Showing papers by "University of Jena published in 2013"

Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.

Abstract: Objective:To provide an update to the “Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock,” last published in 2008.Design:A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at ke

Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock, 2012

Abstract: To provide an update to the “Surviving Sepsis Campaign Guidelines for Management of Severe Sepsis and Septic Shock,” last published in 2008. A consensus committee of 68 international experts representing 30 international organizations was convened. Nominal groups were assembled at key international meetings (for those committee members attending the conference). A formal conflict of interest policy was developed at the onset of the process and enforced throughout. The entire guidelines process was conducted independent of any industry funding. A stand-alone meeting was held for all subgroup heads, co- and vice-chairs, and selected individuals. Teleconferences and electronic-based discussion among subgroups and among the entire committee served as an integral part of the development. The authors were advised to follow the principles of the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system to guide assessment of quality of evidence from high (A) to very low (D) and to determine the strength of recommendations as strong (1) or weak (2). The potential drawbacks of making strong recommendations in the presence of low-quality evidence were emphasized. Recommendations were classified into three groups: (1) those directly targeting severe sepsis; (2) those targeting general care of the critically ill patient and considered high priority in severe sepsis; and (3) pediatric considerations. Key recommendations and suggestions, listed by category, include: early quantitative resuscitation of the septic patient during the first 6 h after recognition (1C); blood cultures before antibiotic therapy (1C); imaging studies performed promptly to confirm a potential source of infection (UG); administration of broad-spectrum antimicrobials therapy within 1 h of the recognition of septic shock (1B) and severe sepsis without septic shock (1C) as the goal of therapy; reassessment of antimicrobial therapy daily for de-escalation, when appropriate (1B); infection source control with attention to the balance of risks and benefits of the chosen method within 12 h of diagnosis (1C); initial fluid resuscitation with crystalloid (1B) and consideration of the addition of albumin in patients who continue to require substantial amounts of crystalloid to maintain adequate mean arterial pressure (2C) and the avoidance of hetastarch formulations (1B); initial fluid challenge in patients with sepsis-induced tissue hypoperfusion and suspicion of hypovolemia to achieve a minimum of 30 mL/kg of crystalloids (more rapid administration and greater amounts of fluid may be needed in some patients (1C); fluid challenge technique continued as long as hemodynamic improvement is based on either dynamic or static variables (UG); norepinephrine as the first-choice vasopressor to maintain mean arterial pressure ≥65 mmHg (1B); epinephrine when an additional agent is needed to maintain adequate blood pressure (2B); vasopressin (0.03 U/min) can be added to norepinephrine to either raise mean arterial pressure to target or to decrease norepinephrine dose but should not be used as the initial vasopressor (UG); dopamine is not recommended except in highly selected circumstances (2C); dobutamine infusion administered or added to vasopressor in the presence of (a) myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output, or (b) ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate mean arterial pressure (1C); avoiding use of intravenous hydrocortisone in adult septic shock patients if adequate fluid resuscitation and vasopressor therapy are able to restore hemodynamic stability (2C); hemoglobin target of 7–9 g/dL in the absence of tissue hypoperfusion, ischemic coronary artery disease, or acute hemorrhage (1B); low tidal volume (1A) and limitation of inspiratory plateau pressure (1B) for acute respiratory distress syndrome (ARDS); application of at least a minimal amount of positive end-expiratory pressure (PEEP) in ARDS (1B); higher rather than lower level of PEEP for patients with sepsis-induced moderate or severe ARDS (2C); recruitment maneuvers in sepsis patients with severe refractory hypoxemia due to ARDS (2C); prone positioning in sepsis-induced ARDS patients with a Pao 2/Fio 2 ratio of ≤100 mm Hg in facilities that have experience with such practices (2C); head-of-bed elevation in mechanically ventilated patients unless contraindicated (1B); a conservative fluid strategy for patients with established ARDS who do not have evidence of tissue hypoperfusion (1C); protocols for weaning and sedation (1A); minimizing use of either intermittent bolus sedation or continuous infusion sedation targeting specific titration endpoints (1B); avoidance of neuromuscular blockers if possible in the septic patient without ARDS (1C); a short course of neuromuscular blocker (no longer than 48 h) for patients with early ARDS and a Pao 2/Fi o 2 180 mg/dL, targeting an upper blood glucose ≤180 mg/dL (1A); equivalency of continuous veno-venous hemofiltration or intermittent hemodialysis (2B); prophylaxis for deep vein thrombosis (1B); use of stress ulcer prophylaxis to prevent upper gastrointestinal bleeding in patients with bleeding risk factors (1B); oral or enteral (if necessary) feedings, as tolerated, rather than either complete fasting or provision of only intravenous glucose within the first 48 h after a diagnosis of severe sepsis/septic shock (2C); and addressing goals of care, including treatment plans and end-of-life planning (as appropriate) (1B), as early as feasible, but within 72 h of intensive care unit admission (2C). Recommendations specific to pediatric severe sepsis include: therapy with face mask oxygen, high flow nasal cannula oxygen, or nasopharyngeal continuous PEEP in the presence of respiratory distress and hypoxemia (2C), use of physical examination therapeutic endpoints such as capillary refill (2C); for septic shock associated with hypovolemia, the use of crystalloids or albumin to deliver a bolus of 20 mL/kg of crystalloids (or albumin equivalent) over 5–10 min (2C); more common use of inotropes and vasodilators for low cardiac output septic shock associated with elevated systemic vascular resistance (2C); and use of hydrocortisone only in children with suspected or proven “absolute”’ adrenal insufficiency (2C). Strong agreement existed among a large cohort of international experts regarding many level 1 recommendations for the best care of patients with severe sepsis. Although a significant number of aspects of care have relatively weak support, evidence-based recommendations regarding the acute management of sepsis and septic shock are the foundation of improved outcomes for this important group of critically ill patients.

