TGF-β receptor levels regulate the specificity of signaling pathway activation and biological effects of TGF-β

AbstractTGF-β is a pluripotent cytokine that mediates its effects through a receptor composed of TGF-β receptor type II (TGFBR2) and type I (TGFBR1). The TGF-β receptor can regulate Smad and nonSmad signaling pathways, which then ultimately dictate TGF-β's biological effects. We postulated that control of the level of TGFBR2 is a mechanism for regulating the specificity of TGF-β signaling pathway activation and TGF-β's biological effects. We used a precisely regulatable TGFBR2 expression system to assess the effects of TGFBR2 expression levels on signaling and TGF-β mediated apoptosis. We found Smad signaling and MAPK–ERK signaling activation levels correlate directly with TGFBR2 expression levels. Furthermore, p21 levels and TGF-β induced apoptosis appear to depend on relatively high TGFBR2 expression and on the activation of the MAPK–ERK and Smad pathways. Thus, control of TGFBR2 expression and the differential activation of TGF-β signaling pathways appears to be a mechanism for regulating the specificity of the biological effects of TGF-β

Barrett's oesophagus: Epidemiology, cancer risk and implications for management

Although endoscopic surveillance of patients with Barrett's oesophagus has been widely implemented, its effectiveness is debateable. The recently reported low annual oesophageal adenocarcinoma risk in population studies, the failure to identify most Barrett's patients at risk of disease progression, the poor adherence to surveillance and biopsy protocols, and the significant risk of misclassification of dysplasia all tend to undermine the effectiveness of current management, in particular, endoscopic surveillance programmes, to prevent or improve the outcomes of patients with oesophageal adenocarcinoma. The ongoing increase in incidence of Barrett's oesophagus and consequent growth of the surveillance population, together with the associated discomfort and costs of endoscopic surveillance, demand improved techniques for accurately determining individual risk of oesophageal adenocarcinoma. More accurate techniques are needed to run efficient surveillance programmes in the coming decades. In this review, we will discuss the current knowledge on the epidemiology of Barrett's oesophagus, and the challenging epidemiological dilemmas that need to be addressed when a

TGF-beta has paradoxical and context dependent effects on proliferation and anoikis in human colorectal cancer cell lines.

Transforming growth factor-beta (TGF-beta) is a pluripotent cytokine that can have both tumor suppressing and tumor promoting effects on epithelial cells. It is unclear what determines when TGF-beta and its signaling pathway act predominantly as a tumor suppressor pathway or as a tumor-promoter pathway and whether TGF-beta can have both classes of effects concurrently on a cell. We investigated the effect of TGF-beta on anoikis in colorectal cancer cell lines sensitive to TGF-beta-mediated growth inhibition to determine if the context of the cells could be one of the factors that would affect whether TGF-beta exerts tumor suppressor or oncogene activity on colon cancer cells. We observed variable effects of TGF-beta on anoikis in these cell lines, even though they all are growth-inhibited by TGF-beta. Thus, we show that TGF-beta has variable effects on anoikis in colon cancer cell lines that likely reflects the effects of concurrent gene mutations in the cancer cells and the activation state of the signaling pathways controlled by these genes

Growth Rates and Histopathological Outcomes of Small (6-9 MM) Colorectal Polyps Based on CT Colonography Surveillance and Endoscopic Removal

