Search

In 2019, the EAT-LancetCommission proposed a global reference dietary pattern. Although research on the EAT-Lancetreference diet and its associations with mortality, cardiovascular disease, type 2 diabetes, dietary environmental impacts, and cost of diets is increasing, studies done in low-income and middle-income countries remain scarce. This study aimed to assess the health outcomes, environmental impacts, and dietary costs of adherence to the EAT-Lancetreference diet in China.

A closed loop flat plate pulsating heat pipe, filled with Opteon™ SF33 (with a filling ratio of 50%), was experimentally studied in different orientations: 0° (horizontal), 22.5°, 45°, 67.5°, and 90° (“;edge”: vertical with horizontal channels). The results confirm the interest of such configurations, rarely investigated in the literature, on the thermal behavior of the device and on the regularity of the temperatures and pressure signals: If dried-out occurred in horizontal orientation, increase of inclination angle (starting from 22.5°) led to regular oscillatory movement due to help of gravity pressure drop between channels. The thermal performance remains very similar for the device inclination angles from 45° to 90°. Both FFT and wavelet analyses of the pressure signal and temperatures of the external wall of the device (measured with IR camera) were done to characterize the dominant oscillatory frequencies. These orientations led to dominant frequencies, rarely detected in the literature for other classic configurations (with vertical/inclined channels). Similar internal pressure and temperature signals both showed that the dominant frequency increases with decreasing angle (from edge to horizontal orientation), but also with increasing applied heat power, and finally tends to spread and disappear for the highest heat loads.

SOS1 and SOS2 are guanine nucleotide exchange factors that mediate RTK-stimulated RAS activation. Selective SOS1:KRAS PPI inhibitors are currently under clinical investigation, whereas there are no reports to date of SOS2:KRAS PPI inhibitors. SOS2 activity is implicated in MAPK rebound when divergent SOS1 mutant cell lines are treated with the SOS1 inhibitor BI-3406; therefore, SOS2:KRAS inhibitors are of therapeutic interest. In this report, we detail a fragment-based screening strategy to identify X-ray cocrystal structures of five diverse fragment hits bound to SOS2.

The synthesis of caged luminescent peptide substrates remains challenging, especially when libraries of the substrates are required. Most currently available synthetic methods rely on a solution-phase approach, which is less suited for parallel synthesis purposes. We herein present a solid-phase peptide synthesis (SPPS) method for the synthesis of caged aminoluciferin peptides via side chain anchoring of the P1residue. After the synthesis of a preliminary test library consisting of 40 compounds, the synthetic method was validated and optimized for up to >100 g of resin. Subsequently, two separate larger peptide libraries were synthesized either having a P1= lysine or arginine residue containing in total 719 novel peptide substrates. The use of a more stable caged nitrile precursor instead of caged aminoluciferin rendered our parallel synthetic approach completely suitable for SPPS and serine protease profiling was demonstrated using late-stage aminoluciferin generation.

Humans with dysfunctional Bruton’s tyrosine kinase (Btk) are highly susceptible to bacterial infections. Compelling evidence indicates that Btk is essential for B cell-mediated immunity, whereas its role in myeloid cell-mediated immunity against infections is controversial. In this study, we determined the contribution of Btk in B cells and neutrophils to host defense against the extracellular bacterial pathogen Klebsiella pneumoniae, a common cause of pulmonary infections and sepsis. Btk−/−mice were highly susceptible to Klebsiellainfection, which was not reversed by Btk re-expression in B cells and restoration of natural antibody levels. Neutrophil-specific Btk deficiency impaired host defense against Klebsiellato a similar extent as complete Btk deficiency. Neutrophil-specific Btk deficiency abolished extracellular reactive oxygen species production in response to Klebsiella. These data indicate that expression of Btk in neutrophils is crucial, while in B cells, it is dispensable for in vivo host defense against K. pneumoniae.

The global adoption of predominantly plant-based, sustainable, healthy diets will help reduce the risk of obesity- and malnutrition-related noncommunicable diseases while protecting the future health of our planet. This review examines the benefits and limitations of different types of plant-based diets in terms of health and nutrition, affordability and accessibility, cultural (ethical and religious) acceptability, and the environment (i.e., the 4 pillars underlying sustainable healthy diets). Results suggest that, without professional supervision, traditional plant-based diets (vegan, vegetarian, and pescatarian diets) can increase the risk of nutritional deficiencies among infants, children/adolescents, women, pregnant/lactating women, and the elderly. In contrast, flexitarian diets and territorial diversified diets (TDDs; e.g., Mediterranean and New Nordic diets) that include large quantities of plant-sourced foods, low amounts of red meat, and moderate amounts of poultry, fish, eggs, and dairy can meet the energy and nutrition needs of different populations without the need for dietary education or supplementation. Compared with vegan, vegetarian, and pescatarian diets, more diverse flexitarian diets and TDDs are associated with reduced volumes of food waste and may be more acceptable and easier to maintain for people who previously followed Western diets. Although flexitarian diets and TDDs have a greater impact on the environment than vegan, vegetarian, and pescatarian diets, the negative effects are considerably reduced compared with Western diets, especially if diets include locally sourced seasonal foods. Further studies are required to define more precisely optimal sustainable healthy diets for different populations and to ensure that diets are affordable and accessible to people in all countries.

