a transcriptomic analysis was performed at key time points. Both cell models showed that miR-10b-5p depletion severely impaired differentiation into mature adipocytes, as indicated by a lack of lipid droplet formation and reduced adipogenic gene expression. Gene expression analysis supports that miR-10b-5p directs embryonic stem (ES) cells towards the mesoderm lineage, promoting commitment to pre-adipocytes by downregulating Gata6 and its downstream target Bmp2. This mechanism appears to be unaffected in BAs. Our study demonstrated that miR-10b-5p regulates the later stages of adipogenesis, at least in part, by downregulating Tub, a direct target of miR-10b-5p. We also confirmed that miR-10b-5p alleviated the halted differentiation phenotypes of adipocytes by supressing the G Protein Signalling pathway mediated by Tubby. These results evidence that miR-10b inhibition plays a dynamic role in adipocyte biology, as its inhibitory effects manifest differently during the stem cell preadipocyte proliferation state and during the maturation phase of adipocytes. Collectively, our study demonstrated that miR-10b-5p may represent a new potential therapeutic target for lipodystrophy and obesity.

G protein-coupled receptors (GPCRs) play key roles in physiology and are central targets for drug discovery and development, yet the design of protein agonists and antagonists has been challenging as GPCRs are integral membrane proteins and conformationally dynamic. Here we describe computational design methods and a high throughput \"receptor diversion\" microscopy-based screen for generating GPCR binding miniproteins with high affinity, potency and selectivity, and the use of these methods to generate MRGPRX1 agonists and CXCR4, GLP1R, GIPR, GCGR and CGRPR antagonists. Cryo-electron microscopy data reveals atomic-level agreement between designed and experimentally determined structures for CGRPR-bound antagonists and MRGPRX1-bound agonists, confirming precise conformational control of receptor function. Our design and screening approach opens new frontiers in GPCR drug discovery and development.

Conservation and restoration of cultural heritage is something more than a simple process of maintaining the existing. It is an integral part of the improvement of the cultural asset. The social context around the restoration shapes the specific actions. Today, preservation, restoration, enhancement of cultural heritage are increasingly a multidisciplinary science, meeting point of researchers coming from heterogeneous study areas. Data scientists and Information technology (IT) specialists are increasingly important. In this context, networks of a new generation of smart sensors integrated with data mining and artificial intelligence play a crucial role and aim to become the new skin of cultural assets.

It is well established that somatic genomic changes can influence phenotypes in cancer, but the role of adaptive changes in developmental disorders is less well understood. Here we have used next-generation sequencing approaches to identify de novo heterozygous mutations in sterile α motif domain-containing protein 9 (SAMD9, located on chromosome 7q21.2) in 8 children with a multisystem disorder termed MIRAGE syndrome that is characterized by intrauterine growth restriction (IUGR) with gonadal, adrenal, and bone marrow failure, predisposition to infections, and high mortality. These mutations result in gain of function of the growth repressor product SAMD9. Progressive loss of mutated SAMD9 through the development of monosomy 7 (-7), deletions of 7q (7q-), and secondary somatic loss-of-function (nonsense and frameshift) mutations in SAMD9 rescued the growth-restricting effects of mutant SAMD9 proteins in bone marrow and was associated with increased length of survival. However, 2 patients with -7 and 7q- developed myelodysplastic syndrome, most likely due to haploinsufficiency of related 7q21.2 genes. Taken together, these findings provide strong evidence that progressive somatic changes can occur in specific tissues and can subsequently modify disease phenotype and influence survival. Such tissue-specific adaptability may be a more common mechanism modifying the expression of human genetic conditions than is currently recognized.

We prove the existence of entire, radial, and signed bounded solutions for a quasilinear elliptic equation in driven by a Leray-Lions operator of the ( )-type. For this, we need an extension of related results by Boccardo-Murat-Puel and a variational approach in intersections of Banach spaces introduced by Candela-Palmieri.