Photonic Floquet topological insulators

Abstract: Topological insulators are a new phase of matter, with the striking property that conduction of electrons occurs only on their surfaces. In two dimensions, electrons on the surface of a topological insulator are not scattered despite defects and disorder, providing robustness akin to that of superconductors. Topological insulators are predicted to have wide-ranging applications in fault-tolerant quantum computing and spintronics. Substantial effort has been directed towards realizing topological insulators for electromagnetic waves. One-dimensional systems with topological edge states have been demonstrated, but these states are zero-dimensional and therefore exhibit no transport properties. Topological protection of microwaves has been observed using a mechanism similar to the quantum Hall effect, by placing a gyromagnetic photonic crystal in an external magnetic field. But because magnetic effects are very weak at optical frequencies, realizing photonic topological insulators with scatter-free edge states requires a fundamentally different mechanism-one that is free of magnetic fields. A number of proposals for photonic topological transport have been put forward recently. One suggested temporal modulation of a photonic crystal, thus breaking time-reversal symmetry and inducing one-way edge states. This is in the spirit of the proposed Floquet topological insulators, in which temporal variations in solid-state systems induce topological edge states. Here we propose and experimentally demonstrate a photonic topological insulator free of external fields and with scatter-free edge transport-a photonic lattice exhibiting topologically protected transport of visible light on the lattice edges. Our system is composed of an array of evanescently coupled helical waveguides arranged in a graphene-like honeycomb lattice. Paraxial diffraction of light is described by a Schrodinger equation where the propagation coordinate (z) acts as 'time'. Thus the helicity of the waveguides breaks z-reversal symmetry as proposed for Floquet topological insulators. This structure results in one-way edge states that are topologically protected from scattering.

Rapid formation of plasma protein corona critically affects nanoparticle pathophysiology

Abstract: In biological fluids, proteins bind to the surface of nanoparticles to form a coating known as the protein corona, which can critically affect the interaction of the nanoparticles with living systems. As physiological systems are highly dynamic, it is important to obtain a time-resolved knowledge of protein-corona formation, development and biological relevancy. Here we show that label-free snapshot proteomics can be used to obtain quantitative time-resolved profiles of human plasma coronas formed on silica and polystyrene nanoparticles of various size and surface functionalization. Complex time- and nanoparticle-specific coronas, which comprise almost 300 different proteins, were found to form rapidly (<0.5 minutes) and, over time, to change significantly in terms of the amount of bound protein, but not in composition. Rapid corona formation is found to affect haemolysis, thrombocyte activation, nanoparticle uptake and endothelial cell death at an early exposure time.

