Decomposing the queue length distribution of processor-sharing models into queue lengths of permanent customer queues

We obtain a decomposition result for the steady state queue length distribution in egalitarian processor-sharing (PS) models. In particular, for an egalitarian PS queue with $K$ customer classes, we show that the marginal queue length distribution for class $k$ factorizes over the number of other customer types. The factorizing coefficients equal the queue length probabilities of a PS queue for type $k$ in isolation, in which the customers of the other types reside \textit{ permanently} in the system. Similarly, the (conditional) mean sojourn time for class $k$ can be obtained by conditioning on the number of permanent customers of the other types. The decomposition result implies linear relations between the marginal queue length probabilities, which also hold for other PS models such as the egalitarian processor-sharing models with state-dependent system capacity that only depends on the total number of customers in the system. Based on the exact decomposition result for egalitarian PS queues, we propose a similar decomposition for discriminatory processor-sharing (DPS) models, and numerically show that the approximation is accurate for moderate differences in service weights. \u

Personalized Bladder Cancer Management

Bladder cancer incidence in the Netherlands has increased over 1.5-fold since the 1990s, with currently over 7.000 new cases each year in the Netherlands. Over two thirds of new patients are diagnosed with NMIBC, the remaining one third of patients are diagnosed with MIBC. The 5-year survival of NMIBC patients is very good (>90%), however recurrence rates are high (>50%) and the disease may progress to MIBC. Consequently, NMIBC necessitates long and costly surveillance. On the other hand, the prognosis of MIBC is very poor; the 5-year survival rate is around 60% for stage T2 and only 6% for stage T4 disease 6. Treatment options for MIBC are limited and the survival rates have not improved much over the past 20 years, although recently introduced immune therapies present promising results. The high incidence and recurrence rate of NMIBC, together with the poor survival rate of MIBC and the immense costs make bladder cancer a serious public health problem. The general aim of this thesis was to evaluate and validate the use of (epi)genetic biomarkers in personalized bladder cancer management; including diagnosis of primary disease, prognosis of disease, tools for treatment allocation and their use in individualized surveillance regimens

Early IL-1 signaling promotes iBALT induction after influenza virus infection

Inducible bronchus-associated lymphoid tissue (iBALT) is a long lasting tertiary lymphoid tissue that can be induced following influenza A virus (IAV) infection. Previous studies have shown that iBALT structures containing germinal center (GC) B cells protect against repeated infection by contributing locally to the cellular and humoral immune response. If we are to exploit this in vaccination strategies, we need a better understanding on how iBALT structures are induced. One hypothesis is that the strength of the initial innate response dictates induction of iBALT. In the present study, we investigated the role of interleukin (IL)-1 and IL-1R signaling on iBALT formation. Mice lacking the IL-1R had a delayed viral clearance and, thus, a prolonged exposure to viral replication, leading to increased disease severity, compared to wild-type mice. Contradictorily, iBALT formation following clearance of the virus was heavily compromised in Il1r1-/- mice. Quantification of gene induction after IAV infection demonstrated induction of IL-1α and to a much lesser extent of IL-1β. Administration of recombinant IL-1α to the lungs of wild-type mice, early but not late, after IAV infection led to more pronounced iBALT formation and an increased amount of GC B cells in the lungs. Bone marrow chimeric mice identified the stromal compartment as the crucial IL-1 responsive cell for iBALT induction. Mechanistically, Q-PCR analysis of lung homogenates revealed a strongly diminished production of CXCL13, a B cell-attracting chemokine, in Il1r-/- mice during the early innate phase of IAV infection. These experiments demonstrate that appropriate innate IL-1α-IL-1R signaling is necessary for IAV clearance and at the same time instructs the formation of organized tertiary lymphoid tissues through induction of CXCL13 early after infection. These findings are discussed in the light of recent insights on the pathogenesis of tertiary lymphoid organ formation in the lung in various diseases where the IL-1 axis is hyperactive, such as rheumatoid arthritis and COPD

A reported 20-gene expression signature to predict lymph node-positive disease at radical cystectomy for muscle-invasive bladder cancer is clinically not applicable