The global adoption of predominantly plant-based, sustainable, healthy diets will help reduce the risk of obesity- and malnutrition-related noncommunicable diseases while protecting the future health of our planet. This review examines the benefits and limitations of different types of plant-based diets in terms of health and nutrition, affordability and accessibility, cultural (ethical and religious) acceptability, and the environment (i.e., the 4 pillars underlying sustainable healthy diets). Results suggest that, without professional supervision, traditional plant-based diets (vegan, vegetarian, and pescatarian diets) can increase the risk of nutritional deficiencies among infants, children/adolescents, women, pregnant/lactating women, and the elderly. In contrast, flexitarian diets and territorial diversified diets (TDDs; e.g., Mediterranean and New Nordic diets) that include large quantities of plant-sourced foods, low amounts of red meat, and moderate amounts of poultry, fish, eggs, and dairy can meet the energy and nutrition needs of different populations without the need for dietary education or supplementation. Compared with vegan, vegetarian, and pescatarian diets, more diverse flexitarian diets and TDDs are associated with reduced volumes of food waste and may be more acceptable and easier to maintain for people who previously followed Western diets. Although flexitarian diets and TDDs have a greater impact on the environment than vegan, vegetarian, and pescatarian diets, the negative effects are considerably reduced compared with Western diets, especially if diets include locally sourced seasonal foods. Further studies are required to define more precisely optimal sustainable healthy diets for different populations and to ensure that diets are affordable and accessible to people in all countries.Statement of Significance: In reviewing the criteria for sustainable healthy diets, we show that flexitarian and territorial diversified diets (TDDs) may offer the optimal balance between human and planetary health without the need for support from health care professionals. This is particularly pertinent to those populations at risk of nutritional deficiency from traditional plant-sourced diets such as veganism or vegetarianism. A global switch to flexitarian/TDDs may be a practical and affordable contributor to controlling climate change.

A prolonged prothrombin time (PT) is a common feature in sepsis indicating consumptive coagulopathy.

A prolonged prothrombin time (PT) is a common feature in sepsis indicating consumptive coagulopathy. To determine the association between a prolonged PT and aberrations in other host response mechanisms in sepsis. Patients admitted to the intensive care unit with sepsis were divided in quartiles according to the highest PT value measured within 24 h after admission. The host response was evaluated by measuring 19 plasma biomarkers reflecting pathways implicated in sepsis pathogenesis and by blood leukocyte gene expression profiling. Of 1524 admissions for sepsis, 386 (25.3%) involved patients with a normal PT (≤12.7 s); the remaining quartiles entailed 379 (24.9%) patients with a slightly prolonged PT (12.8 ≤ PT ≤ 15.0 s), 383 (25.1%) with an intermediately prolonged PT (15.1 ≤ PT ≤ 17.2 s), and 376 (24.7%) with an extremely prolonged PT (≥17.3 s). While patients with an extremely prolonged PT showed an increased crude mortality up to 1 year after admission, none of the prolonged PT groups was independently associated with 30‐day adjusted mortality. Comparison of the host response between patients with a normal PT or an extremely prolonged PT matched for baseline characteristics including severity of disease showed that an extremely prolonged PT was associated with impaired anticoagulant mechanisms, a more disturbed endothelial barrier integrity and increased systemic inflammation, and blood leukocyte transcriptomes indicating more prominent metabolic reprogramming and protein catabolism. A prolonged PT is associated with stronger anomalies in pathways implicated in the pathogenesis of sepsis, suggesting that activation of coagulation impacts other host response mechanisms.

AbstractLoneliness among older adults is a major societal problem. Research shows that feelings of loneliness are often linked to a lack of social relationships and social connectivity. Therefore, most loneliness interventions are focussing on strengthening and expanding the social life of older adults. Lonely older adults can also experience a lack of meaning in life, which can be countered by meaning-making interventions. Literature provides minimal insight into the design rationale of those interventions. This paper aims to provide insight into the design rationale of a Virtual Reality (VR) artefact for older adults with feelings of loneliness. The artefact focuses on retrieving meaningful memories through reminiscence. The needs and context of the participants were mapped by Research through Design (RtD), and a prototype was designed and tested. Preliminary test results suggest that VR-reminiscence can promote the well-being of lonely older adults, as well as the participatory design approach itself. VR-reminiscence triggered in-depth conversations about past, present, and future life. Based on the results of this study, it is recommended to design loneliness interventions beyond merely social relationships and social connectivity through designing tailored interventions that focus on the individual experience of loneliness by engaging older adults in the design process.