Candida albicans pathogenicity mechanisms

Abstract: The polymorphic fungus Candida albicans is a member of the normal human microbiome. In most individuals, C. albicans resides as a lifelong, harmless commensal. Under certain circumstances, however, C. albicans can cause infections that range from superficial infections of the skin to life-threatening systemic infections. Several factors and activities have been identified which contribute to the pathogenic potential of this fungus. Among them are molecules which mediate adhesion to and invasion into host cells, the secretion of hydrolases, the yeast-to-hypha transition, contact sensing and thigmotropism, biofilm formation, phenotypic switching and a range of fitness attributes. Our understanding of when and how these mechanisms and factors contribute to infection has significantly increased during the last years. In addition, novel virulence mechanisms have recently been discovered. In this review we present an update on our current understanding of the pathogenicity mechanisms of this important human pathogen.

The Norway spruce genome sequence and conifer genome evolution.

Abstract: Conifers have dominated forests for more than 200 million years and are of huge ecological and economic importance. Here we present the draft assembly of the 20-gigabase genome of Norway spruce (Picea abies), the first available for any gymnosperm. The number of well-supported genes (28,354) is similar to the >100 times smaller genome of Arabidopsis thaliana, and there is no evidence of a recent whole-genome duplication in the gymnosperm lineage. Instead, the large genome size seems to result from the slow and steady accumulation of a diverse set of long-terminal repeat transposable elements, possibly owing to the lack of an efficient elimination mechanism. Comparative sequencing of Pinus sylvestris, Abies sibirica, Juniperus communis, Taxus baccata and Gnetum gnemon reveals that the transposable element diversity is shared among extant conifers. Expression of 24-nucleotide small RNAs, previously implicated in transposable element silencing, is tissue-specific and much lower than in other plants. We further identify numerous long (>10,000 base pairs) introns, gene-like fragments, uncharacterized long non-coding RNAs and short RNAs. This opens up new genomic avenues for conifer forestry and breeding.

Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.

Abstract: This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro. In a complex architecture of nested, zonated lobules, the liver consists of approximately 80 % hepatocytes and 20 % non-parenchymal cells, the latter being involved in a secondary phase that may dramatically aggravate the initial damage. Hepatotoxicity, as well as hepatic metabolism, is controlled by a set of nuclear receptors (including PXR, CAR, HNF-4α, FXR, LXR, SHP, VDR and PPAR) and signaling pathways. When isolating liver cells, some pathways are activated, e.g., the RAS/MEK/ERK pathway, whereas others are silenced (e.g. HNF-4α), resulting in up- and downregulation of hundreds of genes. An understanding of these changes is crucial for a correct interpretation of in vitro data. The possibilities and limitations of the most useful liver in vitro systems are summarized, including three-dimensional culture techniques, co-cultures with non-parenchymal cells, hepatospheres, precision cut liver slices and the isolated perfused liver. Also discussed is how closely hepatoma, stem cell and iPS cell-derived hepatocyte-like-cells resemble real hepatocytes. Finally, a summary is given of the state of the art of liver in vitro and mathematical modeling systems that are currently used in the pharmaceutical industry with an emphasis on drug metabolism, prediction of clearance, drug interaction, transporter studies and hepatotoxicity. One key message is that despite our enthusiasm for in vitro systems, we must never lose sight of the in vivo situation. Although hepatocytes have been isolated for decades, the hunt for relevant alternative systems has only just begun.

A Phase 2 Trial of Ponatinib in Philadelphia Chromosome–Positive Leukemias

Abstract: Background Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor–refractory threonineto-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome– positive acute lymphoblastic leukemia (Ph-positive ALL). Methods We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. Results Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event.

Social network changes and life events across the life span: a meta-analysis.

