PGC-1α induced browning promotes involution and inhibits lactation in mammary glands.

The PPARγ coactivator 1α (PGC-1α) is a transcriptional regulator of mitochondrial biogenesis and oxidative metabolism. Recent studies have highlighted a fundamental role of PGC-1α in promoting breast cancer progression and metastasis, but the physiological role of this coactivator in the development of mammary glands is still unknown. First, we show that PGC-1α is highly expressed during puberty and involution, but nearly disappeared in pregnancy and lactation.

Correction to: Paragangliomas arise through an autonomous vasculo-angio-neurogenic program inhibited by imatinib.

The given and family names of two co-authors were incorrect in the published article. The correct spelling should read as: Sampath Chandra Prasad and Vinagolu K Rajasekhar.

Paragangliomas arise through an autonomous vasculo-angio-neurogenic program inhibited by imatinib.

Tumours can be viewed as aberrant tissues or organs sustained by tumorigenic stem-like cells that engage into dysregulated histo/organogenetic processes. Paragangliomas, prototypical organoid tumours constituted by dysmorphic variants of the vascular and neural tissues found in normal paraganglia, provide a model to test this hypothesis. To understand the origin of paragangliomas, we built a biobank comprising 77 cases, 18 primary cultures, 4 derived cell lines, 80 patient-derived xenografts and 11 cell-derived xenografts.

TRIM8 restores p53 tumour suppressor function by blunting N-MYC activity in chemo-resistant tumours.

Background: TRIM8 plays a key role in controlling the p53 molecular switch that sustains the transcriptional activation of cell cycle arrest genes and response to chemotherapeutic drugs. The mechanisms that regulate TRIM8, especially in cancers like clear cell Renal Cell Carcinoma (ccRCC) and colorectal cancer (CRC) where it is low expressed, are still unknown. However, recent studies suggest the potential involvement of some microRNAs belonging to miR-17-92 and its paralogous clusters, which could include TRIM8 in a more complex pathway.

PGC-1β promotes enterocyte lifespan and tumorigenesis in the intestine.

The mucosa of the small intestine is renewed completely every 3-5 d throughout the entire lifetime by small populations of adult stem cells that are believed to reside in the bottom of the crypts and to migrate and differentiate into all the different populations of intestinal cells. When the cells reach the apex of the villi and are fully differentiated, they undergo cell death and are shed into the lumen. Reactive oxygen species (ROS) production is proportional to the electron transfer activity of the mitochondrial respiration chain.

Transcriptional regulation of the intestinal nuclear bile acid farnesoid X receptor (FXR) by the caudal-related homeobox 2 (CDX2).

Farnesoid X receptor (FXR, NR1H4) is a bile acid-activated transcription factor that belongs to the nuclear receptor superfamily. It is highly expressed in the enterohepatic system, where it senses bile acid levels to consequently reduce their synthesis while inducing their detoxification. Bile acids are intestinal tumor promoters and their concentrations have to be tightly regulated.

Prevention of spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice by intestinal-specific farnesoid X receptor reactivation.

Unlabelled: Farnesoid X receptor (FXR) is the master regulator of bile acid (BA) homeostasis because it controls BA synthesis, influx, efflux, and detoxification in the gut/liver axis. Deregulation of BA homeostasis has been linked to hepatocellular carcinoma (HCC), and spontaneous hepatocarcinogenesis has been observed in FXR-null mice. This dreaded liver neoplasm has been associated with both FXR gene deletion and BA-mediated metabolic abnormalities after inactivation of FXR transcriptional activity.

Transient GFER knockdown in vivo impairs liver regeneration after partial hepatectomy.

Background And Aims: Augmenter of Liver Regeneration is a protein encoded by the Growth Factor Erv1-Like gene. Its biological properties are crucial for cell survival since knock-out mice for Growth Factor Erv1-Like gene do not survive. In this study, we injected hepatotropic adenoviral particles harboring oligonucleotide sequences against Growth Factor Erv1-Like gene into 70% partially hepatectomized rats and studied the effect of gene silencing on the progression liver regeneration.

BRCA1 point mutations in premenopausal breast cancer patients from Central Sudan.

Premenopausal breast cancer (BC) is one of the most common cancers of women in rural Africa and part of the disease load may be related to hereditary predisposition, including mutations in the BRCA1 gene. However, the BRCA1 mutations associated with BC in Africa are scarcely characterized. We report here 33 BRCA1 point mutations, among which 2 novel missense variants, found in 59 Central Sudanese premenopausal BC patients.

Integrative genetic, epigenetic and pathological analysis of paraganglioma reveals complex dysregulation of NOTCH signaling.

