Selective inhibition of HDAC6 regulates expression of the oncogenic driver EWSR1-FLI1 through the EWSR1 promoter in Ewing sarcoma

Ewing sarcoma (EWS) is an aggressive bone and soft tissue tumor of children and young adults in which the principal driver is a fusion gene, EWSR1-FLI1. Although the essential role of EWSR1-FLI1 protein in the regulation of oncogenesis, survival, and tumor progression processes has been described in-depth, little is known about the regulation of chimeric fusion-gene expression. Here, we demonstrate that the active nuclear HDAC6 in EWS modulates the acetylation status of specificity protein 1 (SP1), consequently regulating the SP1/P300 activator complex binding to EWSR1 and EWSR1-FLI1 promoters. Selective inhibition of HDAC6 impairs binding of the activator complex SP1/P300, thereby inducing EWSR1-FLI1 downregulation and significantly reducing its oncogenic functions. In addition, sensitivity of EWS cell lines to HDAC6 inhibition is higher than other tumor or non-tumor cell lines. High expression of HDAC6 in primary EWS tumor samples from patients correlates with a poor prognosis in two independent series accounting 279 patients. Notably, a combination treatment of a selective HDAC6 and doxorubicin (a DNA damage agent used as a standard therapy of EWS patients) dramatically inhibits tumor growth in two EWS murine xenograft models. These results could lead to suitable and promising therapeutic alternatives for patients with EWS.Research in the E.D.A. lab is supported by Asociación Española Contra el Cáncer (AECC), the Ministry of Science of Spain-FEDER (CIBERONC, PI1700464, PI2000003, RD06/0020/0059)S. D.G.D. and L.H.P. are supported by CIBERONC (CB16/12/00361). D.G.D., M.J.R. and L.H.P. are PhD researchers funded by the Consejería de Salud, Junta de Andalucía (PI-0197-2016, ECAI F2-0012-2018 and PI-0013-2018, respectively).Peer reviewe

Repurposing Anti-Inflammasome NRTIs for Improving Insulin Sensitivity and Reducing Type 2 Diabetes Development

Innate immune signaling through the NLRP3 inflammasome is activated by multiple diabetes-related stressors, but whether targeting the inflammasome is beneficial for diabetes is still unclear. Nucleoside reverse-transcriptase inhibitors (NRTI), drugs approved to treat HIV-1 and hepatitis B infections, also block inflammasome activation. Here, we show, by analyzing five health insurance databases, that the adjusted risk of incident diabetes is 33% lower in patients with NRTI exposure among 128,861 patients with HIV-1 or hepatitis B (adjusted hazard ratio for NRTI exposure, 0.673; 95% confidence interval, 0.638 to 0.710; P \u3c 0.0001; 95% prediction interval, 0.618 to 0.734). Meanwhile, an NRTI, lamivudine, improves insulin sensitivity and reduces inflammasome activation in diabetic and insulin resistance-induced human cells, as well as in mice fed with high-fat chow; mechanistically, inflammasome-activating short interspersed nuclear element (SINE) transcripts are elevated, whereas SINE-catabolizing DICER1 is reduced, in diabetic cells and mice. These data suggest the possibility of repurposing an approved class of drugs for prevention of diabetes

Investigating the Effect of Galaxy Interactions on Star Formation at 0.5<z<3.0

Observations and simulations of interacting galaxies and mergers in the local universe have shown that interactions can significantly enhance the star formation rates (SFR) and fueling of Active Galactic Nuclei (AGN). However, at higher redshift, some simulations suggest that the level of star formation enhancement induced by interactions is lower due to the higher gas fractions and already increased SFRs in these galaxies. To test this, we measure the SFR enhancement in a total of 2351 (1327) massive ($M_*>10^{10}M_\odot$) major ($1<M_1/M_2<4$) spectroscopic galaxy pairs at 0.5<z<3.0 with $\Delta V <5000$ km s$^{-1}$ (1000 km s$^{-1}$) and projected separation <150 kpc selected from the extensive spectroscopic coverage in the COSMOS and CANDELS fields. We find that the highest level of SFR enhancement is a factor of 1.23$^{+0.08}_{-0.09}$ in the closest projected separation bin (<25 kpc) relative to a stellar mass-, redshift-, and environment-matched control sample of isolated galaxies. We find that the level of SFR enhancement is a factor of $\sim1.5$ higher at 0.5<z<1 than at 1<z<3 in the closest projected separation bin. Among a sample of visually identified mergers, we find an enhancement of a factor of 1.86$^{+0.29}_{-0.18}$ for coalesced systems. For this visually identified sample, we see a clear trend of increased SFR enhancement with decreasing projected separation (2.40$^{+0.62}_{-0.37}$ vs.\ 1.58$^{+0.29}_{-0.20}$ for 0.5<z<1.6 and 1.6<z<3.0, respectively). The SFR enhancement seen in our interactions and mergers are all lower than the level seen in local samples at the same separation, suggesting that the level of interaction-induced star formation evolves significantly over this time period.Comment: 23 pages, 13 figures, Accepted for publication in Ap