Abstract: For researchers and practitioners interested in social relationships, the question remains as to how large social networks typically are, and how their size and composition change across adulthood. On the basis of predictions of socioemotional selectivity theory and social convoy theory, we conducted a meta-analysis on age-related social network changes and the effects of life events on social networks using 277 studies with 177,635 participants from adolescence to old age. Cross-sectional as well as longitudinal studies consistently showed that (a) the global social network increased up until young adulthood and then decreased steadily, (b) both the personal network and the friendship network decreased throughout adulthood, (c) the family network was stable in size from adolescence to old age, and (d) other networks with coworkers or neighbors were important only in specific age ranges. Studies focusing on life events that occur at specific ages, such as transition to parenthood, job entry, or widowhood, demonstrated network changes similar to such age-related network changes. Moderator analyses detected that the type of network assessment affected the reported size of global, personal, and family networks. Period effects on network sizes occurred for personal and friendship networks, which have decreased in size over the last 35 years. Together the findings are consistent with the view that a portion of normative, age-related social network changes are due to normative, age-related life events. We discuss how these patterns of normative social network development inform research in social, evolutionary, cultural, and personality psychology.

Regulation of fungal secondary metabolism

Abstract: Fungi produce a multitude of low-molecular-mass compounds known as secondary metabolites, which have roles in a range of cellular processes such as transcription, development and intercellular communication. In addition, many of these compounds now have important applications, for instance, as antibiotics or immunosuppressants. Genome mining efforts indicate that the capability of fungi to produce secondary metabolites has been substantially underestimated because many of the fungal secondary metabolite biosynthesis gene clusters are silent under standard cultivation conditions. In this Review, I describe our current understanding of the regulatory elements that modulate the transcription of genes involved in secondary metabolism. I also discuss how an improved knowledge of these regulatory elements will ultimately lead to a better understanding of the physiological and ecological functions of these important compounds and will pave the way for a novel avenue to drug discovery through targeted activation of silent gene clusters.

High-power fibre lasers

Abstract: High-power fibre lasers are in demand for industrial, defence and scientific applications. This review provides an overview of the present state of the art in the field and discusses present challenges and the future outlook.

Cardiac metabolism in heart failure: implications beyond ATP production.

Abstract: The heart has a high rate of ATP production and turnover that is required to maintain its continuous mechanical work. Perturbations in ATP-generating processes may therefore affect contractile function directly. Characterizing cardiac metabolism in heart failure (HF) revealed several metabolic alterations called metabolic remodeling, ranging from changes in substrate use to mitochondrial dysfunction, ultimately resulting in ATP deficiency and impaired contractility. However, ATP depletion is not the only relevant consequence of metabolic remodeling during HF. By providing cellular building blocks and signaling molecules, metabolic pathways control essential processes such as cell growth and regeneration. Thus, alterations in cardiac metabolism may also affect the progression to HF by mechanisms beyond ATP supply. Our aim is therefore to highlight that metabolic remodeling in HF not only results in impaired cardiac energetics but also induces other processes implicated in the development of HF such as structural remodeling and oxidative stress. Accordingly, modulating cardiac metabolism in HF may have significant therapeutic relevance that goes beyond the energetic aspect.

Experimental boson sampling

Abstract: The boson-sampling problem is experimentally solved by implementing Aaronson and Arkhipov's model of computation with photons in integrated optical circuits. These results set a benchmark for a type of quantum computer that can potentially outperform a conventional computer by using only a few photons and linear optical elements.

Regulation of μ-opioid receptors: desensitization, phosphorylation, internalization, and tolerance.

Abstract: Morphine and related µ-opioid receptor (MOR) agonists remain among the most effective drugs known for acute relief of severe pain. A major problem in treating painful conditions is that tolerance limits the long-term utility of opioid agonists. Considerable effort has been expended on developing an understanding of the molecular and cellular processes that underlie acute MOR signaling, short-term receptor regulation, and the progression of events that lead to tolerance for different MOR agonists. Although great progress has been made in the past decade, many points of contention and controversy cloud the realization of this progress. This review attempts to clarify some confusion by clearly defining terms, such as desensitization and tolerance, and addressing optimal pharmacological analyses for discerning relative importance of these cellular mechanisms. Cellular and molecular mechanisms regulating MOR function by phosphorylation relative to receptor desensitization and endocytosis are comprehensively reviewed, with an emphasis on agonist-biased regulation and areas where knowledge is lacking or controversial. The implications of these mechanisms for understanding the substantial contribution of MOR signaling to opioid tolerance are then considered in detail. While some functional MOR regulatory mechanisms contributing to tolerance are clearly understood, there are large gaps in understanding the molecular processes responsible for loss of MOR function after chronic exposure to opioids. Further elucidation of the cellular mechanisms that are regulated by opioids will be necessary for the successful development of MOR-based approaches to new pain therapeutics that limit the development of tolerance.

