Bio+mine project: empowering the community to develop a site-specific system for the rehabilitation of a legacy mine

The rehabilitation of legacy mines continues to be a big challenge because of the difficulties in returning them to safe and stable conditions and ensuring that the mined-out areas become productive to support the economic activity of the host community. Previous efforts are often focused on purely technical and environmental aspects, leading to resistance from the local community due to their exclusion from the rehabilitation process. To address the issues associated with legacy mines and lack of participation of the community, we have developed a project, Biodiversity Positive Mining For The Net Zero Challenge (Bio + Mine), focusing on the abandoned Sto. Niño copper mine (Benguet, Philippines). The mine was closed in 1982 without a plan involving local stakeholders and leaving a significant ongoing negative legacy. Using the social-ecological-technological system framework, we will explore the intersections of the structure and functions of socio-economicdemographic, ecological, and technological data useful in devising a more inclusive mitigation strategy for the reconstruction of the supporting ecosystem. We aim to develop a site-specific system, underpinned by the local community's knowledge and practices, that can be a model for wider implementation in other legacy and active mines worldwide

An Investigation of a Role for U2 snRNP Spliceosomal Components in Regulating Transcription

There is mounting evidence to suggest that the synthesis of pre-mRNA transcripts and their subsequent splicing are coordinated events. Previous studies have implicated the mammalian spliceosomal U2 snRNP as having a novel role in stimulating transcriptional elongation in vitro through interactions with the elongation factors P-TEFb and Tat-SF1; however, the mechanism remains unknown [1]. These factors are conserved in Saccharomyces cerevisiae, a fact that suggests that a similar interaction may occur in yeast to stimulate transcriptional elongation in vivo. To address this possibility we have looked for evidence of a role for the yeast Tat-SF1 homolog, Cus2, and the U2 snRNA in regulating transcription. Specifically, we have performed a genetic analysis to look for functional interactions between Cus2 or U2 snRNA and the P-TEFb yeast homologs, the Bur1/2 and Ctk1/2/3 complexes. In addition, we have analyzed Cus2-deleted or -overexpressing cells and U2 snRNA mutant cells to determine if they show transcription-related phenotypes similar to those displayed by the P-TEFb homolog mutants. In no case have we been able to observe phenotypes consistent with a role for either spliceosomal factor in transcription elongation. Furthermore, we did not find evidence for physical interactions between the yeast U2 snRNP factors and the P-TEFb homologs. These results suggest that in vivo, S. cerevisiae do not exhibit functional or physical interactions similar to those exhibited by their mammalian counterparts in vitro. The significance of the difference between our in vivo findings and the previously published in vitro results remains unclear; however, we discuss the potential importance of other factors, including viral proteins, in mediating the mammalian interactions

Molecular control of HIV-1 postintegration latency: implications for the development of new therapeutic strategies

The persistence of HIV-1 latent reservoirs represents a major barrier to virus eradication in infected patients under HAART since interruption of the treatment inevitably leads to a rebound of plasma viremia. Latency establishes early after infection notably (but not only) in resting memory CD4+ T cells and involves numerous host and viral trans-acting proteins, as well as processes such as transcriptional interference, RNA silencing, epigenetic modifications and chromatin organization. In order to eliminate latent reservoirs, new strategies are envisaged and consist of reactivating HIV-1 transcription in latently-infected cells, while maintaining HAART in order to prevent de novo infection. The difficulty lies in the fact that a single residual latently-infected cell can in theory rekindle the infection. Here, we review our current understanding of the molecular mechanisms involved in the establishment and maintenance of HIV-1 latency and in the transcriptional reactivation from latency. We highlight the potential of new therapeutic strategies based on this understanding of latency. Combinations of various compounds used simultaneously allow for the targeting of transcriptional repression at multiple levels and can facilitate the escape from latency and the clearance of viral reservoirs. We describe the current advantages and limitations of immune T-cell activators, inducers of the NF-κB signaling pathway, and inhibitors of deacetylases and histone- and DNA- methyltransferases, used alone or in combinations. While a solution will not be achieved by tomorrow, the battle against HIV-1 latent reservoirs is well- underway