IMPORTANCE: Pathologic complete response (pCR) is a known prognostic biomarker for long-term outcomes. The I-SPY2 trial evaluated if the strength of this clinical association persists in the context of a phase 2 neoadjuvant platform trial. OBJECTIVE: To evaluate the association of pCR with event-free survival (EFS) and pCR with distant recurrence–free survival (DRFS) in subpopulations of women with high-risk operable breast cancer treated with standard therapy or one of several novel agents. DESIGN, SETTING, AND PARTICIPANTS: Multicenter platform trial of women with operable clinical stage 2 or 3 breast cancer with no prior surgery or systemic therapy for breast cancer; primary tumors were 2.5 cm or larger. Women with tumors that were ERBB2 negative/hormone receptor (HR) positive with low 70-gene assay score were excluded. Participants were adaptively randomized to one of several different investigational regimens or control therapy within molecular subtypes from March 2010 through 2016. The analysis included participants with follow-up data available as of February 26, 2019. INTERVENTIONS: Standard-of-care neoadjuvant therapy consisting of taxane treatment with or without (as control) one of several investigational agents or combinations followed by doxorubicin and cyclophosphamide. MAIN OUTCOMES AND MEASURES: Pathologic complete response and 3-year EFS and DRFS. RESULTS: Of the 950 participants (median [range] age, 49 [23-77] years), 330 (34.7%) achieved pCR. Three-year EFS and DRFS for patients who achieved pCR were both 95%. Hazard ratios for pCR vs non-pCR were 0.19 for EFS (95% CI, 0.12-0.31) and 0.21 for DRFS (95% CI, 0.13-0.34) and were similar across molecular subtypes, varying from 0.14 to 0.18 for EFS and 0.10 to 0.20 for DRFS. CONCLUSIONS AND RELEVANCE: The 3-year outcomes from the I-SPY2 trial show that, regardless of subtype and/or treatment regimen, including 9 novel therapeutic combinations, achieving pCR after neoadjuvant therapy implies approximately an 80% reduction in recurrence rate. The goal of the I-SPY2 trial is to rapidly identify investigational therapies that may improve pCR when validated in a phase 3 confirmatory trial. Whether pCR is a validated surrogate in the sense that a therapy that improves pCR rate can be assumed to also improve long-term outcome requires further study. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01042379

Klebsiella pneumoniae is an important cause of Gram-negative pneumonia and sepsis. Mice deficient for TIR-domain-containing adaptor-inducing interferon-β (TRIF) demonstrate enhanced bacterial growth and dissemination during Klebsiella pneumonia. We show here that the impaired antibacterial defense of TRIF mutant mice is associated with absent interferon (IFN)-γ production in the lungs. IFN-γ production by splenocytes in response to K. pneumoniae in vitro was critically dependent on Toll-like receptor 4 (TLR4), the common TLR adaptor myeloid differentiation primary response gene (MyD88) and TRIF. Reconstitution of TRIF mutant mice with recombinant IFN-γ via the airways reduced bacterial loads in lungs and distant body sites to levels measured in wild-type mice, and partially restored pulmonary cytokine levels. The IFN-γ-induced, improved, enhanced antibacterial response in TRIF mutant mice occurred at the expense of increased hepatocellular injury. These data indicate that TRIF mediates antibacterial defense during Gram-negative pneumonia, at least in part, by inducing IFN-γ at the primary site of infection. © 2015 S. Karger AG, Basel

Supplemental Digital Content is available in the text.

To address cancer as a multifaceted adaptive system, the increasing momentum for cross-disciplinary connectivity between cancer biologists, physical scientists, mathematicians, chemists, biomedical engineers, computer scientists, clinicians, and advocates is fueling the emergence of new scientific frontiers, principles, and opportunities within physical sciences and oncology. In parallel to highlighting the advances, challenges, and acceptance of advocates as credible contributors, we offer recommendations for addressing real world hurdles in advancing equitable partnerships among advocacy stakeholders.

Unlabelled Boxce:textbox-body/

We present new spectroscopic observations of the pre-main sequence eclipsing spectroscopic binary RS Cha. A sample of 174 spectra were obtained with the GIRAFFE spectrograph at the SAAO at 32 000 resolution. The radial velocity curves derived from these spectra were combined with previous observations spanning a period of about 30 years to correct the ephemeris of the system, and the result indicates that the orbital period is not constant.
Residuals of the binary radial velocity curve for both components with amplitudes up to a few km s-1and periods on the order of 1 h are clearly seen in our data, which we interpret as the signatures of delta-Scuti type pulsations.
We revisited the masses of both components and determined the surface metallicity Zof both components of the RS Cha system by fitting synthetic spectra to observed spectra in a set of selected spectral regions. The synthetic spectra are calculated with the SYNTH code using stellar atmosphere models computed with the Kurucz ATLAS 9 code, along with a list of lines obtained from the VALD database. A selection of the best spectra and the most relevant spectral regions allowed us to determine $Z = 0.028 \pm 0.005$. We also derived new values of $v\sin i$: $64 \pm 6$km s-1and $70 \pm 6$km s-1for the primary and the secondary star, respectively. Finally, we observationally confirm that the RS Cha system is a synchronized and circularized system.

One of the goals of the ground-based support program for the corotand mons/rømersatellite missions is to characterize suitable target stars for the part of the missions dedicated to asteroseismology. We present the detailed abundance analysis of nine of the potential corotmain targets using the semi-automatic software vwa. For two additional corottargets we could not perform the analysis due to the high rotational velocity of these stars. For five stars with low rotational velocity we have also performed abundance analysis by a classical equivalent width method in order to test the reliability of the vwasoftware. The agreement between the different methods is good. We find that it is necessary to measure abundances extracted from each line relative to the abundances found from a spectrum of the Sun in order to remove systematic errors. We have constrained the global atmospheric parameters Teff, $\log g$, and [Fe/H] to within $70{-}100$K, $0.1{-}0.2$dex, and 0.1 dex for five stars which are slow rotators ($v\sin i < 15 {\rm km\,s}^{-1}$). For most of the stars we find good agreement with the parameters found from line depth ratios, H αlines, Strömgren indices, previous spectroscopic studies, and also $\log g$determined from the hipparcosparallaxes. For the fast rotators ($v\sin i > 60 {\rm km\,s}^{-1}$) it is not possible to constrain the atmospheric parameters.