Guided hierarchical co-assembly of soft patchy nanoparticles

Abstract: Different polymers can be used in combination to produce coexisting nanoparticles of different symmetry and tailored to co-assemble into well-ordered binary and ternary hierarchical structures. There is considerable practical interest in developing the tools to fabricate multicomponent artificial systems that mimic the hierarchical ordering seen in the natural world — complex biomaterials can be assembled from the simple but precisely defined molecular building blocks. Andre Groschel and colleagues have developed a bottom-up approach that's a step in that direction. Previously they designed simple linear polymers that self-assemble in solution to produce monodisperse nanoparticles with well-defined interaction anisotropies — surface 'patches' that direct self-assembly of the particles into larger structures. Now they show that different polymers can be used in combination to produce coexisting nanoparticles of different symmetry and tailored to co-assemble into well-ordered binary and ternary hierarchical structures. Possible applications of this approach range from smart materials to photonics. The concept of hierarchical bottom-up structuring commonly encountered in natural materials provides inspiration for the design of complex artificial materials with advanced functionalities1,2. Natural processes have achieved the orchestration of multicomponent systems across many length scales with very high precision3,4, but man-made self-assemblies still face obstacles in realizing well-defined hierarchical structures5,6,7,8,9,10,11. In particle-based self-assembly, the challenge is to program symmetries and periodicities of superstructures by providing monodisperse building blocks with suitable shape anisotropy or anisotropic interaction patterns (‘patches’). Irregularities in particle architecture are intolerable because they generate defects that amplify throughout the hierarchical levels. For patchy microscopic hard colloids, this challenge has been approached by using top-down methods (such as metal shading or microcontact printing), enabling molecule-like directionality during aggregation12,13,14,15,16. However, both top-down procedures and particulate systems based on molecular assembly struggle to fabricate patchy particles controllably in the desired size regime (10–100 nm). Here we introduce the co-assembly of dynamic patchy nanoparticles—that is, soft patchy nanoparticles that are intrinsically self-assembled and monodisperse—as a modular approach for producing well-ordered binary and ternary supracolloidal hierarchical assemblies. We bridge up to three hierarchical levels by guiding triblock terpolymers (length scale ∼10 nm) to form soft patchy nanoparticles (20–50 nm) of different symmetries that, in combination, co-assemble into substructured, compartmentalized materials (>10 μm) with predictable and tunable nanoscale periodicities. We establish how molecular control over polymer composition programs the building block symmetries and regulates particle positioning, offering a route to well-ordered mixed mesostructures of high complexity.

Multiple independent variants at the TERT locus are associated with telomere length and risks of breast and ovarian cancer

Abstract: TERT-locus SNPs and leukocyte telomere measures are reportedly associated with risks of multiple cancers. Using the Illumina custom genotyping array iCOG, we analyzed similar to 480 SNPs at the TERT locus in breast (n = 103,991), ovarian (n = 39,774) and BRCA1 mutation carrier (n = 11,705) cancer cases and controls. Leukocyte telomere measurements were also available for 53,724 participants. Most associations cluster into three independent peaks. The minor allele at the peak 1 SNP rs2736108 associates with longer telomeres (P = 5.8 x 10(-7)), lower risks for estrogen receptor (ER)-negative (P = 1.0 x 10(-8)) and BRCA1 mutation carrier (P = 1.1 x 10(-5)) breast cancers and altered promoter assay signal. The minor allele at the peak 2 SNP rs7705526 associates with longer telomeres (P = 2.3 x 10(-14)), higher risk of low-malignant-potential ovarian cancer (P = 1.3 x 10(-15)) and greater promoter activity. The minor alleles at the peak 3 SNPs rs10069690 and rs2242652 increase ER-negative (P = 1.2 x 10(-12)) and BRCA1 mutation carrier (P = 1.6 x 10-14) breast and invasive ovarian (P = 1.3 x 10(-11)) cancer risks but not via altered telomere length. The cancer risk alleles of rs2242652 and rs10069690, respectively, increase silencing and generate a truncated TERT splice variant.