<i>SPITZER</i> Mid-IR Spectroscopy of Powerful 2Jy and 3CRR Radio Galaxies. II. AGN Power Indicators and Unification

It remains uncertain which continuum and emission line diagnostics best indicate the bolometric powers of active galactic nuclei (AGNs), especially given the attenuation caused by the circumnuclear material and the possible contamination by components related to star formation. Here we use mid-IR spectra along with multiwavelength data to investigate the merit of various diagnostics of AGN radiative power, including the mid-IR [Ne III] λ25.89 μm and [O IV] λ25.89 μm fine-structure lines, the optical [O III] λ5007 forbidden line, and mid-IR 24 μm, 5 GHz radio, and X-ray continuum emission, for complete samples of 46 2Jy radio galaxies (0.05 < z < 0.7) and 17 3CRR FRII radio galaxies (z < 0.1). We find that the mid-IR [O IV] line is the most reliable indicator of AGN power for powerful radio-loud AGNs. By assuming that the [O IV] is emitted isotropically, and comparing the [O III] and 24 μm luminosities of the broad- and narrow-line AGNs in our samples at fixed [O IV] luminosity, we show that the [O III] and 24 μm emission are both mildly attenuated in the narrow-line compared to the broad-line objects by a factor of ≈2. However, despite this attenuation, the [O III] and 24 μm luminosities are better AGN power indicators for our sample than either the 5 GHz radio or the X-ray continuum luminosities. We also detect the mid-IR 9.7 μm silicate feature in the spectra of many objects but not ubiquitously: at least 40% of the sample shows no clear evidence for these features. We conclude that, for the majority of powerful radio galaxies, the mid-IR lines are powered by AGN photoionization

Follicular Lymphoma: Recent and Emerging Therapies, Treatment Strategies, and Remaining Unmet Needs

Follicular lymphoma (FL) is a heterogeneous disease with varying prognosis owing to differences in clinical, laboratory, and disease parameters. Although generally considered incurable, prognosis for early- and advanced-stage disease has improved because of therapeutic advances, several of which have resulted from elucidation of the biologic and molecular basis of the disease. The choice of treatment for FL is highly dependent on patient and disease characteristics. Several tools are available for risk stratification, although limitations in their routine clinical use exist. For limited disease, treatment options include radiotherapy, rituximab monotherapy or combination regimens, and surveillance. Treatment of advanced disease is often determined by tumor burden, with surveillance or rituximab considered for low tumor burden and chemoimmunotherapy for high tumor burden disease. Treatment for relapsed or refractory disease is influenced by initial first-line therapy and the duration and quality of the response. Presently, there is no consensus for treatment of patients with early or multiply relapsed disease; however, numerous agents, combination regimens, and transplant options have demonstrated efficacy. Although the number of therapies available to treat FL has increased together with an improved understanding of the underlying biologic basis of disease, the best approach to select the most appropriate treatment strategy for an individual patient at a particular time continues to be elucidated. This review considers prognostication and the evolving treatment landscape of FL, including recent and emergent therapies as well as remaining unmet needs. Implications for Practice: In follicular lymphoma, a personalized approach to management based on disease biology, patient characteristics, and other factors continues to emerge. However, application of current management requires an understanding of the available therapeutic options for first-line treatment and knowledge of current development in therapies for previously untreated and for relapsed or refractory disease. Thus, this work reviews for clinicians the contemporary data in follicular lymphoma, from advances in characterizing disease biology to current treatments and emerging novel therapies

Primary thromboprophylaxis for cancer patients with central venous catheters – a reappraisal of the evidence

