Steroid therapy and outcome of parapneumonic pleural effusions (STOPPE): Study protocol for a multicenter, double-blinded, placebo-controlled randomized clinical trial

BACKGROUND: Community-acquired pneumonia (CAP) is a major global disease. Parapneumonic effusions often complicate CAP and range from uninfected (simple) to infected (complicated) parapneumonic effusions and empyema (pus). CAP patients who have a pleural effusion at presentation are more likely to require hospitalization, have a longer length of stay and higher mortality than those without an effusion. Conventional management of pleural infection, with antibiotics and chest tube drainage, fails in about 30% of cases. Several randomized controlled trials (RCT) have evaluated the use of corticosteroids in CAP and demonstrated some potential benefits. Importantly, steroid use in pneumonia has an acceptable safety profile with no adverse impact on mortality. A RCT focused on pediatric patients with pneumonia and a parapneumonic effusion demonstrated shorter time to recovery. The effects of corticosteroid use on clinical outcomes in adults with parapneumonic effusions have not been tested. We hypothesize that parapneumonic effusions develop from an exaggerated pleural inflammatory response. Treatment with systemic steroids may dampen the inflammation and lead to improved clinical outcomes. The steroid therapy and outcome of parapneumonic pleural effusions (STOPPE) trial will assess the efficacy and safety of systemic corticosteroid as an adjunct therapy in adult patients with CAP and pleural effusions. METHODS: STOPPE is a pilot multicenter, double-blinded, placebo-controlled RCT that will randomize 80 patients with parapneumonic effusions (2:1) to intravenous dexamethasone or placebo, administered twice daily for 48 hours. This exploratory study will capture a wide range of clinically relevant endpoints which have been used in clinical trials of pneumonia and/or pleural infection; including, but not limited to: time to clinical stability, inflammatory markers, quality of life, length of hospital stay, proportion of patients requiring escalation of care (thoracostomy or thoracoscopy), and mortality. Safety will be assessed by monitoring for the incidence of adverse events during the study. DISCUSSION: STOPPE is the first trial to assess the efficacy and safety profile of systemic corticosteroids in adults with CAP and pleural effusions. This will inform future studies on feasibility and appropriate trial endpoints. TRIAL REGISTRATION: ACTRN1261800094720

JMJD6 is a tumorigenic factor and therapeutic target in neuroblastoma

Chromosome 17q21-ter is commonly gained in neuroblastoma, but it is unclear which gene in the region is important for tumorigenesis. The JMJD6 gene at 17q21-ter activates gene transcription. Here we show that JMJD6 forms protein complexes with N-Myc and BRD4, and is important for E2F2, N-Myc and c-Myc transcription. Knocking down JMJD6 reduces neuroblastoma cell proliferation and survival in vitro and tumor progression in mice, and high levels of JMJD6 expression in human neuroblastoma tissues independently predict poor patient prognosis. In addition, JMJD6 gene is associated with transcriptional super-enhancers. Combination therapy with the CDK7/super-enhancer inhibitor THZ1 and the histone deacetylase inhibitor panobinostat synergistically reduces JMJD6, E2F2, N-Myc, c-Myc expression, induces apoptosis in vitro and leads to neuroblastoma tumor regression in mice, which are significantly reversed by forced JMJD6 over-expression. Our findings therefore identify JMJD6 as a neuroblastoma tumorigenesis factor, and the combination therapy as a treatment strategy

Expression in Antennae and Reproductive Organs Suggests a Dual Role of an Odorant-Binding Protein in Two Sibling Helicoverpa Species

Odorant-binding proteins (OBPs) mediate both perception and release of semiochemicals in insects. These proteins are the ideal targets for understanding the olfactory code of insects as well as for interfering with their communication system in order to control pest species. The two sibling Lepidopteran species Helicoverpa armigera and H. assulta are two major agricultural pests. As part of our aim to characterize the OBP repertoire of these two species, here we focus our attention on a member of this family, OBP10, particularly interesting for its expression pattern. The protein is specifically expressed in the antennae of both sexes, being absent from other sensory organs. However, it is highly abundant in seminal fluid, is transferred to females during mating and is eventually found on the surface of fertilised eggs. Among the several different volatile compounds present in reproductive organs, OBP10 binds 1-dodecene, a compound reported as an insect repellent. These results have been verified in both H. armigera and H. assulta with no apparent differences between the two species. The recombinant OBP10 binds, besides 1-dodecene, some linear alcohols and several aromatic compounds. The structural similarity of OBP10 with OBP1 of the mosquito Culex quinquefasciatus, a protein reported to bind an oviposition pheromone, and its affinity with 1-dodecene suggest that OBP10 could be a carrier for oviposition deterrents, favouring spreading of the eggs in these species where cannibalism is active among larvae

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Pulmonary Arterial Hypertension: Pathophysiology and Treatment

Pulmonary arterial hypertension (PAH), the first category of pulmonary hypertension, is a chronic and progressive disorder characterised by angioproliferative vasculopathy in the pulmonary arterioles, leading to endothelial and smooth muscle proliferation and dysfunction, inflammation and thrombosis. These changes increase pulmonary vascular resistance and subsequent pulmonary arterial pressure, causing right ventricular failure which leads to eventual death if untreated. The management of PAH has advanced rapidly in recent years due to improved understanding of the condition’s pathophysiology, specifically the nitric oxide, prostacyclin-thromboxane and endothelin-1 pathways. Five classes of drugs targeting these pathways are now available: phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, prostacyclin analogues, prostacyclin receptor agonists and endothelin receptor antagonists. These developments have led to substantial improvements in mortality rate in recent decades. Recently, long-term studies have demonstrated sustained progression-free survival and have created a new paradigm of initial combination therapy. Despite these targeted therapies, PAH is still associated with significant morbidity and mortality. As such, further research into broadening our understanding of PAH pathophysiology is underway with potential of increasing the repertoire of drugs available

The long noncoding RNA lncNB1 promotes tumorigenesis by interacting with ribosomal protein RPL35.

The majority of patients with neuroblastoma due to MYCN oncogene amplification and consequent N-Myc oncoprotein over-expression die of the disease. Here our analyses of RNA sequencing data identify the long noncoding RNA lncNB1 as one of the transcripts most over-expressed in MYCN-amplified, compared with MYCN-non-amplified, human neuroblastoma cells and also the most over-expressed in neuroblastoma compared with all other cancers. lncNB1 binds to the ribosomal protein RPL35 to enhance E2F1 protein synthesis, leading to DEPDC1B gene transcription. The GTPase-activating protein DEPDC1B induces ERK protein phosphorylation and N-Myc protein stabilization. Importantly, lncNB1 knockdown abolishes neuroblastoma cell clonogenic capacity in vitro and leads to neuroblastoma tumor regression in mice, while high levels of lncNB1 and RPL35 in human neuroblastoma tissues predict poor patient prognosis. This study therefore identifies lncNB1 and its binding protein RPL35 as key factors for promoting E2F1 protein synthesis, N-Myc protein stability and N-Myc-driven oncogenesis, and as therapeutic targets