Novel Process Windows for Enabling, Accelerating, and Uplifting Flow Chemistry

Abstract: Novel Process Windows make use of process conditions that are far from conventional practices. This involves the use of high temperatures, high pressures, high concentrations (solvent-free), new chemical transformations, explosive conditions, and process simplification and integration to boost synthetic chemistry on both the laboratory and production scale. Such harsh reaction conditions can be safely reached in microstructured reactors due to their excellent transport intensification properties. This Review discusses the different routes towards Novel Process Windows and provides several examples for each route grouped into different classes of chemical and process-design intensification.

Methods of measurement and evaluation of natural antioxidant capacity/activity (IUPAC Technical Report)

Abstract: The chemical diversity of natural antioxidants (AOXs) makes it difficult to sepa- rate, detect, and quantify individual antioxidants from a complex food/biological matrix. Moreover, the total antioxidant power is often more meaningful to evaluate health beneficial effects because of the cooperative action of individual antioxidant species. Currently, there is no single antioxidant assay for food labeling because of the lack of standard quantification methods. Antioxidant assays may be broadly classified as the electron transfer (ET)- and hydrogen atom transfer (HAT)-based assays. The results obtained are hardly comparable because of the different mechanisms, redox potentials, pH and solvent dependencies, etc. of various assays. This project will aid the identification and quantification of properties and mutual effects of antioxidants, bring a more rational basis to the classification of antioxidant assays with their constraints and challenges, and make the results more comparable and understandable. In this regard, the task group members convey their own experiences in var- ious methods of antioxidants measurement.

A genomics-based classification of human lung tumors

Abstract: We characterized genome alterations in 1255 clinically annotated lung tumors of all histological subgroups to identify genetically defined and clinically relevant subtypes. More than 55% of all cases had at least one oncogenic genome alteration potentially amenable to specific therapeutic intervention, including several personalized treatment approaches that are already in clinical evaluation. Marked differences in the pattern of genomic alterations existed between and within histological subtypes, thus challenging the original histomorphological diagnosis. Immunohistochemical studies confirmed many of these reassigned subtypes. The reassignment eliminated almost all cases of large cell carcinomas, some of which had therapeutically relevant alterations. Prospective testing of our genomics-based diagnostic algorithm in 5145 lung cancer patients enabled a genome-based diagnosis in 3863 (75%) patients, confirmed the feasibility of rational reassignments of large cell lung cancer, and led to improvement in overall survival in patients with EGFR-mutant or ALK-rearranged cancers. Thus, our findings provide support for broad implementation of genome-based diagnosis of lung cancer.

Efficacy and Safety of Ivacaftor in Patients Aged 6 to 11 Years with Cystic Fibrosis with a G551D Mutation

Abstract: Rationale: Ivacaftor (VX-770), a cystic fibrosis transmembrane conductance regulator (CFTR) potentiator, has been shown to improve lung function, pulmonary exacerbation rate, respiratory symptoms, and weight gain compared with placebo in patients with cystic fibrosis aged 12 years or older with a G551D-CFTR mutation.Objectives: This randomized, double-blind, placebo-controlled trial evaluated ivacaftor in patients with cystic fibrosis aged 6–11 years with a G551D-CFTR mutation on at least one allele.Methods: Patients were randomly assigned to receive ivacaftor administered orally at 150 mg (n = 26) or placebo (n = 26) every 12 hours for 48 weeks in addition to existing prescribed cystic fibrosis therapies.Measurements and Main Results: Despite near-normal mean baseline values in FEV1, patients receiving ivacaftor had a significant increase in percent predicted FEV1 from baseline through Week 24 versus placebo group (treatment effect, 12.5 percentage points; P < 0.001). Effects on pulmonary function were e...