BACKGROUND AND AIMS: The natural history of small polyps is not well established and rests on limited evidence from barium enema studies decades ago. Patients with one or two small polyps (6-9 mm) at screening CT colonography (CTC) are offered CTC surveillance at 3 years but may elect immediate colonoscopy. This practice allows direct observation of the growth of subcentimetre polyps, with histopathological correlation in patients undergoing subsequent polypectomy. DESIGN: Of 11 165 asymptomatic patients screened by CTC over a period of 16.4 years, 1067 had one or two 6-9 mm polyps detected (with no polyps ≥10 mm). Of these, 314 (mean age, 57.4 years; M:F, 141:173; 375 total polyps) elected immediate colonoscopic polypectomy, and 382 (mean age 57.0 years; M:F, 217:165; 481 total polyps) elected CTC surveillance over a mean of 4.7 years. Volumetric polyp growth was analysed, with histopathological correlation for resected polyps. Polyp growth and regression were defined as volume change of ±20% per year, with rapid growth defined as +100% per year (annual volume doubling). Regression analysis was performed to evaluate predictors of advanced histology, defined as the presence of cancer, high-grade dysplasia (HGD) or villous components. RESULTS: Of the 314 patients who underwent immediate polypectomy, 67.8% (213/314) harboured adenomas, 2.2% (7/314) with advanced histology; no polyps contained cancer or HGD. Of 382 patients who underwent CTC surveillance, 24.9% (95/382) had polyps that grew, while 62.0% (237/382) remained stable and 13.1% (50/382) regressed in size. Of the 58.6% (224/382) CTC surveillance patients who ultimately underwent colonoscopic resection, 87.1% (195/224) harboured adenomas, 12.9% (29/224) with advanced histology. Of CTC surveillance patients with growing polyps who underwent resection, 23.2% (19/82) harboured advanced histology vs 7.0% (10/142) with stable or regressing polyps (OR: 4.0; p CONCLUSION: Small 6-9 mm polyps present overall low risk to patients, with polyp growth strongly associated with higher risk lesions. Most patients (75%) with small 6-9 mm polyps will see polyp stability or regression, with advanced histology seen in only 7%. The minority of patients (25%) with small polyps that do grow have a 3-fold increased risk of advanced histology

Wavelength-Dependent Extinction and Grain Sizes in Dippers

We have examined inter-night variability of K2-discovered Dippers that are not close to being viewed edge-on, as determined from previously-reported ALMA images, using the SpeX spectrograph and the NASA Infrared Telescope facility (IRTF). The three objects observed were EPIC 203850058, EPIC 205151387, and EPIC 204638512 (2MASS J16042165-2130284). Using the ratio of the fluxes between two successive nights, we find that for EPIC 204638512 and EPIC 205151387, we find that the properties of the dust differ from that seen in the diffuse interstellar medium and denser molecular clouds. However, the grain properties needed to explain the extinction does resemble those used to model the disks of many young stellar objects. The wavelength-dependent extinction models of both EPIC 204638512 and EPIC 205151387 includes grains at least 500 microns in size, but lacks grains smaller than 0.25 microns. The change in extinction during the dips, and the timescale for these variations to occur, imply obscuration by the surface layers of the inner disks. The recent discovery of a highly mis-inclined inner disk in EPIC 204638512 is suggests that the variations in this disk system may point to due to rapid changes in obscuration by the surface layers of its inner disk, and that other face-on Dippers might have similar geometries. The He I line at 1.083 microns in EPIC 205151387 and EPIC 20463851 were seen to change from night to night, suggesting that we are seeing He I gas mixed in with the surface dust.Comment: 13 pages, 6 figures, 2 table

Altered RECQ Helicase Expression in Sporadic Primary Colorectal Cancers

AbstractDeregulation of DNA repair enzymes occurs in cancers and may create a susceptibility to chemotherapy. Expression levels of DNA repair enzymes have been shown to predict the responsiveness of cancers to certain chemotherapeutic agents. The RECQ helicases repair damaged DNA including damage caused by topoisomerase I inhibitors, such as irinotecan. Altered expression levels of these enzymes in colorectal cancer (CRC) may influence the response of the cancers to irinotecan. Thus, we assessed RECQ helicase (WRN, BLM, RECQL, RECQL4, and RECQL5) expression in primary CRCs, matched normal colon, and CRC cell lines. We found that BLM and RECQL4 mRNA levels are significantly increased in CRC (P = .0011 and P < .0001, respectively), whereas RECQL and RECQL5 are significantly decreased (P = .0103 and P = .0029, respectively). RECQ helicase expression patterns varied between specific molecular subtypes of CRCs. The mRNA and protein expression of the majority of the RECQ helicases was closely correlated, suggesting that altered mRNA expression is the predominant mechanism for deregulated RECQ helicase expression. Immunohistochemistry localized the RECQ helicases to the nucleus. RECQ helicase expression is altered in CRC, suggesting that RECQ helicase expression has potential to identify CRCs that are susceptible to specific chemotherapeutic agents