The concern about cancer recurrence has traditionally resulted in delaying kidney transplantation for 2–5 years after a cancer diagnosis in patients who are otherwise eligible for transplant. This period of inactive status to observe the tumor biology can result in significant morbidity and decreased quality of life for patients with end‐stage renal disease (ESRD). We reported the novel application of genomic profiling assays in breast cancer to identify low‐risk cancers in two patients with ESRDwho were able to have the mandatory inactive status eliminated prior to kidney transplantation. In a novel approach to stratify risk of recurrence in two patients diagnosed with breast cancer during the pretransplantation evaluation period, tumor genomic profiling, via commercially available tests, demonstrating low risk of recurrence enables a decision to proceed with kidney transplant without the typical waiting period, with excellent results.

The concern about cancer recurrence has traditionally resulted in delaying kidney transplantation for 2–5 years after a cancer diagnosis in patients who are otherwise eligible for transplant. This period of inactive status to observe the tumor biology can result in significant morbidity and decreased quality of life for patients with end-stage renal disease (ESRD). We reported the novel application of genomic profiling assays in breast cancer to identify low-risk cancers in two patients with ESRD who were able to have the mandatory inactive status eliminated prior to kidney transplantation.

By pursuing the goal to find new variables in the COROT field–of–view we characterised a sample of stars located in the lower part of the instability strip. Our sample is composed of stars belonging to the disk population in the solar neighbourhood. We found that 23% of the stars display multiperiodic light variability up to a few mmag in amplitude, i.e., easily detectable on a single night of photometry. $uvby\beta$photometry fixed most of the variables in the middle of the instability strip and high–resolution spectroscopy established that they have $v\sin i >100$km s-1. An analysis of the Rodriguez & Breger ([CITE]) sample (δSct stars in the whole Galaxy) shows slightly different features, i.e., most δSct stars have a 0.05–mag redder $(b-y)_0$index and lower $v\sin i$values. Additional investigation in the open cluster NGC 6633 confirms the same incidence of variability, i.e., around 20%. The wide variety of pulsational behaviours of δSct stars (including unusual objects such as a variable beyond the blue edge or a rapidly rotating high–amplitude pulsator) makes them very powerful asteroseismic tools to be used by COROT. Being quite common among bright stars, δSct stars are suitable targets for optical observations from space.

Using up-to-date model atmospheres (Heiter et al. 2002) with the turbulent convection approach developed by Canuto et al. (1996, CGM), quadratic, cubic and square root limb darkening coefficients (LDC) are calculated with a least square fit method for the Strömgren photometric system. This is done for a sample of solar metallicity models with effective temperatures between 6000 and 8500 K and with $\log g$between 2.5 and 4.5. A comparison is made between these LDC and the ones computed from model atmospheres using the classical mixing length prescription with a mixing length parameter $\alpha=1.25$and $\alpha=0.5$. For CGM model atmospheres, the law which reproduces better the model intensity is found to be the square root one for the uband and the cubic law for the vband. The results are more complex for the band ybands depending on the temperature and gravity of the model. Similar conclusions are reached for MLT $\alpha=0.5$models. As expected much larger differences are found between CGM and MLT with $\alpha=1.25$. In a second part, the weighted limb-darkening integrals, $b_{\ell}$, and their derivatives with respect to temperature and gravity, are then computed using the best limb-darkening law. These integrals are known to be very important in the context of photometric mode identification of non-radial pulsating stars. The effect of convection treatment on these quantities is discussed and as expected differences in the $b_\ell$coefficients and derivatives computed with CGM and MLT $\alpha=0.5$are much smaller than differences obtained between computations with CGM and MLT $\alpha=1.25$.

One of the goals of the ground-based support program for the COROT and MONS/Rømer satellite missions is to select and characterise suitable target stars for the part of the missions dedicated to asteroseismology. While the global atmospheric parameters may be determined with good accuracy from the Strömgren indices, careful abundance analysis must be made for the proposed main targets. This is a time consuming process considering the long list of primary and secondary targets. We have therefore developed new software called vwafor this task. The vwaautomatically selects the least blended lines from the atomic line database vald, and consequently adjusts the abundance in order to find the best match between the calculated and observed spectra. The variability of HD 49434 was discovered as part of COROT ground-based support observations. Here we present a detailed abundance analysis of HD 49434 using vwa. For most elements we find abundances somewhat below the Solar values, in particular we find [Fe/H] $= -0.13 \pm 0.14$. We also present the results from the study of the variability that is seen in spectroscopic and photometric time series observations. From the characteristics of the variation seen in photometry and in the line profiles we propose that HD 49434 is a variable star of the γDoradus type.

Major depressive disorder (MDD) is a highly recurrent condition, and improving our understanding of the abnormalities that persist in remitted MDD (rMDD) may provide insight into mechanisms that contribute to relapse. Reward learning deficits linked to dysfunction in frontostriatal regions are characteristic of MDD. Although initial behavioral evidence of reward learning deficits in rMDD has emerged, it is unclear whether these deficits reflect impairments in neural reward processing that persist into remission.

In the Fractional Flow Reserve Versus Angiography for Multivessel Evaluation (FAME) study, fractional flow reserve (FFR)-guided percutaneous coronary intervention (PCI) improved outcome compared with angiography-guided PCI for up to 2 years of follow-up. The aim in this study was to investigate whether the favourable clinical outcome with the FFR-guided PCI in the FAME study persisted over a 5-year follow-up.

