Major milestones in translational oncology.

Translational oncology represents a bridge between basic research and clinical practice in cancer medicine. Today, translational research in oncology benefits from an abundance of knowledge resulting from genome-scale studies regarding the molecular pathways involved in tumorigenesis. In this Forum article, we highlight the state of the art of translational oncology in five major cancer types. We illustrate the use of molecular profiling to subtype colorectal cancer for both diagnosis and treatment, and summarize the results of a nationwide screening program for ovarian cancer based on detection of a tumor biomarker in serum. Additionally, we discuss how circulating tumor DNA can be assayed to safely monitor breast cancer over the course of treatment, and report on how therapy with immune checkpoint inhibitors is proving effective in advanced lung cancer. Finally, we summarize efforts to use molecular profiling of prostate cancer biopsy specimens to support treatment decisions. Despite encouraging early successes, we cannot disregard the complex genetics of individual susceptibility to cancer nor the enormous complexity of the somatic changes observed in tumors, which urge particular attention to the development of personalized therapies

Differences in genotype and virulence among four multidrug-resistant <i>Streptococcus pneumoniae</i> isolates belonging to the PMEN1 clone

We report on the comparative genomics and characterization of the virulence phenotypes of four &lt;i&gt;S. pneumoniae&lt;/i&gt; strains that belong to the multidrug resistant clone PMEN1 (Spain&lt;sup&gt;23F&lt;/sup&gt; ST81). Strains SV35-T23 and SV36-T3 were recovered in 1996 from the nasopharynx of patients at an AIDS hospice in New York. Strain SV36-T3 expressed capsule type 3 which is unusual for this clone and represents the product of an in vivo capsular switch event. A third PMEN1 isolate - PN4595-T23 - was recovered in 1996 from the nasopharynx of a child attending day care in Portugal, and a fourth strain - ATCC700669 - was originally isolated from a patient with pneumococcal disease in Spain in 1984. We compared the genomes among four PMEN1 strains and 47 previously sequenced pneumococcal isolates for gene possession differences and allelic variations within core genes. In contrast to the 47 strains - representing a variety of clonal types - the four PMEN1 strains grouped closely together, demonstrating high genomic conservation within this lineage relative to the rest of the species. In the four PMEN1 strains allelic and gene possession differences were clustered into 18 genomic regions including the capsule, the blp bacteriocins, erythromycin resistance, the MM1-2008 prophage and multiple cell wall anchored proteins. In spite of their genomic similarity, the high resolution chinchilla model was able to detect variations in virulence properties of the PMEN1 strains highlighting how small genic or allelic variation can lead to significant changes in pathogenicity and making this set of strains ideal for the identification of novel virulence determinant

Evolutionary connectionism: algorithmic principles underlying the evolution of biological organisation in evo-devo, evo-eco and evolutionary transitions

The mechanisms of variation, selection and inheritance, on which evolution by natural selection depends, are not fixed over evolutionary time. Current evolutionary biology is increasingly focussed on understanding how the evolution of developmental organisations modifies the distribution of phenotypic variation, the evolution of ecological relationships modifies the selective environment, and the evolution of reproductive relationships modifies the heritability of the evolutionary unit. The major transitions in evolution, in particular, involve radical changes in developmental, ecological and reproductive organisations that instantiate variation, selection and inheritance at a higher level of biological organisation. However, current evolutionary theory is poorly equipped to describe how these organisations change over evolutionary time and especially how that results in adaptive complexes at successive scales of organisation (the key problem is that evolution is self-referential, i.e. the products of evolution change the parameters of the evolutionary process). Here we first reinterpret the central open questions in these domains from a perspective that emphasises the common underlying themes. We then synthesise the findings from a developing body of work that is building a new theoretical approach to these questions by converting well-understood theory and results from models of cognitive learning. Specifically, connectionist models of memory and learning demonstrate how simple incremental mechanisms, adjusting the relationships between individually-simple components, can produce organisations that exhibit complex system-level behaviours and improve the adaptive capabilities of the system. We use the term “evolutionary connectionism” to recognise that, by functionally equivalent processes, natural selection acting on the relationships within and between evolutionary entities can result in organisations that produce complex system-level behaviours in evolutionary systems and modify the adaptive capabilities of natural selection over time. We review the evidence supporting the functional equivalences between the domains of learning and of evolution, and discuss the potential for this to resolve conceptual problems in our understanding of the evolution of developmental, ecological and reproductive organisations and, in particular, the major evolutionary transitions

