A New Probe of the Planet-Forming Region in T Tauri Disks

We present new observations of the FUV (1100-2200 Angstrom) radiation field and the near- to mid-IR (3--13.5 micron) spectral energy distribution (SED) of a sample of T Tauri stars selected on the basis of bright molecular disks (GM Aur, DM Tau, LkCa15). In each source we find evidence for Ly alpha induced H2 fluorescence and an additional source of FUV continuum emission below 1700 Angstroms. Comparison of the FUV spectra to a model of H2 excitation suggests that the strong continuum emission is due to electron impact excitation of H2. The ultimate source of this excitation is likely X-ray irradiation which creates hot photo-electrons mixed in the molecular layer. Analysis of the SED of each object finds the presence of inner disk gaps with sizes of a few AU in each of these young (~1 Myr) stellar systems. We propose that the presence of strong H2 continuum emission and inner disk clearing are related by the increased penetration power of high energy photons in gas rich regions with low grain opacity.Comment: 5 pages, 3 figures, accepted by ApJ Letter

Targeting RRM2 and mutant BRAF is a novel combinatorial strategy for melanoma

© 2016 American Association for Cancer Research.The majority of patients with melanoma harbor mutations in the BRAF oncogene, thus making it a clinically relevant target. However, response to mutant BRAF inhibitors (BRAFi) is relatively short-lived with progression-free survival of only 6 to 7 months. Previously, we reported high expression of ribonucleotide reductase M2 (RRM2), which is rate-limiting for de novo dNTP synthesis, as a poor prognostic factor in patients with mutant BRAF melanoma. In this study, the notion that targeting de novo dNTP synthesis through knockdown of RRM2 could prolong the response of melanoma cells to BRAFi was investigated. Knockdown of RRM2 in combination with the mutant BRAFi PLX4720 (an analog of the FDA-approved drug vemurafenib) inhibited melanoma cell proliferation to a greater extent than either treatment alone. This occurred in vitro in multiple mutant BRAF cell lines and in a novel patient-derived xenograft (PDX) model system. Mechanistically, the combination increased DNA damage accumulation, which correlated with a global decrease in DNA damage repair (DDR) gene expression and increased apoptotic markers. After discontinuing PLX4720 treatment, cells showed marked recurrence. However, knockdown of RRM2 attenuated this rebound growth both in vitro and in vivo, which correlated with maintenance of the senescence-associated cell-cycle arrest. Implications: Inhibition of RRM2 converts the transient response of melanoma cells to BRAFi to a stable response and may be a novel combinatorial strategy to prolong therapeutic response of patients with melanoma

High-Contrast NIR Polarization Imaging of MWC480

One of the key predictions of modeling from the IR excess of Herbig Ae stars is that for protoplanetary disks, where significant grain growth and settling has occurred, the dust disk has flattened to the point that it can be partially or largely shadowed by the innermost material at or near the dust sublimation radius. When the self-shadowing has already started, the outer disk is expected to be detected in scattered light only in the exceptional cases that the scale height of the dust disk at the sublimation radius is smaller than usual. High-contrast imaging combined with the IR spectral energy distribution allow us to measure the degree of flattening of the disk, as well as to determine the properties of the outer disk. We present polarimetric differential imaging in $H$ band obtained with Subaru/HiCIAO of one such system, MWC 480. The HiCIAO data were obtained at a historic minimum of the NIR excess. The disk is detected in scattered light from 0\farcs2-1\farcs0 (27.4-137AU). Together with the marginal detection of the disk from 1998 February 24 by HST/NICMOS, our data constrain the opening half angle for the disk to lie between 1.3$\leq\theta\leq 2.2^\circ$. When compared with similar measures in CO for the gas disk from the literature, the dust disk subtends only $\sim$30% of the gas disk scale height (H/R$\sim$0.03). Such a dust disk is a factor of 5-7 flatter than transitional disks, which have structural signatures that giant planets have formed.Comment: 21 pages, 6 figures, 1 table, ApJ accepted 2012-05-0

Variability of Disk Emission in Pre-Main Sequence and Related Stars. I. HD 31648 and HD 163296 - Isolated Herbig Ae Stars Driving Herbig-Haro Flows

Infrared photometry and spectroscopy covering a time span of a quarter century are presented for HD 31648 (MWC 480) and HD 163296 (MWC 275). Both are isolated Herbig Ae stars that exhibit signs of active accretion, including driving bipolar flows with embedded Herbig-Haro (HH) objects. HD 163296 was found to be relatively quiescent photometrically in its inner disk region, with the exception of a major increase in emitted flux in a broad wavelength region centered near 3 microns in 2002. In contrast, HD 31648 has exhibited sporadic changes in the entire 3-13 micron region throughout this span of time. In both stars the changes in the 1-5 micron flux indicate structural changes in the region of the disk near the dust sublimation zone, possibly causing its distance from the star to vary with time. Repeated thermal cycling through this region will result in the preferential survival of large grains, and an increase in the degree of crystallinity. The variability observed in these objects has important consequences for the interpretation of other types of observations. For example, source variability will compromise models based on interferometry measurements unless the interferometry observations are accompanied by nearly-simultaneous photometric data.Comment: 55 pages, 18 figures, 2 tables, Accepted by Ap