Sepsis is associated with activation of platelets and endothelial cells accompanied by enhanced P-selectin surface expression. Both platelet- and endothelial P-selectin have been associated with leukocyte recruitment and induction of inflammatory alterations. Klebsiella (K.) pneumoniaeis a common human sepsis pathogen, particularly in the context of pneumonia.

Mitochondrial genomes are separated from the nuclear genome for most of the cell cycle by the nuclear double membrane, intervening cytoplasm, and the mitochondrial double membrane. Despite these physical barriers, we show that somatically acquired mitochondrial-nuclear genome fusion sequences are present in cancer cells. Most occur in conjunction with intranuclear genomic rearrangements, and the features of the fusion fragments indicate that nonhomologous end joining and/or replication-dependent DNA double-strand break repair are the dominant mechanisms involved. Remarkably, mitochondrial-nuclear genome fusions occur at a similar rate per base pair of DNA as interchromosomal nuclear rearrangements, indicating the presence of a high frequency of contact between mitochondrial and nuclear DNA in some somatic cells. Transmission of mitochondrial DNA to the nuclear genome occurs in neoplastically transformed cells, but we do not exclude the possibility that some mitochondrial-nuclear DNA fusions observed in cancer occurred years earlier in normal somatic cells.

AbstractStreptococcus pneumoniaeis a common cause of pneumonia and sepsis. Toll-like receptors (TLRs) play a pivotal role in the host defense against infection. In this study, we sought to determine the role of single immunoglobulin interleukin-1 receptor-related molecule (SIGIRR a.k.a. TIR8), a negative regulator of TLR signaling, in pneumococcal pneumonia and sepsis.Wild-type and SIGIRR-deficient (sigirr-/-) mice were infected intranasally (to induce pneumonia) or intravenously (to induce primary sepsis) with S. pneumoniaeand euthanized after 6, 24, or 48 h for analyses. Additionally, survival studies were performed. sigirr-/-mice showed delayed mortality during lethal pneumococcal pneumonia. Accordingly, sigirr-/-mice displayed lower bacterial loads in lungs and less dissemination of the infection 24 h after the induction of pneumonia. SIGIRR deficiency was associated with increased interstitial and perivascular inflammation in lung tissue early after infection, with no impact on neutrophil recruitment or cytokine production. sigirr-/-mice also demonstrated reduced bacterial burdens at multiple body sites during S. pneumoniae sepsis. sigirr-/-alveolar macrophages and neutrophils exhibited an increased capacity to phagocytose viable pneumococci. These results suggest that SIGIRR impairs the antibacterial host defense during pneumonia and sepsis caused by S. pneumoniae.© 2014 S. Karger AG, Basel

Macrolide resistance is an increasing problem; there is therefore debate about when to implement maintenance treatment with macrolides in patients with chronic obstructive pulmonary disease (COPD). We aimed to investigate whether patients with COPD who had received treatment for three or more exacerbations in the previous year would have a decrease in exacerbation rate when maintenance treatment with azithromycin was added to standard care.

First-generation molecular profiles for human breast cancers have enabled the identification of features that can predict therapeutic response; however, little is known about how the various data types can best be combined to yield optimal predictors. Collections of breast cancer cell lines mirror many aspects of breast cancer molecular pathobiology, and measurements of their omic and biological therapeutic responses are well-suited for development of strategies to identify the most predictive molecular feature sets. We used least squares-support vector machines and random forest algorithms to identify molecular features associated with responses of a collection of 70 breast cancer cell lines to 90 experimental or approved therapeutic agents. The datasets analyzed included measurements of copy number aberrations, mutations, gene and isoform expression, promoter methylation and protein expression. Transcriptional subtype contributed strongly to response predictors for 25% of compounds, and adding other molecular data types improved prediction for 65%. No single molecular dataset consistently out-performed the others, suggesting that therapeutic response is mediated at multiple levels in the genome. Response predictors were developed and applied to TCGA data, and were found to be present in subsets of those patient samples. These results suggest that matching patients to treatments based on transcriptional subtype will improve response rates, and inclusion of additional features from other profiling data types may provide additional benefit. Further, we suggest a systems biology strategy for guiding clinical trials so that patient cohorts most likely to respond to new therapies may be more efficiently identified.

Abstract: Objectives: The aim of our study was to investigate the circadian and weekly variation and assess the influence of environmental variables on the occurrence of acute myocardial infarction (AMI). Methods: Our study population consisted of 2983 consecutive patients admitted with AMI between January 2006 and May 2008. Data were abstracted from hospital records and partially from an electronic database. In patients with a known time of onset of AMI, circadian variation was analysed. In all patients, weekly variation of onset of AMI was analysed. Information on daily mean temperature, sunny hours, rainy hours, maximal humidity and mean atmospheric pressure was obtained from the KNMI database and the influence of these environmental variables on the incidence of AMI was analysed. Results and conclusion: Incidence of AMI shows a circadian pattern with an increase in occurrence during daylight. AMI occurs equally on each day of the week and no relation was found between environmental variables and the occurrence of AMI.

