Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III

A small proportion of 4H (Hypomyelination, Hypodontia and Hypogonadotropic Hypogonadism) or RNA polymerase III (POLR3)-related leukodystrophy cases are negative for mutations in the previously identified causative genes POLR3A and POLR3B. Here we report eight of these cases carrying recessive mutations in POLR1C, a gene encoding a shared POLR1 and POLR3 subunit, also mutated in some Treacher Collins syndrome (TCS) cases. Using shotgun proteomics and ChIP sequencing, we demonstrate that leukodystrophy-causative mutations, but not TCS mutations, in POLR1C impair assembly and nuclear import of POLR3, but not POLR1, leading to decreased binding to POLR3 target genes. This study is the first to show that distinct mutations in a gene coding for a shared subunit of two RNA polymerases lead to selective modification of the enzymes’ availability leading to two different clinical conditions and to shed some light on the pathophysiological mechanism of one of the most common hypomyelinating leukodystrophies, POLR3-related leukodystrophy

Characterization of Preoperative, Postsurgical, Acute and Chronic Pain in High Risk Breast Cancer Patients

Funding: The Ketorolac in Breast Cancer trial has been supported by the Anticancer Fund, the Belgian Society of Anaesthesia and Resuscitation, the Fondation Saint-Luc, and the Commission du Patrimoine of the Université catholique de Louvain, Cliniques universitaires Saint-Luc. Acknowledgments: Membership of the KBCt Group, Aline van Maanen, Gauthier Bouche, Alain Dekleermaker, Francois P Duhoux, Marc De Kock, Martine Berliere, Pierre Coulie, Jan Decloedt, Jean-Edouard Guillaume, Marc Ledent, Jean-Pascal Machiels, Véronique Mustin, Walter Swinnen, Lionel Vander Essen, and Jean-Christophe Verougstraete.Peer reviewedPublisher PD

Characterization of Preoperative, Postsurgical, Acute and Chronic Pain in High Risk Breast Cancer Patients

Background: Pain after breast cancer surgery remains largely unexplained and inconsistently quantified. This study aims to describe the perioperative pain patterns in patients with breast cancer, up to two years after surgery. Methods: This is a pre-planned sub-study of the Ketorolac in Breast Cancer (KBC) trial. The KBC trial was a multicentre, prospective, double-blind, placebo-controlled, randomised trial of a single dose of 30 mg of ketorolac just before breast cancer surgery, aiming to test its effect on recurrences. This sub-study focuses only on pain outcomes. From 2013 to 2015, 203 patients were randomised to ketorolac (n = 96) or placebo (n = 107). Structured questionnaires were delivered by telephone after one and two years, exploring the presence, location, permanence, and frequency of pain. Patients’ perceptions of pain were captured by an open-ended question, the responses to which were coded and classified using hierarchical clustering. Results: There was no difference in pain between the ketorolac and the placebo group. The reported incidence of permanent pain was 67% and 45% at one and two years, respectively. The largest category was musculoskeletal pain. Permanent pain was mainly described in patients with musculoskeletal pain. The description of pain changed in most patients during the second postoperative year, i.e., moved from one category to another (no pain, permanent, or non-permanent pain, but also, the localisation). This phenomenon includes patients without pain at one year. Conclusions: Pain is a complex phenomenon, but also a fragile and unstable endpoint. Pain after breast cancer surgery does not necessarily mean breast pain but also musculoskeletal and other pains. The permanence of pain and the pain phenotype can change over time

Durvalumab Plus Carboplatin/Paclitaxel Followed by Maintenance Durvalumab With or Without Olaparib as First-Line Treatment for Advanced Endometrial Cancer: The Phase III DUO-E Trial

PURPOSE Immunotherapy and chemotherapy combinations have shown activity in endometrial cancer, with greater benefit in mismatch repair (MMR)-deficient (dMMR) than MMR-proficient (pMMR) disease. Adding a poly(ADP-ribose) polymerase inhibitor may improve outcomes, especially in pMMR disease. METHODS This phase III, global, double-blind, placebo-controlled trial randomly assigned eligible patients with newly diagnosed advanced or recurrent endometrial cancer 1:1:1 to: carboplatin/paclitaxel plus durvalumab placebo followed by placebo maintenance (control arm); carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib placebo (durvalumab arm); or carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab plus olaparib (durvalumab + olaparib arm). The primary end points were progression-free survival (PFS) in the durvalumab arm versus control and the durvalumab + olaparib arm versus control. RESULTS Seven hundred eighteen patients were randomly assigned. In the intention-to-treat population, statistically significant PFS benefit was observed in the durvalumab (hazard ratio [HR], 0.71 [95% CI, 0.57 to 0.89]; P = .003) and durvalumab + olaparib arms (HR, 0.55 [95% CI, 0.43 to 0.69]; P < .0001) versus control. Prespecified, exploratory subgroup analyses showed PFS benefit in dMMR (HR [durvalumab v control], 0.42 [95% CI, 0.22 to 0.80]; HR [durvalumab + olaparib v control], 0.41 [95% CI, 0.21 to 0.75]) and pMMR subgroups (HR [durvalumab v control], 0.77 [95% CI, 0.60 to 0.97]; HR [durvalumab + olaparib v control] 0.57; [95% CI, 0.44 to 0.73]); and in PD-L1-positive subgroups (HR [durvalumab v control], 0.63 [95% CI, 0.48 to 0.83]; HR [durvalumab + olaparib v control], 0.42 [95% CI, 0.31 to 0.57]). Interim overall survival results (maturity approximately 28%) were supportive of the primary outcomes (durvalumab v control: HR, 0.77 [95% CI, 0.56 to 1.07]; P = .120; durvalumab + olaparib v control: HR, 0.59 [95% CI, 0.42 to 0.83]; P = .003). The safety profiles of the experimental arms were generally consistent with individual agents. CONCLUSION Carboplatin/paclitaxel plus durvalumab followed by maintenance durvalumab with or without olaparib demonstrated a statistically significant and clinically meaningful PFS benefit in patients with advanced or recurrent endometrial cancer