Venous thromboembolism (VTE) is responsible for an estimated 25 000 deaths per annum in UK hospital practice. It is well established that many of these deaths could be prevented through the use of appropriate thromboprophylaxis. This issue is of particular relevance in oncology practice, where the risks of VTE and bleeding are both significantly higher than those observed in general medical patients. Cancer patients with in-dwelling central venous catheters (CVCs) are at particularly high risk of developing thrombotic complications. However, the literature has produced conflicting conclusions regarding the efficacy of using routine primary thromboprophylaxis in these patients. Indeed such is the level of confusion around this topic, that the most recent version of the American College of Chest Physicians (ACCP) guidelines published in 2004 actually reversed their previous recommendation (published in 2001). Nevertheless, minidose warfarin continues to be routinely used in many oncology centres in the UK. In this article, we have performed a systematic review of the published literature regarding the efficacy and the risks, associated with using thromboprophylaxis (either minidose warfarin or low-dose LMWH) in cancer patients with CVC. On the basis of this evidence, we conclude that there is no proven role for using such thromboprophylaxis. However, asymptomatic CVC-related venous thrombosis remains common, and further more highly powered studies of better design are needed in order to define whether specific subgroups of cancer patients might benefit from receiving thromboprophylaxis

Investigating the Effect of Galaxy Interactions on the Enhancement of Active Galactic Nuclei at 0.5 < z < 3.0

Galaxy interactions and mergers are thought to play an important role in the evolution of galaxies. Studies in the nearby universe show a higher AGN fraction in interacting and merging galaxies than their isolated counterparts, indicating that such interactions are important contributors to black hole growth. To investigate the evolution of this role at higher redshifts, we have compiled the largest known sample of major spectroscopic galaxy pairs (2381 with $\Delta V <5000$ km s$^{-1}$) at $0.5<z<3.0$ from observations in the COSMOS and CANDELS surveys. We identify X-ray and IR AGN among this kinematic pair sample, a visually identified sample of mergers and interactions, and a mass-, redshift-, and environment-matched control sample for each in order to calculate AGN fractions and the level of AGN enhancement as a function of relative velocity, redshift, and X-ray luminosity. While we see a slight increase in AGN fraction with decreasing projected separation, overall, we find no significant enhancement relative to the control sample at any separation. In the closest projected separation bin ($<25$ kpc, $\Delta V <1000$ km s$^{-1}$), we find enhancements of a factor of 0.94$^{+0.21}_{-0.16}$ and 1.00$^{+0.58}_{-0.31}$ for X-ray and IR-selected AGN, respectively. While we conclude that galaxy interactions do not significantly enhance AGN activity on average over $0.5<z<3.0$ at these separations, given the errors and the small sample size at the closest projected separations, our results would be consistent with the presence of low-level AGN enhancement

Investigating the Effect of Galaxy Interactions on Star Formation at 0.5 < z < 3.0

Observations and simulations of interacting galaxies and mergers in the local universe have shown that interactions can significantly enhance the star formation rates (SFRs) and fueling of active galactic nuclei (AGN). However, at higher redshift, some simulations suggest that the level of star formation enhancement induced by interactions is lower due to the higher gas fractions and already increased SFRs in these galaxies. To test this, we measure the SFR enhancement in a total of 2351 (1327) massive (M * > 1010 M ⊙) major (1 < M 1/M 2 < 4) spectroscopic galaxy pairs at 0.5 < z < 3.0 with ΔV < 5000 km s−1 (1000 km s−1) and projected separation <150 kpc selected from the extensive spectroscopic coverage in the COSMOS and CANDELS fields. We find that the highest level of SFR enhancement is a factor of 1.23 − 0.09 + 0.08 in the closest projected separation bin (<25 kpc) relative to a stellar mass-, redshift-, and environment-matched control sample of isolated galaxies. We find that the level of SFR enhancement is a factor of ∼1.5 higher at 0.5 < z < 1 than at 1 < z < 3 in the closest projected separation bin. Among a sample of visually identified mergers, we find an enhancement of a factor of 1.86 − 0.18 + 0.29 (∼3σ) for coalesced systems. For this visually identified sample, we see a clear trend of increased SFR enhancement with decreasing projected separation (2.40 − 0.37 + 0.62 versus 1.58 − 0.20 + 0.29 for 0.5 < z < 1.6 and 1.6 < z < 3.0, respectively). The SFR enhancements seen in our interactions and mergers are all lower than the level seen in local samples at the same separation, suggesting that the level of interaction-induced star formation evolves significantly over this time period