The year 2011 marked the 40 year anniversary of Richard Nixon signing the National Cancer Act, thus declaring the beginning of the “War on Cancer” in the United States. Whereas we have made tremendous progress toward understanding the genetics of tumors in the past four decades, and in developing enabling technology to dissect the molecular underpinnings of cancer at unprecedented resolution, it is only recently that the important role of the stromal microenvironment has been studied in detail. Cancer is a tissue-specific disease, and it is becoming clear that much of what we know about breast cancer progression parallels the biology of the normal breast differentiation, of which there is still much to learn. In particular, the normal breast and breast tumors share molecular, cellular, systemic and microenvironmental influences necessary for their progression. It is therefore enticing to consider a tumor to be a “rogue hacker”—one who exploits the weaknesses of a normal program for personal benefit. Understanding normal mammary gland biology and its “security vulnerabilities” may thus leave us better equipped to target breast cancer. In this review, we will provide a brief overview of the heterotypic cellular and molecular interactions within the microenvironment of the developing mammary gland that are necessary for functional differentiation, provide evidence suggesting that similar biology—albeit imbalanced and exaggerated—is observed in breast cancer progression particularly during the transition from carcinoma in situ to invasive disease. Lastly we will present evidence suggesting that the multigene signatures currently used to model cancer heterogeneity and clinical outcome largely reflect signaling from a heterogeneous microenvironment—a recurring theme that could potentially be exploited therapeutically.

Background:Melioidosis is a frequent cause of sepsis in Southeast Asia caused by the Gram‐negative bacterium Burkholderia pseudomallei. Patients with melioidosis have elevated circulating levels of plasminogen activator inhibitor type 1 (PAI‐1), an important regulator of inflammation and fibrinolysis. Objectives:In this study, we aimed to investigate the role of PAI‐1 during melioidosis. Methods:Wild‐type (WT) and PAI‐1‐deficient (PAI‐1–/1−/−) mice were intranasally infected with B. pseudomallei. Mice were killed after 24, 48 or 72 h. Lungs, liver and blood were harvested for measurement of bacterial loads, cytokines, clinical chemistry, histopathology, and coagulation parameters. Additionally, survival studies were performed. Results:PAI‐1−/−mice demonstrated enhanced susceptibility to B. pseudomalleiinfection, as shown by a strongly increased mortality rate (100% vs. 58% among WT mice, P<0.001), associated with enhanced bacterial loads in lungs, liver, and blood. Additionally, PAI‐1−/−mice showed elevated levels of proinflammatory cytokines in lungs and plasma, accompanied by enhanced local and systemic coagulation activation (thrombin–antithrombin complexes and D‐dimer), increased hepatocellular injury (plasma aspartate aminotransferase and alanine aminotransferase), and renal failure (plasma creatinine and urea). Conclusions:PAI‐1 has a protective role during severe Gram‐negative sepsis caused by B. pseudomalleiby limiting bacterial growth, inflammation, and coagulation, and probably, as a consequence thereof, distant organ injury.

The features of 100 mixed-phenotype acute leukemias (MPALs), fulfilling WHO 2008 criteria, are documented. Myeloid and T-lineage features were demonstrated by cytoplasmic myeloperoxidase and CD3; B-lineage features were demonstrated by at least 2 B-lymphoid markers. There were 62 men and 38 women; 68% were adults. Morphology was consistent with acute lymphoblastic leukemia (ALL; 43%), acute myeloid leukemia (AML; 42%), or inconclusive (15%). Immunophenotyping disclosed B + myeloid (59%), T + myeloid (35%), B + T (4%), or trilineage (2%) combinations. Cytogenetics evidenced t(9;22)/(Ph+) (20%), 11q23/MLLrearrangements (8%), complex (32%), aberrant (27%), or normal (13%) karyotypes. There was no correlation between age, morphology, immunophenotype, or cytogenetics. Response to treatment and outcome were available for 67 and 70 patients, respectively; 27 received ALL, 34 AML, 5 a combination of ALL + AML therapy, and 1 imatinib. ALL treatment induced a response in 85%, AML therapy in 41%; 3 of 5 patients responded to the combination therapy. Forty (58%) patients died, 33 of resistant disease. Overall median survival was 18 months and 37% of patients are alive at 5 years. Age, Ph+, and AML therapy were predictors for poor outcome (P< .001; P= .002; P= .003). MPAL is confirmed to be a poor-risk disease. Adults and Ph+patients should be considered for transplantation in first remission.

The features of 100 mixed-phenotype acute leukemias (MPALs), fulfilling WHO 2008 criteria, are documented. Myeloid and T-lineage features were demonstrated by cytoplasmic myeloperoxidase and CD3; B-lineage features were demonstrated by at least 2 B-lymphoid markers. There were 62 men and 38 women; 68% were adults. Morphology was consistent with acute lymphoblastic leukemia (ALL; 43%), acute myeloid leukemia (AML; 42%), or inconclusive (15%). Immunophenotyping disclosed B + myeloid (59%), T + myeloid (35%), B + T (4%), or trilineage (2%) combinations. Cytogenetics evidenced t(9;22)/(Ph+) (20%), 11q23/MLL rearrangements (8%), complex (32%), aberrant (27%), or normal (13%) karyotypes. There was no correlation between age, morphology, immunophenotype, or cytogenetics. Response to treatment and outcome were available for 67 and 70 patients, respectively; 27 received ALL, 34 AML, 5 a combination of ALL + AML therapy, and 1 imatinib. ALL treatment induced a response in 85%, AML therapy in 41%; 3 of 5 patients responded to the combination therapy. Forty (58%) patients died, 33 of resistant disease. Overall median survival was 18 months and 37% of patients are alive at 5 years. Age, Ph+, and AML therapy were predictors for poor outcome (P < .001; P = .002; P = .003). MPAL is confirmed to be a poor-risk disease. Adults and Ph+ patients should be considered for transplantation in first remission.