Differences in the gas and dust distribution in the transitional disk of a sun-like young star, PDS 70

We present ALMA 0.87 mm continuum, HCO+ J=4--3 emission line, and CO J=3--2 emission line data of the disk of material around the young, Sun-like star PDS 70. These data reveal the existence of a possible two component transitional disk system with a radial dust gap of 0."2 +/- 0."05, an azimuthal gap in the HCO+ J=4--3 moment zero map, as well as two bridge-like features in the gas data. Interestingly these features in the gas disk have no analogue in the dust disk making them of particular interest. We modeled the dust disk using the Monte Carlo radiative transfer code HOCHUNK3D (Whitney et al. 2013) using a two disk components. We find that there is a radial gap that extends from 15-60 au in all grain sizes which differs from previous work

Variability of Disk Emission in Pre-Main Sequence and Related Stars IV. Investigating the Structural Changes in the Inner Disk Region of MWC 480

We present five epochs of near IR observations of the protoplanetary disk around MWC 480 (HD31648) obtained with the SpeX spectrograph on NASA's Infrared Telescope Facility (IRTF) between 2007 and 2013, inclusive. Using the measured line fluxes in the Pa beta and Br gamma lines, we found the mass accretion rates to be (1.43 - 2.61)x10^-8 Msun y^-1 and (1.81 - 2.41)x10^-8 Msun y^-1 respectively, but which varied by more than 50% from epoch to epoch. The spectral energy distribution (SED)reveals a variability of about 30% between 1.5 and 10 microns during this same period of time. We investigated the variability using of the continuum emission of the disk in using the Monte-Carlo Radiative Transfer Code (MCRT) HOCHUNK3D. We find that varying the height of the inner rim successfully produces a change in the NIR flux, but lowers the far IR emission to levels below all measured fluxes. Because the star exhibits bipolar flows, we utilized a structure that simulates an inner disk wind to model the variability in the near IR, without producing flux levels in the far IR that are inconsistent with existing data. For this object, variable near IR emission due to such an outflow is more consistent with the data than changing the scale height of the inner rim of the disk.Comment: 19 pages, 14 figure

Disturbed sleep is associated with reduced verbal episodic memory and entorhinal cortex volume in younger middle-aged women with risk-reducing early ovarian removal

INTRODUCTION: Women with early ovarian removal (&lt;48 years) have an elevated risk for both late-life Alzheimer's disease (AD) and insomnia, a modifiable risk factor. In early midlife, they also show reduced verbal episodic memory and hippocampal volume. Whether these reductions correlate with a sleep phenotype consistent with insomnia risk remains unexplored.METHODS: We recruited thirty-one younger middleaged women with risk-reducing early bilateral salpingo-oophorectomy (BSO), fifteen of whom were taking estradiol-based hormone replacement therapy (BSO+ERT) and sixteen who were not (BSO). Fourteen age-matched premenopausal (AMC) and seventeen spontaneously peri-postmenopausal (SM) women who were ~10y older and not taking ERT were also enrolled. Overnight polysomnography recordings were collected at participants' home across multiple nights (M=2.38 SEM=0.19), along with subjective sleep quality and hot flash ratings. In addition to group comparisons on sleep measures, associations with verbal episodic memory and medial temporal lobe volume were assessed.RESULTS: Increased sleep latency and decreased sleep efficiency were observed on polysomnography recordings of those not taking ERT, consistent with insomnia symptoms. This phenotype was also observed in the older women in SM, implicating ovarian hormone loss. Further, sleep latency was associated with more forgetting on the paragraph recall task, previously shown to be altered in women with early BSO. Both increased sleep latency and reduced sleep efficiency were associated with smaller anterolateral entorhinal cortex volume.DISCUSSION: Together, these findings confirm an association between ovarian hormone loss and insomnia symptoms, and importantly, identify an younger onset age in women with early ovarian removal, which may contribute to poorer cognitive and brain outcomes in these women.</p