Averting biodiversity collapse in tropical forest protected areas

The rapid disruption of tropical forests probably imperils global biodiversity more than any other contemporary phenomenon¹⁻³. With deforestation advancing quickly, protected areas are increasingly becoming final refuges for threatened species and natural ecosystem processes. However, many protected areas in the tropics are themselves vulnerable to human encroachment and other environmental stresses⁴⁻⁹. As pressures mount, it is vital to know whether existing reserves can sustain their biodiversity. A critical constraint in addressing this question has been that data describing a broad array of biodiversity groups have been unavailable for a sufficiently large and representative sample of reserves. Here we present a uniquely comprehensive data set on changes over the past 20 to 30 years in 31 functional groups of species and 21 potential drivers of environmental change, for 60 protected areas stratified across the world’s major tropical regions. Our analysis reveals great variation in reserve ‘health’: about half of all reserves have been effective or performed passably, but the rest are experiencing an erosion of biodiversity that is often alarmingly widespread taxonomically and functionally. Habitat disruption, hunting and forest-product exploitation were the strongest predictors of declining reserve health. Crucially, environmental changes immediately outside reserves seemed nearly as important as those inside in determining their ecological fate, with changes inside reserves strongly mirroring those occurring around them. These findings suggest that tropical protected areas are often intimately linked ecologically to their surrounding habitats, and that a failure to stem broad-scale loss and degradation of such habitats could sharply increase the likelihood of serious biodiversity declines.Keywords: Ecology, Environmental scienc

Prostate-Derived Ets Transcription Factor Overexpression is Associated with Nodal Metastasis, Hormone Receptor Positivity in Invasive Breast Cancer

Prostate-derived Ets transcription factor (PDEF) has recently been associated with invasive breast cancer, but no expression profile has been defined in clinical specimens. We undertook a comprehensive PDEF transcriptional expression study of 86 breast cancer clinical specimens, several cell lines, normal tissues. PDEF expression profile was analyzed according to standard clinicopathologic parameters, compared with hormonal receptor, HER-2/neu status, to the expression of the new tumor biomarker Dikkopf-1 (DKK1). Wide ranging PDEF overexpression was observed in 74% of tested tumors, at higher levels than the average expression found in normal breasts. High PDEF expression was associated with hormone receptor positivity (P < .001), moderate to good differentiation (less than grade III, P = .01), dissemination to axillary lymph nodes (P = .002). PDEF was an independent risk factor for nodal involvement (multivariate analysis, odds ratio 1.250, P = .002). It was expressed in a different subgroup compared to DKK1-expressing tumors (P < .001). Our data imply that PDEF mRNA expression could be useful in breast cancer molecular staging. Further insights into PDEF functions at the protein level, possible links with hormone receptors biology, bear great potential for new therapeutic avenues

Photo-Cross-Linking of a Purified Preinitiation Complex Reveals Central Roles for the RNA Polymerase II Mobile Clamp and TFIIE in Initiation Mechanisms

The topological organization of a TATA binding protein-TFIIB-TFIIF-RNA polymerase II (RNAP II)-TFIIE-promoter complex was analyzed using site-specific protein-DNA photo-cross-linking of gel-purified complexes. The cross-linking results for the subunits of RNAP II were used to determine the path of promoter DNA against the structure of the enzyme. The results indicate that promoter DNA wraps around the mobile clamp of RNAP II. Cross-linking of TFIIF and TFIIE both upstream of the TATA element and downstream of the transcription start site suggests that both factors associate with the RNAP II mobile clamp. TFIIEα closely approaches promoter DNA at nucleotide −10, a position immediately upstream of the transcription bubble in the open complex. Increased stimulation of transcription initiation by TFIIEα is obtained when the DNA template is artificially premelted in the −11/−1 region, suggesting that TFIIEα facilitates open complex formation, possibly through its interaction with the upstream end of the partially opened transcription bubble. These results support the central roles of the mobile clamp of RNAP II and TFIIE in transcription initiation