Several observational studies suggest an inverse association of protein with blood pressure (BP). However, little is known about the role of dietary protein from specific sources in BP.

Klebsiella pneumoniaeis a frequently isolated causative pathogen in respiratory tract infections. CD44 is a transmembrane adhesion molecule that has been implicated in several immunological processes. To determine the role of CD44 during Klebsiellapneumonia, we intranasally infected wild-type and CD44 knockout (KO) mice with 102to 104colony-forming units of K. pneumoniaeor administered Klebsiellalipopolysaccharide. During lethal infection, CD44 deficiency was associated with reduced bacterial growth and dissemination accompanied by enhanced pulmonary inflammation. After infection with lower Klebsielladoses, CD44 KO mice but not wild-type mice demonstrated mortality. After infection with even lower bacterial doses, which were cleared by most mice of both strains, CD44 KO mice displayed enhanced lung inflammation 4 and 10 days postinfection, indicating that CD44 is important for the resolution of pulmonary inflammation after nonlethal pneumonia. In accordance, CD44 KO mice showed a diminished resolution of lung inflammation 4 days after intrapulmonary delivery of lipopolysaccharide. CD44 deficiency was associated with the accumulation of hyaluronan together with reduced gene expression levels of the negative regulators of Toll-like receptor signaling, interleukin-1R-associated kinase M, A20, and suppressor of cytokine signaling 3. In conclusion, the absence of CD44 affects various components and phases of the host response during Klebsiellapneumonia, reducing bacterial outgrowth and dissemination and enhancing pulmonary pathology during lethal infection, and diminishing the resolution of lung inflammation during sublethal infection.

Somatic inactivation of the TP53gene in breast tumors is a marker for poor outcome, and breast cancer outcome might also be affected by germ-line variation in the TP53gene or its regulators. We investigated the effects of the germ-line single nucleotide polymorphisms TP53R72P (215G>C) and MDM2SNP309 (-410T>G), and p53 protein expression in breast tumors on survival. We pooled data from four breast cancer cohorts within the Breast Cancer Association Consortium for which both TP53R72P and MDM2SNP309 were genotyped and follow-up was available (n = 3,749). Overall and breast cancer-specific survival analyses were performed using Kaplan-Meier analysis and multivariate Cox's proportional hazards regression models. Survival of patients did not differ by carriership of either germ-line variant, R72P (215G>C) or SNP309 (-410G>T) alone. Immunohistochemical p53 staining of the tumor was available for two cohorts (n = 1,109 patients). Survival was worse in patients with p53-positive tumors (n = 301) compared to patients with p53-negative tumors (n = 808); breast cancer-specific survival: HR 1.6 (95% CI 1.2 to 2.1), P= 0.001. Within the patient group with p53-negative tumors, TP53rare homozygous (CC) carriers had a worse survival than G-allele (GG/GC) carriers; actuarial breast cancer-specific survival 71% versus 80%, P= 0.07; HR 1.8 (1.1 to 3.1), P= 0.03. We also found a differential effect of combinations of the two germ-line variants on overall survival; homozygous carriers of the G-allele in MDM2had worse survival only within the group of TP53C-allele carriers; actuarial overall survival (GG versus TT/TG) 64% versus 75%, P= 0.001; HR (GG versus TT) 1.5 (1.1 to 2.0), P= 0.01. We found no evidence for a differential effect of MDM2SNP309 by p53 protein expression on survival. The TP53R72P variant may be an independent predictor for survival of patients with p53-negative tumors. The combined effect of TP53R72P and MDM2SNP309 on survival is in line with our a priori biologically-supported hypothesis, that is, the role of enhanced DNA repair function of the TP53Pro-variant, combined with increased expression of the Mdm2 protein, and thus overall attenuation of the p53 pathway in the tumor cells.

Background: Over the past few years, a variety of multigene expression profiles have been developed to improve prognostication for early stage breast cancer and reduce overtreatment with chemotherapy. MammaPrint is the only test cleared by the US Food and Drug Administration for the prognostication of early breast cancer. The MammaPrint assay examines the expression of 70 genes in the primary tumor to stratify patients diagnosed with early stage breast cancer into good and poor prognosis groups. Objective: This evaluation reviews the development of the 70-gene profile, including validation studies involving patients with node-negative and 1 – 3 node-positive disease, the conversion of the 70-gene profile to a high-throughput diagnostic test, and the continuing prospective MINDACT clinical trial. Conclusion: The MammaPrint assay should help to determine which women with early breast cancer could be spared adjuvant chemotherapy.

We conducted a cohort-study among 518 female 5-year Hodgkin lymphoma (HL) survivors, aged 14 to 40 years (median: 25 years) at treatment (1965-1995). Multivariable Cox regression was used to quantify treatment effects on risk of premature menopause, defined as cessation of menses before age 40 years. After a median follow up of 9.4 years, 97 women had reached menopause before age 40 years. Chemotherapy was associated with a 12.3-fold increased risk of premature menopause compared with radiotherapy alone. Treatment with MOPP (mechlorethamine, vincristine, procarbazine, prednisone)/ABV (doxorubicine, bleomycine, vinblastine) significantly increased the risk of premature menopause (hazard ratio [HR]: 2.9), although to a lesser extent than MOPP treatment (HR: 5.7). Alkylating agents, especially procarbazine (HR: 8.1) and cyclophosphamide (HR: 3.5), showed the strongest associations. Ten years after treatment, the actuarial risk of premature menopause was 64% after high cumulative doses (> 8.4 g/m2) and 15% after low doses (≤ 4.2 g/m2) of procarbazine. The cumulative risk of menopause at age 40 years did not differ much according to age, but time to premature menopause was much longer in women treated at early ages. As long as alkylating agents will be used for curing HL, premature menopause will remain a frequent adverse treatment effect, with various clinical implications.