Dissemination and implementation of an educational tool for veterans on complementary and alternative medicine: a case study

Background Predicting when and where pathogens will emerge is difficult, yet, as shown by the recent Ebola and Zika epidemics, effective and timely responses are key. It is therefore crucial to transition from reactive to proactive responses for these pathogens. To better identify priorities for outbreak mitigation and prevention, we developed a cohesive framework combining disparate methods and data sources, and assessed subnational pandemic potential for four viral haemorrhagic fevers in Africa, Crimean–Congo haemorrhagic fever, Ebola virus disease, Lassa fever, and Marburg virus disease. Methods In this multistage analysis, we quantified three stages underlying the potential of widespread viral haemorrhagic fever epidemics. Environmental suitability maps were used to define stage 1, index-case potential, which assesses populations at risk of infection due to spillover from zoonotic hosts or vectors, identifying where index cases could present. Stage 2, outbreak potential, iterates upon an existing framework, the Index for Risk Management, to measure potential for secondary spread in people within specific communities. For stage 3, epidemic potential, we combined local and international scale connectivity assessments with stage 2 to evaluate possible spread of local outbreaks nationally, regionally, and internationally. Findings We found epidemic potential to vary within Africa, with regions where viral haemorrhagic fever outbreaks have previously occurred (eg, western Africa) and areas currently considered non-endemic (eg, Cameroon and Ethiopia) both ranking highly. Tracking transitions between stages showed how an index case can escalate into a widespread epidemic in the absence of intervention (eg, Nigeria and Guinea). Our analysis showed Chad, Somalia, and South Sudan to be highly susceptible to any outbreak at subnational levels. Interpretation Our analysis provides a unified assessment of potential epidemic trajectories, with the aim of allowing national and international agencies to pre-emptively evaluate needs and target resources. Within each country, our framework identifies at-risk subnational locations in which to improve surveillance, diagnostic capabilities, and health systems in parallel with the design of policies for optimal responses at each stage. In conjunction with pandemic preparedness activities, assessments such as ours can identify regions where needs and provisions do not align, and thus should be targeted for future strengthening and support

A New Species of River Dolphin from Brazil or:How Little Do We Know Our Biodiversity

True river dolphins are some of the rarest and most endangered of all vertebrates. They comprise relict evolutionary lineages of high taxonomic distinctness and conservation value, but are afforded little protection. We report the discovery of a new species of a river dolphin from the Araguaia River basin of Brazil, the first such discovery in nearly 100 years. The species is diagnosable by a series of molecular and morphological characters and diverged from its Amazonian sister taxon 2.08 million years ago. The estimated time of divergence corresponds to the separation of the Araguaia-Tocantins basin from the Amazon basin. This discovery highlights the immensity of the deficit in our knowledge of Neotropical biodiversity, as well as vulnerability of biodiversity to anthropogenic actions in an increasingly threatened landscape. We anticipate that this study will provide an impetus for the taxonomic and conservation reanalysis of other taxa shared between the Araguaia and Amazon aquatic ecosystems, as well as stimulate historical biogeographical analyses of the two basins

Decision to take osteoporosis medication in patients who have had a fracture and are 'high' risk for future fracture: A qualitative study

