Molecular analysis of the vaginal response to estrogens in the ovariectomized rat and postmenopausal woman

<p>Abstract</p> <p>Background</p> <p>Vaginal atrophy (VA) is the thinning of the vaginal epithelial lining, typically the result of lowered estrogen levels during menopause. Some of the consequences of VA include increased susceptibility to bacterial infection, pain during sexual intercourse, and vaginal burning or itching. Although estrogen treatment is highly effective, alternative therapies are also desired for women who are not candidates for post-menopausal hormone therapy (HT). The ovariectomized (OVX) rat is widely accepted as an appropriate animal model for many estrogen-dependent responses in humans; however, since reproductive biology can vary significantly between mammalian systems, this study examined how well the OVX rat recapitulates human biology.</p> <p>Methods</p> <p>We analyzed 19 vaginal biopsies from human subjects pre and post 3-month 17β-estradiol treated by expression profiling. Data were compared to transcriptional profiling generated from vaginal samples obtained from ovariectomized rats treated with 17β-estradiol for 6 hrs, 3 days or 5 days. The level of differential expression between pre- vs. post- estrogen treatment was calculated for each of the human and OVX rat datasets. Probe sets corresponding to orthologous rat and human genes were mapped to each other using NCBI Homologene.</p> <p>Results</p> <p>A positive correlation was observed between the rat and human responses to estrogen. Genes belonging to several biological pathways and GO categories were similarly differentially expressed in rat and human. A large number of the coordinately regulated biological processes are already known to be involved in human VA, such as inflammation, epithelial development, and EGF pathway activation.</p> <p>Conclusion</p> <p>At the transcriptional level, there is evidence of significant overlap of the effects of estrogen treatment between the OVX rat and human VA samples.</p

A Phase Ib Study of the VEGF Receptor Tyrosine Kinase Inhibitor Tivozanib and Modified FOLFOX-6 in Patients With Advanced Gastrointestinal Malignancies

Combining a modified (m)FOLFOX-6 (leucovorin, 5-fluorouracil [5-FU], and 85 mg/kg(2) oxaliplatin) regimen with antiangiogenic therapy is a standard treatment option in advanced colorectal cancer. In this phase Ib study, safety, pharmacokinetics, and antitumor activity of tivozanib with mFOLFOX-6 were assessed. Tivozanib could be combined at its recommended dose Of 1.5 mg with mFOLFOX-6, demonstrating antitumor activity, A randomized study in advanced colorectal Cancer comparing bevacizumab and tivozanib with mFOLFOX-6 has been performed. Background: Tivozanib hydrochloride (tivozanib) is a potent and selective tyrosine kinase inhibitor of all 3 vascular endothelial growth factor receptors with antitumor activity additive to 5-fluorouracil in preclinical models. This study was conducted to determine maximum tolerated dose (MTD), dose-limiting toxicities (DLTs), pharmacokinetics (PKs), and antitumor activity of escalating doses of tivozanib with a modified (m)FOLFOX-6 (leucovorin, 5-fluorouracil [5-FU], and 85 mg/kg(2) oxaliplatin) regimen in patients with advanced gastrointestinal tumors. Patients and Methods: Tivozanib was administered orally once daily for 21 days in 28-day cycles, with mFOLFOX-6 administered every 14 days. Patients were allowed to continue tivozanib after discontinuation of mFOLFOX-6. Results: Thirty patients were assigned to tivozanib 0.5 mg (n = 9); 1.0 mg (n = 3); or 1.5 mg (n = 18) with mFOLFOX-6. Patients received a median of 5.2 (range, 0.03-26.9) months of tivozanib. DLTs were observed in 2 patients: Grade 3/4 transaminase level increases with tivozanib 0.5 mg, and Grade 3 dizziness with tivozanib 1.5 mg. Other Grade 3/4 adverse events included hypertension (n = 8); fatigue (n = 8), and neutropenia (n = 6): MTD for tivozanib with mFOLFOX-6 was confirmed as 1.5 mg. No PK interactions between tivozanib and mFOLFOX-6 were observed. One patient had an ongoing clinical complete response, 10 had a partial response, and 11 obtained prolonged stable disease. Conclusion: Tivozanib and mFOLFOX-6 is feasible and appears to be safe. The recommended dose for tivozanib with mFOLFOX-6 is 1.5 mg/d. Observed clinical activity merits further exploration in gastrointestinal tumors

Messenger RNA levels for (A) , (B) , (C) , (D) , (E) and (F) are shown for each individual treatment

<p><b>Copyright information:</b></p><p>Taken from "Molecular analysis of the vaginal response to estrogens in the ovariectomized rat and postmenopausal woman"</p><p>http://www.biomedcentral.com/1755-8794/1/27</p><p>BMC Medical Genomics 2008;1():27-27.</p><p>Published online 25 Jun 2008</p><p>PMCID:PMC2453134.</p><p></p

Plotted is the normalized t-statistics for differential expression on the x-axis plotted against the fraction of the gene set that has that x-value or lower on the y-axis

Gene sets that are shifted away from the plot of the entire data set are considered to be significant. (A) Genes involved in TGFβ signaling are down regulated in both species. (B) Genes involved in cholesterol biosynthesis are up regulated in both species.<p><b>Copyright information:</b></p><p>Taken from "Molecular analysis of the vaginal response to estrogens in the ovariectomized rat and postmenopausal woman"</p><p>http://www.biomedcentral.com/1755-8794/1/27</p><p>BMC Medical Genomics 2008;1():27-27.</p><p>Published online 25 Jun 2008</p><p>PMCID:PMC2453134.</p><p></p

A scatterplot of the average t-statistic of estradiol treated vaginal tissue compared to untreated vaginal tissue for each of the human gene sets compared to the average t-statistic for each of the rat gene sets

Each point represents a distinct gene set. A positive correlation is seen suggesting many of the gene sets are coordinately regulated. Gene sets in the upper right and lower left corners represent gene sets that are significantly regulated in both rat and human.<p><b>Copyright information:</b></p><p>Taken from "Molecular analysis of the vaginal response to estrogens in the ovariectomized rat and postmenopausal woman"</p><p>BMC Medical Genomics 2008;1():27-27.</p><p>Published online 25 Jun 2008</p><p>PMCID:PMC2453134.</p><p></p

Molecular Classification of Crohn’s Disease and Ulcerative Colitis Patients Using Transcriptional Profiles in Peripheral Blood Mononuclear Cells

Ulcerative colitis (UC) and Crohn’s disease (CD) are common inflammatory bowel diseases producing intestinal inflammation and tissue damage. Although emerging evidence suggests these diseases are distinct, ∼10% of patients remain classified as indeterminate inflammatory bowel disease even after invasive colonoscopy intended for diagnosis. A molecular diagnostic assay using a clinically accessible tissue would greatly assist in the classification of these diseases. In the present study we assessed transcriptional profiles in peripheral blood mononuclear cells from 42 healthy individuals, 59 CD patients, and 26 UC patients by hybridization to microarrays interrogating more than 22,000 sequences. Supervised analysis identified a set of 12 genes that distinguished UC and CD patient samples with high accuracy. The alterations in transcript levels observed by microarray were verified by real-time polymerase chain reaction. The results suggest that a peripheral blood mononuclear cell-based gene expression signature can provide a molecular biomarker that can complement the standard dia-gnosis of UC and CD