We conducted a cohort-study among 518 female 5-year Hodgkin lymphoma (HL) survivors, aged 14 to 40 years (median: 25 years) at treatment (1965-1995). Multivariable Cox regression was used to quantify treatment effects on risk of premature menopause, defined as cessation of menses before age 40 years. After a median follow up of 9.4 years, 97 women had reached menopause before age 40 years. Chemotherapy was associated with a 12.3-fold increased risk of premature menopause compared with radiotherapy alone. Treatment with MOPP (mechlorethamine, vincristine, procarbazine, prednisone)/ABV (doxorubicine, bleomycine, vinblastine) significantly increased the risk of premature menopause (hazard ratio [HR]: 2.9), although to a lesser extent than MOPP treatment (HR: 5.7). Alkylating agents, especially procarbazine (HR: 8.1) and cyclophosphamide (HR: 3.5), showed the strongest associations. Ten years after treatment, the actuarial risk of premature menopause was 64% after high cumulative doses (> 8.4 g/m2) and 15% after low doses (≤ 4.2 g/m2) of procarbazine. The cumulative risk of menopause at age 40 years did not differ much according to age, but time to premature menopause was much longer in women treated at early ages. As long as alkylating agents will be used for curing HL, premature menopause will remain a frequent adverse treatment effect, with various clinical implications.

Orientation of a bi-leaflet prosthesis (BLP) might influence coronary perfusion. The aim of this study was to investigate the influence of the orientation on coronary perfusion pressure during hyperemia and adrenergic stimulation. During hyperemia perfusion pressure determines coronary blood flow. Fourteen patients with normal coronary angiogram underwent aortic valve replacement (AVR) by a BLP, and seven received a bio-prosthesis. Patients receiving a BLP were randomized to either orientation A (hinge mechanism perpendicular to a line drawn between the coronary ostia) or B (hinge mechanism parallel to the line between the ostia). Six months after surgery all patients underwent cardiac catheterization. Pressures were measured during resting conditions, during maximum hyperemia, and during maximum adrenergic stimulation with a guiding catheter in the aortic arch (P(ao)), simultaneously with a sensor tipped guide wire in the coronary artery (P(cor)) and in the aortic root (P(root)). P(ao)-P(root) described a flow-induced pressure drop in the aortic root (Venturi effect) and the gradient P(root)-P(cor) described coronary ostium abnormalities. Only small non-significant differences in myocardial perfusion pressure were found between different orientations of a bi-leaflet prosthesis or between bi-leaflet prostheses and bio-prostheses in P(ao)-P(root) and P(root)-P(cor).

Very low-dose irradiation (2 × 2 Gy) is a new, effective, and safe local treatment for follicular lymphoma. To understand the biologic mechanisms of this extremely effective response, we compared by microarray the gene-expression profile of patients' biopsies taken before and after radiation. In all patients, a major and consistent induction of p53 target genes was seen. p53 targets involved in cell-cycle arrest and apoptosis showed the same mode of regulation, indicating that, in vivo, both are activated simultaneously. p53 up-regulation and p53-mediated proliferation arrest and apoptosis were substantiated using immunohistochemistry, with activation of both the intrinsic and the extrinsic apoptotic pathways. The other induced genes revealed a whole set of biologically meaningful genes related to macrophage activation and TH1 immune response. Immunohistochemical analysis suggested a specific activation or differentiation of resident macrophages by apoptotic cells. These biologic insights are important arguments to advocate the use of low-dose radiotherapy as an effective palliative treatment for follicular lymphoma. Moreover, this study is the first in vivo report of the radiation-induced p53 apoptotic response in patients and suggests that this apoptotic response is not immunologically silent.

Very low-dose irradiation (2 × 2 Gy) is a new, effective, and safe local treatment for follicular lymphoma. To understand the biologic mechanisms of this extremely effective response, we compared by microarray the gene-expression profile of patients' biopsies taken before and after radiation. In all patients, a major and consistent induction of p53 target genes was seen. p53 targets involved in cell-cycle arrest and apoptosis showed the same mode of regulation, indicating that, in vivo, both are activated simultaneously. p53 up-regulation and p53-mediated proliferation arrest and apoptosis were substantiated using immunohistochemistry, with activation of both the intrinsic and the extrinsic apoptotic pathways. The other induced genes revealed a whole set of biologically meaningful genes related to macrophage activation and TH1 immune response. Immunohistochemical analysis suggested a specific activation or differentiation of resident macrophages by apoptotic cells. These biologic insights are important arguments to advocate the use of low-dose radiotherapy as an effective palliative treatment for follicular lymphoma. Moreover, this study is the first in vivo report of the radiation-induced p53 apoptotic response in patients and suggests that this apoptotic response is not immunologically silent.

To assess the diagnostic accuracy of flow cytometric immunophenotyping in comparison with classic cytomorphology for diagnosing CNS localizations of hematologic malignancies, and to evaluate the implications of CSF pleocytosis and protein content in this context.