Abstract Background Patients' values and preferences are fundamental tenets of evidence-based practice, yet current osteoporosis (OP) clinical guidelines pay little attention to these issues in therapeutic decision making. This may be in part due to the fact that few studies have examined the factors that influence the initial decision to take OP medication. The purpose of our study was to examine patients' experiences with the decision to take OP medication after they sustained a fracture. Methods A phenomenological qualitative study was conducted with outpatients identified in a university teaching hospital fracture clinic OP program. Individuals aged 65+ who had sustained a fragility fracture within 5 years, were 'high risk' for future fracture, and were prescribed OP medication were eligible. Analysis of interview data was guided by Giorgi's methodology. Results 21 patients (6 males, 15 females) aged 65-88 years participated. All participants had low bone mass; 9 had OP. Fourteen patients were taking a bisphosphonate while 7 patients were taking no OP medications. For 12 participants, the decision to take OP medication occurred at the time of prescription and involved minimal contemplation (10/12 were on medication). These patients made their decision because they liked/trusted their health care provider. However, 4/10 participants in this group indicated their OP medication-taking status might change. For the remaining 9 patients, the decision was more difficult (4/9 were on medication). These patients were unconvinced by their health care provider, engaged in risk-benefit analyses using other information sources, and were concerned about side effects; 7/9 patients indicated that their OP medication-taking status might change at a later date. Conclusions Almost half of our older patients who had sustained a fracture found the decision to take OP medication a difficult one. In general, the decision was not considered permanent. Health care providers should be aware of their potential role in patients' decisions and monitor patients' decisions over time

A lightweight, flow-based toolkit for parallel and distributed bioinformatics pipelines

<p>Abstract</p> <p>Background</p> <p>Bioinformatic analyses typically proceed as chains of data-processing tasks. A pipeline, or 'workflow', is a well-defined protocol, with a specific structure defined by the topology of data-flow interdependencies, and a particular functionality arising from the data transformations applied at each step. In computer science, the dataflow programming (DFP) paradigm defines software systems constructed in this manner, as networks of message-passing components. Thus, bioinformatic workflows can be naturally mapped onto DFP concepts.</p> <p>Results</p> <p>To enable the flexible creation and execution of bioinformatics dataflows, we have written a modular framework for parallel pipelines in Python ('PaPy'). A PaPy workflow is created from re-usable components connected by data-pipes into a directed acyclic graph, which together define nested higher-order map functions. The successive functional transformations of input data are evaluated on flexibly pooled compute resources, either local or remote. Input items are processed in batches of adjustable size, all flowing one to tune the trade-off between parallelism and lazy-evaluation (memory consumption). An add-on module ('NuBio') facilitates the creation of bioinformatics workflows by providing domain specific data-containers (<it>e.g</it>., for biomolecular sequences, alignments, structures) and functionality (<it>e.g</it>., to parse/write standard file formats).</p> <p>Conclusions</p> <p>PaPy offers a modular framework for the creation and deployment of parallel and distributed data-processing workflows. Pipelines derive their functionality from user-written, data-coupled components, so PaPy also can be viewed as a lightweight toolkit for extensible, flow-based bioinformatics data-processing. The simplicity and flexibility of distributed PaPy pipelines may help users bridge the gap between traditional desktop/workstation and grid computing. PaPy is freely distributed as open-source Python code at <url>http://muralab.org/PaPy</url>, and includes extensive documentation and annotated usage examples.</p

Surviving Mousepox Infection Requires the Complement System

Poxviruses subvert the host immune response by producing immunomodulatory proteins, including a complement regulatory protein. Ectromelia virus provides a mouse model for smallpox where the virus and the host's immune response have co-evolved. Using this model, our study investigated the role of the complement system during a poxvirus infection. By multiple inoculation routes, ectromelia virus caused increased mortality by 7 to 10 days post-infection in C57BL/6 mice that lack C3, the central component of the complement cascade. In C3−/− mice, ectromelia virus disseminated earlier to target organs and generated higher peak titers compared to the congenic controls. Also, increased hepatic inflammation and necrosis correlated with these higher tissue titers and likely contributed to the morbidity in the C3−/− mice. In vitro, the complement system in naïve C57BL/6 mouse sera neutralized ectromelia virus, primarily through the recognition of the virion by natural antibody and activation of the classical and alternative pathways. Sera deficient in classical or alternative pathway components or antibody had reduced ability to neutralize viral particles, which likely contributed to increased viral dissemination and disease severity in vivo. The increased mortality of C4−/− or Factor B−/− mice also indicates that these two pathways of complement activation are required for survival. In summary, the complement system acts in the first few minutes, hours, and days to control this poxviral infection until the adaptive immune response can react, and loss of this system results in lethal infection