Diagnosis of Lung Cancer in Small Biopsies and Cytology: Implications of the 2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Classification

Abstract: The new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society lung adenocarcinoma classification provides, for the first time, standardized terminology for lung cancer diagnosis in small biopsies and cytology; this was not primarily addressed by previous World Health Organization classifications. Until recently there have been no therapeutic implications to further classification of NSCLC, so little attention has been given to the distinction of adenocarcinoma and squamous cell carcinoma in small tissue samples. This situation has changed dramatically in recent years with the discovery of several therapeutic options that are available only to patients with adenocarcinoma or NSCLC, not otherwise specified, rather than squamous cell carcinoma. This includes recommendation for use of special stains as an aid to diagnosis, particularly in the setting of poorly differentiated tumors that do not show clear differentiation by routine light microscopy. A lim...

Photonic Floquet topological insulators

Abstract: Topological insulators are a new phase of matter, with the striking property that conduction of electrons occurs only on the surface. In two dimensions, surface electrons in topological insulators do not scatter despite defects and disorder, providing robustness akin to superconductors. Topological insulators are predicted to have wideranging applications in fault-tolerant quantum computing and spintronics. Recently, large theoretical efforts were directed towards achieving topological insulation for electromagnetic waves. One-dimensional systems with topological edge states have been demonstrated, but these states are zero-dimensional, and therefore exhibit no transport properties. Topological protection of microwaves has been observed using a mechanism similar to the quantum Hall effect, by placing a gyromagnetic photonic crystal in an external magnetic field. However, since magnetic effects are very weak at optical frequencies, realizing photonic topological insulators with scatterfree edge states requires a fundamentally different mechanism - one that is free of magnetic fields. Recently, a number of proposals for photonic topological transport have been put forward. Specifically, one suggested temporally modulating a photonic crystal, thus breaking time-reversal symmetry and inducing one-way edge states. This is in the spirit of the proposed Floquet topological insulators, where temporal variations in solidstate systems induce topological edge states. Here, we propose and experimentally demonstrate the first external field-free photonic topological insulator with scatter-free edge transport: a photonic lattice exhibiting topologically protected transport of visible light on the lattice edges. Our system is composed of an array of evanescently coupled helical waveguides arranged in a graphene-like honeycomb lattice. Paraxial diffraction of light is described by a Schrodinger equation where the propagation coordinate acts as ‘time’. Thus the waveguides' helicity breaks zreversal symmetry in the sense akin to Floquet Topological Insulators. This structure results in scatter-free, oneway edge states that are topologically protected from scattering.

Strain-induced pseudomagnetic field and photonic Landau levels in dielectric structures

Abstract: Magnetic effects are fundamentally weak at optical frequencies. Now, by applying inhomogeneous strain in photonic band structures of a honeycomb lattice of waveguides, scientists show experimentally and theoretically that it is possible to induce a pseudomagnetic field at optical frequencies. The field yields 'photonic Landau levels', which suggests the possibility of achieving greater field enhancements and slow-light effects in aperiodic photonic crystal structures than those available in periodic structures.

GWAS meta-analysis and replication identifies three new susceptibility loci for ovarian cancer

Abstract: Genome-wide association studies (GWAS) have identified four susceptibility loci for epithelial ovarian cancer (EOC), with another two suggestive loci reaching near genome-wide significance. We pooled data from a GWAS conducted in North America with another GWAS from the UK. We selected the top 24,551 SNPs for inclusion on the iCOGS custom genotyping array. We performed follow-up genotyping in 18,174 individuals with EOC (cases) and 26,134 controls from 43 studies from the Ovarian Cancer Association Consortium. We validated the two loci at 3q25 and 17q21 that were previously found to have associations close to genome-wide significance and identified three loci newly associated with risk: two loci associated with all EOC subtypes at 8q21 (rs11782652, P = 5.5 × 10(-9)) and 10p12 (rs1243180, P = 1.8 × 10(-8)) and another locus specific to the serous subtype at 17q12 (rs757210, P = 8.1 × 10(-10)). An integrated molecular analysis of genes and regulatory regions at these loci provided evidence for functional mechanisms underlying susceptibility and implicated CHMP4C in the pathogenesis of ovarian cancer.