Cancer initiation and progression: an unsimplifiable complexity

BACKGROUND: Cancer remains one of the most complex diseases affecting humans and, despite the impressive advances that have been made in molecular and cell biology, how cancer cells progress through carcinogenesis and acquire their metastatic ability is still widely debated. CONCLUSION: There is no doubt that human carcinogenesis is a dynamic process that depends on a large number of variables and is regulated at multiple spatial and temporal scales. Viewing cancer as a system that is dynamically complex in time and space will, however, probably reveal more about its underlying behavioural characteristics. It is encouraging that mathematicians, biologists and clinicians continue to contribute together towards a common quantitative understanding of cancer complexity. This way of thinking may further help to clarify concepts, interpret new and old experimental data, indicate alternative experiments and categorize the acquired knowledge on the basis of the similarities and/or shared behaviours of very different tumours

Risky sexual practices and related factors among ART attendees in Addis Ababa Public Hospitals, Ethiopia: A cross-sectional study

Background Many HIV-positive persons avoid risky sexual practices after testing HIV sero-positive. However, a substantial number continue to engage in risky sexual practices that may further transmit the virus, put them at risk of contracting secondary sexually transmitted infections and lead to problems with drug resistance. Thus, this study was intended to assess risky sexual practices and related factors among HIV- positive ART attendees in public hospitals of Addis Ababa. Methods A cross-sectional study was conducted among ART attendees from February to March, 2009. Questionnaire-based face-to-face interviews were used to gather data. SPSS software was used to perform descriptive and logistic regression analyses. Results Six hundred and one ART attendees who fulfilled the inclusion criteria was included in the study and interviewed. More than one-third (36.9%) had a history of risky sexual practices in the three months prior to the study. The major reasons given for not using condoms were: partner's dislike of them, both partners being positive for HIV and the desire to have a child. Factors associated with risky sexual practices included: lack of discussion about condom use (Adjusted Odds Ratio (AOR = 7.23, 95% CI: 4.14, 12.63); lack of self-efficacy in using condoms (AOR = 3.29, 95% CI: 2.07, 5.23); lack of sexual pleasure when using a condom (AOR = 2.39, 95% CI: 1.52, 3.76); and multiple sexual partners (AOR = 2.67, 95% CI: 1.09, 6.57). Being with a negative sero-status partner (AOR = 0.33, 95% CI: 0.14, 0.80), or partners of unknown sero-status (AOR = 0.19, 95% CI: 0.09, 0.39) were associated with less risky practice. Conclusions A considerable proportion (36.9%) of respondents engaged in unprotected sexual intercourse, potentially resulting in re-infection by a new virus strain, other sexually transmitted infections and onward transmission of the HIV virus. Health education and counseling which focuses on the identified factors has to be provided. The health education and counseling can be provided to these people at ART appointments on follow- up care. It can be provided in a one-on-one basis or through patient group educational discussions at the clinics

Targeting RRM2 and mutant BRAF is a novel combinatorial strategy for melanoma

© 2016 American Association for Cancer Research.The majority of patients with melanoma harbor mutations in the BRAF oncogene, thus making it a clinically relevant target. However, response to mutant BRAF inhibitors (BRAFi) is relatively short-lived with progression-free survival of only 6 to 7 months. Previously, we reported high expression of ribonucleotide reductase M2 (RRM2), which is rate-limiting for de novo dNTP synthesis, as a poor prognostic factor in patients with mutant BRAF melanoma. In this study, the notion that targeting de novo dNTP synthesis through knockdown of RRM2 could prolong the response of melanoma cells to BRAFi was investigated. Knockdown of RRM2 in combination with the mutant BRAFi PLX4720 (an analog of the FDA-approved drug vemurafenib) inhibited melanoma cell proliferation to a greater extent than either treatment alone. This occurred in vitro in multiple mutant BRAF cell lines and in a novel patient-derived xenograft (PDX) model system. Mechanistically, the combination increased DNA damage accumulation, which correlated with a global decrease in DNA damage repair (DDR) gene expression and increased apoptotic markers. After discontinuing PLX4720 treatment, cells showed marked recurrence. However, knockdown of RRM2 attenuated this rebound growth both in vitro and in vivo, which correlated with maintenance of the senescence-associated cell-cycle arrest. Implications: Inhibition of RRM2 converts the transient response of melanoma cells to BRAFi to a stable response and may be a novel combinatorial strategy to prolong therapeutic response of patients with melanoma

Targeting RRM2 and mutant BRAF is a novel combinatorial strategy for melanoma

© 2016 American Association for Cancer Research.The majority of patients with melanoma harbor mutations in the BRAF oncogene, thus making it a clinically relevant target. However, response to mutant BRAF inhibitors (BRAFi) is relatively short-lived with progression-free survival of only 6 to 7 months. Previously, we reported high expression of ribonucleotide reductase M2 (RRM2), which is rate-limiting for de novo dNTP synthesis, as a poor prognostic factor in patients with mutant BRAF melanoma. In this study, the notion that targeting de novo dNTP synthesis through knockdown of RRM2 could prolong the response of melanoma cells to BRAFi was investigated. Knockdown of RRM2 in combination with the mutant BRAFi PLX4720 (an analog of the FDA-approved drug vemurafenib) inhibited melanoma cell proliferation to a greater extent than either treatment alone. This occurred in vitro in multiple mutant BRAF cell lines and in a novel patient-derived xenograft (PDX) model system. Mechanistically, the combination increased DNA damage accumulation, which correlated with a global decrease in DNA damage repair (DDR) gene expression and increased apoptotic markers. After discontinuing PLX4720 treatment, cells showed marked recurrence. However, knockdown of RRM2 attenuated this rebound growth both in vitro and in vivo, which correlated with maintenance of the senescence-associated cell-cycle arrest. Implications: Inhibition of RRM2 converts the transient response of melanoma cells to BRAFi to a stable response and may be a novel combinatorial strategy to prolong therapeutic response of patients with melanoma