The highly attenuated oncolytic recombinant vaccinia virus GLV-1h68: comparative genomic features and the contribution of F14.5L inactivation

As a new anticancer treatment option, vaccinia virus (VACV) has shown remarkable antitumor activities (oncolysis) in preclinical studies, but potential infection of other organs remains a safety concern. We present here genome comparisons between the de novo sequence of GLV-1h68, a recombinant VACV, and other VACVs. The identified differences in open reading frames (ORFs) include genes encoding host-range selection, virulence and immune modulation proteins, e.g., ankyrin-like proteins, serine proteinase inhibitor SPI-2/CrmA, tumor necrosis factor (TNF) receptor homolog CrmC, semaphorin-like and interleukin-1 receptor homolog proteins. Phylogenetic analyses indicate that GLV-1h68 is closest to Lister strains but has lost several ORFs present in its parental LIVP strain, including genes encoding CrmE and a viral Golgi anti-apoptotic protein, v-GAAP. The reduced pathogenicity of GLV-1h68 is confirmed in male mice bearing C6 rat glioma and in immunocompetent mice bearing B16-F10 murine melanoma. The contribution of foreign gene expression cassettes in the F14.5L, J2R and A56R loci is analyzed, in particular the contribution of F14.5L inactivation to the reduced virulence is demonstrated by comparing the virulence of GLV-1h68 with its F14.5L-null and revertant viruses. GLV-1h68 is a promising engineered VACV variant for anticancer therapy with tumor-specific replication, reduced pathogenicity and benign tissue tropism

Dual Neonate Vaccine Platform against HIV-1 and M. tuberculosis

Acquired immunodeficiency syndrome and tuberculosis (TB) are two of the world's most devastating diseases. The first vaccine the majority of infants born in Africa receive is Mycobacterium bovis bacillus Calmette-Guérin (BCG) as a prevention against TB. BCG protects against disseminated disease in the first 10 years of life, but provides a variable protection against pulmonary TB and enhancing boost delivered by recombinant modified vaccinia virus Ankara (rMVA) expressing antigen 85A (Ag85A) of M. tuberculosis is currently in phase IIb evaluation in African neonates. If the newborn's mother is positive for human immunodeficiency virus type 1 (HIV-1), the baby is at high risk of acquiring HIV-1 through breastfeeding. We suggested that a vaccination consisting of recombinant BCG expressing HIV-1 immunogen administered at birth followed by a boost with rMVA sharing the same immunogen could serve as a strategy for prevention of mother-to-child transmission of HIV-1 and rMVA expressing an African HIV-1-derived immunogen HIVA is currently in phase I trials in African neonates. Here, we aim to develop a dual neonate vaccine platform against HIV-1 and TB consisting of BCG.HIVA administered at birth followed by a boost with MVA.HIVA.85A. Thus, mMVA.HIVA.85A and sMVA.HIVA.85A vaccines were constructed, in which the transgene transcription is driven by either modified H5 or short synthetic promoters, respectively, and tested for immunogenicity alone and in combination with BCG.HIVA222. mMVA.HIVA.85A was produced markerless and thus suitable for clinical manufacture. While sMVA.HIVA.85A expressed higher levels of the immunogens, it was less immunogenic than mMVA.HIVA.85A in BALB/c mice. A BCG.HIVA222–mMVA.HIVA.85A prime-boost regimen induced robust T cell responses to both HIV-1 and M. tuberculosis. Therefore, proof-of-principle for a dual anti-HIV-1/M. tuberculosis infant vaccine platform is established. Induction of immune responses against these pathogens soon after birth is highly desirable and may provide a basis for lifetime protection maintained by boosts later in life