Background Neoadjuvant chemotherapy (NAC) for muscle-invasive bladder cancer (MIBC) provides a small but significant survival benefit. Nevertheless, controversies on applying NAC remain because the limited benefit must be weight against chemotherapy-related toxicity and the delay of definitive local treatment. Therefore, there is a clear clinical need for tools to guide treatment decisions on NAC in MIBC. Here, we aimed to validate a previously reported 20-gene expression signature that predicted lymph node-positive disease at radical cystectomy in clinically node-negative MIBC patients, which would be a justification for upfront chemotherapy. Methods We studied diagnostic transurethral resection of bladder tumors (dTURBT) of 150 MIBC patients (urothelial carcinoma) who were subsequently treated by radical cystectomy and pelvic lymph node dissection. RNA was isolated and the expression level of the 20 genes was determined on a qRT-PCR platform. Normalized Ct values were used to calculate a risk score to predict the presence of node-positive disease. The Cancer Genome Atlas (TCGA) RNA expression data was analyzed to subsequently validate the results. Results In a univariate regression analysis, none of the 20 genes significantly correlated with nodepositive disease. The area under the curve of the risk score calculated by the 20-gene expression signature was 0.54 (95% Confidence Interval: 0.44-0.65) versus 0.67 for the model published by Smith et al. Node-negative patients had a significantly lower tumor grade at TURBT (p = 0.03), a lower pT stage (p<0.01) and less frequent lymphovascular invasion (13% versus 38%, p<0.01) at radical cystectomy than node-positive patients. In addition, in the TCGA data, none of the 20 genes was differentially expressed in node-negative versus node-positive patients. Conclusions We conclude that a 20-gene expression signature developed for nodal staging of MIBC at radical cystectomy could not be validated on a qRT-PCR platform in a large cohort of dTURBT specimens

Maximizing efficiency of rumen microbial protein production.

Rumen microbes produce cellular protein inefficiently partly because they do not direct all ATP toward growth. They direct some ATP toward maintenance functions, as long-recognized, but they also direct ATP toward reserve carbohydrate synthesis and energy spilling (futile cycles that dissipate heat). Rumen microbes expend ATP by vacillating between (1) accumulation of reserve carbohydrate after feeding (during carbohydrate excess) and (2) mobilization of that carbohydrate thereafter (during carbohydrate limitation). Protozoa account for most accumulation of reserve carbohydrate, and in competition experiments, protozoa accumulated nearly 35-fold more reserve carbohydrate than bacteria. Some pure cultures of bacteria spill energy, but only recently have mixed rumen communities been recognized as capable of the same. When these communities were dosed glucose in vitro, energy spilling could account for nearly 40% of heat production. We suspect that cycling of glycogen (a major reserve carbohydrate) is a major mechanism of spilling; such cycling has already been observed in single-species cultures of protozoa and bacteria. Interconversions of short-chain fatty acids (SCFA) may also expend ATP and depress efficiency of microbial protein production. These interconversions may involve extensive cycling of intermediates, such as cycling of acetate during butyrate production in certain butyrivibrios. We speculate this cycling may expend ATP directly or indirectly. By further quantifying the impact of reserve carbohydrate accumulation, energy spilling, and SCFA interconversions on growth efficiency, we can improve prediction of microbial protein production and guide efforts to improve efficiency of microbial protein production in the rumen

Urinary peptide panel for prognostic assessment of bladder cancer relapse

Non-invasive tools stratifying bladder cancer (BC) patients according to the risk of relapse are urgently needed to guide clinical intervention. As a follow-up to the previously published study on CE-MSbased urinary biomarkers for BC detection and recurrence monitoring, we expanded the investigation towards BC patients with longitudinal data. Profling datasets of BC patients with follow-up information regarding the relapse status were investigated. The peptidomics dataset (n=98) was split into training and test set. Cox regression was utilized for feature selection in the training set. Investigation of the entire training set at the single peptide level revealed 36 peptides being strong independent prognostic markers of disease relapse. Those features were further integrated into a Random Forest-based model evaluating the risk of relapse for BC patients. Performance of the model was assessed in the test cohort, showing high signifcance in BC relapse prognosis [HR=5.76, p-value=0.0001, c-index=0.64]. Urinary peptide profles integrated into a prognostic model allow for quantitative risk assessment of BC relapse highlighting the need for its incorporation in prospective studies to establish its value in the clinical management of BC

