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

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

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

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

Rare loss of function variants in candidate genes and risk of colorectal cancer

Although ~ 25% of colorectal cancer or polyp (CRC/P) cases show familial aggregation, current germline genetic testing identifies a causal genotype in the 16 major genes associated with high penetrance CRC/P in only 20% of these cases. As there are likely other genes underlying heritable CRC/P, we evaluated the association of variation at novel loci with CRC/P. We evaluated 158 a priori selected candidate genes by comparing the number of rare potentially disruptive variants (PDVs) found in 84 CRC/P cases without an identified CRC/P risk-associated variant and 2440 controls. We repeated this analysis using an additional 73 CRC/P cases. We also compared the frequency of PDVs in select genes among CRC/P cases with two publicly available data sets. We found a significant enrichment of PDVs in cases vs. controls: 20% of cases vs. 11.5% of controls with ≥ 1 PDV (OR = 1.9, p = 0.01) in the original set of cases. Among the second cohort of CRC/P cases, 18% had a PDV, significantly different from 11.5% (p = 0.02). Logistic regression, adjusting for ancestry and multiple testing, indicated association between CRC/P and PDVs in NTHL1 (p = 0.0001), BRCA2 (p = 0.01) and BRIP1 (p = 0.04). However, there was no significant difference in the frequency of PDVs at each of these genes between all 157 CRC/P cases and two publicly available data sets. These results suggest an increased presence of PDVs in CRC/P cases and support further investigation of the association of NTHL1, BRCA2 and BRIP1 variation with CRC/P