2 nd Brazilian Consensus on Chagas Disease, 2015

Abstract Chagas disease is a neglected chronic condition with a high burden of morbidity and mortality. It has considerable psychological, social, and economic impacts. The disease represents a significant public health issue in Brazil, with different regional patterns. This document presents the evidence that resulted in the Brazilian Consensus on Chagas Disease. The objective was to review and standardize strategies for diagnosis, treatment, prevention, and control of Chagas disease in the country, based on the available scientific evidence. The consensus is based on the articulation and strategic contribution of renowned Brazilian experts with knowledge and experience on various aspects of the disease. It is the result of a close collaboration between the Brazilian Society of Tropical Medicine and the Ministry of Health. It is hoped that this document will strengthen the development of integrated actions against Chagas disease in the country, focusing on epidemiology, management, comprehensive care (including families and communities), communication, information, education, and research

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Optimisation of Perioperative Cardiovascular Management to Improve Surgical Outcome II (OPTIMISE II) trial: study protocol for a multicentre international trial of cardiac output-guided fluid therapy with low-dose inotrope infusion compared with usual care in patients undergoing major elective gastrointestinal surgery.

INTRODUCTION: Postoperative morbidity and mortality in older patients with comorbidities undergoing gastrointestinal surgery are a major burden on healthcare systems. Infections after surgery are common in such patients, prolonging hospitalisation and reducing postoperative short-term and long-term survival. Optimal management of perioperative intravenous fluids and inotropic drugs may reduce infection rates and improve outcomes from surgery. Previous small trials of cardiac-output-guided haemodynamic therapy algorithms suggested a modest reduction in postoperative morbidity. A large definitive trial is needed to confirm or refute this and inform widespread clinical practice. METHODS: The Optimisation of Perioperative Cardiovascular Management to Improve Surgical Outcome II (OPTIMISE II) trial is a multicentre, international, parallel group, open, randomised controlled trial. 2502 high-risk patients undergoing major elective gastrointestinal surgery will be randomly allocated in a 1:1 ratio using minimisation to minimally invasive cardiac output monitoring to guide protocolised administration of intravenous fluid combined with low-dose inotrope infusion, or usual care. The trial intervention will be carried out during and for 4 hours after surgery. The primary outcome is postoperative infection of Clavien-Dindo grade II or higher within 30 days of randomisation. Participants and those delivering the intervention will not be blinded to treatment allocation; however, outcome assessors will be blinded when feasible. Participant recruitment started in January 2017 and is scheduled to last 3 years, within 50 hospitals worldwide. ETHICS/DISSEMINATION: The OPTIMISE II trial has been approved by the UK National Research Ethics Service and has been approved by responsible ethics committees in all participating countries. The findings will be disseminated through publication in a widely accessible peer-reviewed scientific journal. TRIAL REGISTRATION NUMBER: ISRCTN39653756.The OPTIMISE II trial is supported by Edwards Lifesciences (Irvine, CA) and the UK National Institute for Health Research through RMP’s NIHR Professorship

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Genetic profiling of colorectal cancer liver metastases by combined comparative genomic hybridization and G-banding analysis

The majority of genetic studies of colorectal carcinogenesis have focused on changes found in primary tumors. Despite the fact that liver metastases are a leading cause of colorectal cancer deaths, the molecular genetic basis of the advanced disease stages remains poorly understood. We performed comparative genomic hybridization (CGH) on 17 liver metastases from colorectal carcinomas and compared the quantitative profile with the qualitative profile previously obtained with chromosome banding. An average of 12.6 aberrations per tumor was found by CGH. Chromosome 18 and chromosome arms 4q, 8p, and 17p were most frequently lost, whereas chromosomes 7 and 20 and chromosome arms 6p, 8q, and 13q were most frequently gained. We compared the chromosome banding and CGH data after converting the karyotypes into net copy number gains and losses. Ten tumors showed agreement between the findings of the two techniques, whereas five tumors did not (in two cases, no mitotic cells were obtained for banding analysis). All five discordant cases had a "simple" abnormal or normal karyotype, but revealed multiple changes by CGH. A likely explanation for this discrepancy is that in vitro growth before G-banding selected against the cancer cells. Interestingly, by comparing the CGH profiles of the "complex" vs. the "simple"/normal karyotype groups, deletion of 8p and gain of 16q were seen more frequently in the former group. The liver metastases had the same aberrations as seen in primary colorectal carcinomas, summarized in a literature survey. However, these aberrations were seen more frequently in liver metastases, which may be attributable to increased genetic instability. (C) 2003 Wiley-Liss, Inc