Glutamine as an Immunonutrient

Dietary supplementation with nutrients enhancing immune function is beneficial in patients with surgical and critical illness. Malnutrition and immune dysfunction are common features in hospitalized patients. Specific nutrients with immunological and pharmacological effects, when consumed in amounts above the daily requirement, are referred to as immune-enhancing nutrients or immunonutrients. Supplementation of immunonutrients is important especially for patients with immunodeficiency, virus or overwhelming infections accompanied by a state of malnutrition. Representative immunonutrients are arginine, omega-3 fatty acids, glutamine, nucleotides, beta-carotene, and/or branched-chain amino acids. Glutamine is the most abundant amino acid and performs multiple roles in human body. However, glutamine is depleted from muscle stores during severe metabolic stress including sepsis and major surgery. Therefore it is considered conditionally essential under these conditions. This review discusses the physiological role of glutamine, mode and dose for glutamine administration, as well as improvement of certain disease state after glutamine supplementation. Even though immunonutrition has not been widely assimilated by clinicians other than nutritionists, immunonutrients including glutamine may exert beneficial influence on diverse patient populations

Large scale galactic turbulence: can self-gravity drive the observed HI velocity dispersions?

Observations of turbulent velocity dispersions in the HI component of galactic disks show a characteristic floor in galaxies with low star formation rates and within individual galaxies the dispersion profiles decline with radius. We carry out several high resolution adaptive mesh simulations of gaseous disks embedded within dark matter haloes to explore the roles of cooling, star-formation, feedback, shearing motions and baryon fraction in driving turbulent motions. In all simulations the disk slowly cools until gravitational and thermal instabilities give rise to a multi-phase medium in which a large population of dense self-gravitating cold clouds are embedded within a warm gaseous phase that forms through shock heating. The diffuse gas is highly turbulent and is an outcome of large scale driving of global non-axisymmetric modes as well as cloud-cloud tidal interactions and merging. At low star-formation rates these processes alone can explain the observed HI velocity dispersion profiles and the characteristic value of ~10 km/s observed within a wide range of disk galaxies. Supernovae feedback creates a significant hot gaseous phase and is an important driver of turbulence in galaxies with a star-formation rate per unit area >10^-3 M_sun/yr/kpc^2.Comment: 18 pages, 23 figures, MNRAS accepted. Typos and minor errors corrected. A version with high-resolution figures can be found at http://www-theorie.physik.unizh.ch/~agertz/DISK

Comparative genomic analysis of mycobacteriophage Tweety: evolutionary insights and construction of compatible site-specific integration vectors for mycobacteria

Mycobacteriophage Tweety is a newly isolated phage of Mycobacterium smegmatis. It has a viral morphology with an isometric head and a long flexible tail, and forms turbid plaques from which stable lysogens can be isolated. The Tweety genome is 58 692 bp in length, contains 109 protein-coding genes, and shows significant but interrupted nucleotide sequence similarity with the previously described mycobacteriophages Llij, PMC and Che8. However, overall the genome possesses mosaic architecture, with gene products being related to other mycobacteriophages such as Che9d, Omega and Corndog. A gene encoding an integrase of the tyrosine-recombinase family is located close to the centre of the genome, and a putative attP site has been identified within a short intergenic region immediately upstream of int. This Tweety attP–int cassette was used to construct a new set of integration-proficient plasmid vectors that efficiently transform both fast- and slow-growing mycobacteria through plasmid integration at a chromosomal locus containing a tRNALys gene. These vectors are maintained well in the absence of selection and are completely compatible with integration vectors derived from mycobacteriophage L5, enabling the simple construction of complex recombinants with genes integrated simultaneously at different chromosomal positions