Head and neck paragangliomas, rare neoplasms of the paraganglia composed of nests of neurosecretory and glial cells embedded in vascular stroma, provide a remarkable example of organoid tumor architecture. To identify genes and pathways commonly deregulated in head and neck paraganglioma, we integrated high-density genome-wide copy number variation (CNV) analysis with microRNA and immunomorphological studies. Gene-centric CNV analysis of 24 cases identified a list of 104 genes most significantly targeted by tumor-associated alterations.

The insulin receptor substrate 1 (IRS1) in intestinal epithelial differentiation and in colorectal cancer.

Colorectal cancer (CRC) is associated with lifestyle factors that affect insulin/IGF signaling, of which the insulin receptor substrate 1 (IRS1) is a key transducer. We investigated expression, localization and pathologic correlations of IRS1 in cancer-uninvolved colonic epithelium, primary CRCs with paired liver metastases and in vitro polarizing Caco2 and HT29 cells. IRS1 mRNA and protein resulted higher, relative to paired mucosa, in adenomas of familial adenomatous polyposis patients and in CRCs that overexpressed c-MYC, ß-catenin, InsRß, and IGF1R.

SEL1L, an UPR response protein, a potential marker of colonic cell transformation.

Background: SEL1L gene product is implicated in the endoplasmic reticulum (ER)-associated protein degradation and Unfolded Protein Response pathways. This gene and associated miRNAs have been indicated as predictive and prognostic markers of pancreatic cancer.

Aim: Explore the role of SEL1L in colorectal cancer (CRC) progression.

Down-regulation of the LXR transcriptome provides the requisite cholesterol levels to proliferating hepatocytes.

Cholesterol homeostasis is critical for cellular proliferation. Liver X receptor (LXR) alpha and beta are the nuclear receptors responsible for regulation of cholesterol metabolism. In physiological conditions, high intracellular cholesterol levels cause increased synthesis of oxysterols, which activate LXR, thus triggering a transcriptional response for cholesterol secretion and catabolism.

High-risk human papilloma virus infection, tumor pathophenotypes, and BRCA1/2 and TP53 status in juvenile breast cancer.

Juvenile breast cancer is rare and poorly known. We studied a series of five breast cancer patients diagnosed within 25 years of age that included two adolescents, 12- and 15-years-old, and 3 young women, 21-, 21-, and 25-years-old, respectively. All cases were scanned for germline mutations along the entire BRCA1/2 coding sequences and TP53 exons 4-10, using protein truncation test, denaturing high performance liquid chromatography and direct sequencing.

Synthesis and biological evaluation of 2-heteroarylthioalkanoic acid analogues of clofibric acid as peroxisome proliferator-activated receptor alpha agonists.

A series of 2-heteroarylthioalkanoic acids were synthesized through systematic structural modifications of clofibric acid and evaluated for human peroxisome proliferator-activated receptor alpha (PPARalpha) transactivation activity, with the aim of obtaining new hypolipidemic compounds. Some thiophene and benzothiazole derivatives showing a good activation of the receptor alpha were screened for activity against the PPARgamma isoform. The gene induction of selected compounds was also investigated in the human hepatoma cell line.

Micellar lipid composition profoundly affects LXR-dependent cholesterol transport across CaCo2 cells.

Intraluminal phospholipids affect micellar solubilization and absorption of cholesterol. We here study cholesterol transport from taurocholate-phospholipid-cholesterol micelles to CaCo2 cells, and associated effects on ABC-A1 mediated cholesterol efflux. Micellar incorporation of egg-yolk-phosphatidylcholine markedly increased apical retention of the sterol with decreased expression of ABC-A1, an effect that is prevented by synthetic liver X receptor (LXR) or retinoid X receptor (RXR) agonists.

Methods for routine diagnosis of genomic rearrangements: multiplex PCR-based methods and future perspectives.

Germline and somatic genomic rearrangement play a relevant role in the pathogenesis of genetic disorders, and their identification is a fundamental task in molecular diagnosis. However, screening for structural genomic abnormalities is often not included in routine mutational analyses and consequently the proportion of rearrangements playing a pathogenic role in several genetic disorders is likely to be underestimated. A wide range of molecular techniques for the detection of large genomic rearrangements has been developed: some methods have the power to screen the whole genome, others are designed to analyze one or few loci that are known to be involved in a specific disease; some may detect balanced rearrangements, while others only unbalanced rearrangements; some are suitable for detection of germline abnormalities, yet others also detect somatic abnormalities.

BRCA1 and BRCA2 status in a Central Sudanese series of breast cancer patients: interactions with genetic, ethnic and reproductive factors.

The etiology of breast cancer in Africa is scarcely investigated. Breast cancer was responsible for 456/2,233 cancer patients (20.4%) ascertained between 1999 and 2004 at Gezira University, Central Sudan.