Integrated Molecular Characterization of Uterine Carcinosarcoma

SummaryWe performed genomic, epigenomic, transcriptomic, and proteomic characterizations of uterine carcinosarcomas (UCSs). Cohort samples had extensive copy-number alterations and highly recurrent somatic mutations. Frequent mutations were found in TP53, PTEN, PIK3CA, PPP2R1A, FBXW7, and KRAS, similar to endometrioid and serous uterine carcinomas. Transcriptome sequencing identified a strong epithelial-to-mesenchymal transition (EMT) gene signature in a subset of cases that was attributable to epigenetic alterations at microRNA promoters. The range of EMT scores in UCS was the largest among all tumor types studied via The Cancer Genome Atlas. UCSs shared proteomic features with gynecologic carcinomas and sarcomas with intermediate EMT features. Multiple somatic mutations and copy-number alterations in genes that are therapeutic targets were identified

Integrated genomic characterization of pancreatic ductal adenocarcinoma

We performed integrated genomic, transcriptomic, and proteomic profiling of 150 pancreatic ductal adenocarcinoma (PDAC) specimens, including samples with characteristic low neoplastic cellularity. Deep whole-exome sequencing revealed recurrent somatic mutations in KRAS, TP53, CDKN2A, SMAD4, RNF43, ARID1A, TGFβR2, GNAS, RREB1, and PBRM1. KRAS wild-type tumors harbored alterations in other oncogenic drivers, including GNAS, BRAF, CTNNB1, and additional RAS pathway genes. A subset of tumors harbored multiple KRAS mutations, with some showing evidence of biallelic mutations. Protein profiling identified a favorable prognosis subset with low epithelial-mesenchymal transition and high MTOR pathway scores. Associations of non-coding RNAs with tumor-specific mRNA subtypes were also identified. Our integrated multi-platform analysis reveals a complex molecular landscape of PDAC and provides a roadmap for precision medicine

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

WHO global research priorities for antimicrobial resistance in human health

The WHO research agenda for antimicrobial resistance (AMR) in human health has identified 40 research priorities to be addressed by the year 2030. These priorities focus on bacterial and fungal pathogens of crucial importance in addressing AMR, including drug-resistant pathogens causing tuberculosis. These research priorities encompass the entire people-centred journey, covering prevention, diagnosis, and treatment of antimicrobial-resistant infections, in addition to addressing the overarching knowledge gaps in AMR epidemiology, burden and drivers, policies and regulations, and awareness and education. The research priorities were identified through a multistage process, starting with a comprehensive scoping review of knowledge gaps, with expert inputs gathered through a survey and open call. The priority setting involved a rigorous modified Child Health and Nutrition Research Initiative approach, ensuring global representation and applicability of the findings. The ultimate goal of this research agenda is to encourage research and investment in the generation of evidence to better understand AMR dynamics and facilitate policy translation for reducing the burden and consequences of AMR

Neurovascular unit dysfunction with blood-brain barrier hyperpermeability contributes to major depressive disorder: a review of clinical and experimental evidence

About one-third of people with major depressive disorder (MDD) fail at least two antidepressant drug trials at 1 year. Together with clinical and experimental evidence indicating that the pathophysiology of MDD is multifactorial, this observation underscores the importance of elucidating mechanisms beyond monoaminergic dysregulation that can contribute to the genesis and persistence of MDD. Oxidative stress and neuroinflammation are mechanistically linked to the presence of neurovascular dysfunction with blood-brain barrier (BBB) hyperpermeability in selected neurological disorders, such as stroke, epilepsy, multiple sclerosis, traumatic brain injury, and Alzheimer’s disease. In contrast to other major psychiatric disorders, MDD is frequently comorbid with such neurological disorders and constitutes an independent risk factor for morbidity and mortality in disorders characterized by vascular endothelial dysfunction (cardiovascular disease and diabetes mellitus). Oxidative stress and neuroinflammation are implicated in the neurobiology of MDD. More recent evidence links neurovascular dysfunction with BBB hyperpermeability to MDD without neurological comorbidity. We review this emerging literature and present a theoretical integration between these abnormalities to those involving oxidative stress and neuroinflammation in MDD. We discuss our hypothesis that alterations in endothelial nitric oxide levels and endothelial nitric oxide synthase uncoupling are central mechanistic links in this regard. Understanding the contribution of neurovascular dysfunction with BBB hyperpermeability to the pathophysiology of MDD may help to identify novel therapeutic and preventative approaches

Data from: Efficacy of visual surveys for white-nose syndrome at bat hibernacula

White-Nose Syndrome (WNS) is an epizootic disease in hibernating bats caused by the fungus Pseudogymnoascus destructans. Surveillance for P. destructans at bat hibernacula consists primarily of visual surveys of bats, collection of potentially infected bats, and submission of these bats for laboratory testing. Cryptic infections (bats that are infected but display no visual signs of fungus) could lead to the mischaracterization of the infection status of a site and the inadvertent spread of P. destructans. We determined the efficacy of visual detection of P. destructans by examining visual signs and molecular detection of P. destructans on 928 bats of six species at 27 sites during surveys conducted from January through March in 2012–2014 in the southeastern USA on the leading edge of the disease invasion. Cryptic infections were widespread with 77% of bats that tested positive by qPCR showing no visible signs of infection. The probability of exhibiting visual signs of infection increased with sampling date and pathogen load, the latter of which was substantially higher in three species (Myotis lucifugus, M. septentrionalis, and Perimyotis subflavus). In addition, M. lucifugus was more likely to show visual signs of infection than other species given the same pathogen load. Nearly all infections were cryptic in three species (Eptesicus fuscus, M. grisescens, and M. sodalis), which had much lower fungal loads. The presence of M. lucifugus or M. septentrionalis at a site increased the probability that P. destructans was visually detected on bats. Our results suggest that cryptic infections of P. destructans are common in all bat species, and visible infections rarely occur in some species. However, due to very high infection prevalence and loads in some species, we estimate that visual surveys examining at least 17 individuals of M. lucifugus and M. septentrionalis, or 29 individuals of P. subflavus are still effective to determine whether a site has bats infected with P. destructans. In addition, because the probability of visually detecting the fungus was higher later in winter, surveys should be done as close to the end of the hibernation period as possible

Efficacy of Visual Surveys for White-Nose Syndrome at Bat Hibernacula

White-Nose Syndrome (WNS) is an epizootic disease in hibernating bats caused by the fungus Pseudogymnoascus destructans. Surveillance for P. destructans at bat hibernacula consists primarily of visual surveys of bats, collection of potentially infected bats, and submission of these bats for laboratory testing. Cryptic infections (bats that are infected but display no visual signs of fungus) could lead to the mischaracterization of the infection status of a site and the inadvertent spread of P. destructans. We determined the efficacy of visual detection of P. destructans by examining visual signs and molecular detection of P. destructans on 928 bats of six species at 27 sites during surveys conducted from January through March in 2012–2014 in the southeastern USA on the leading edge of the disease invasion. Cryptic infections were widespread with 77% of bats that tested positive by qPCR showing no visible signs of infection. The probability of exhibiting visual signs of infection increased with sampling date and pathogen load, the latter of which was substantially higher in three species (Myotis lucifugus, M. septentrionalis, and Perimyotis subflavus). In addition, M. lucifugus was more likely to show visual signs of infection than other species given the same pathogen load. Nearly all infections were cryptic in three species (Eptesicus fuscus, M. grisescens, and M. sodalis), which had much lower fungal loads. The presence of M. lucifugus or M. septentrionalis at a site increased the probability that P. destructans was visually detected on bats. Our results suggest that cryptic infections of P. destructans are common in all bat species, and visible infections rarely occur in some species. However, due to very high infection prevalence and loads in some species, we estimate that visual surveys examining at least 17 individuals of M. lucifugus and M. septentrionalis, or 29 individuals of P. subflavus are still effective to determine whether a site has bats infected with P. destructans. In addition, because the prob