Insulin-like growth factor-1 induces hyperproliferation of PKD1 cystic cells via a Ras/Raf dependent signalling pathway

Autosomal dominant polycystic kidney disease (ADPKD) largely results from mutations in the PKD1 gene leading to hyperproliferation of renal tubular epithelial cells and consequent cyst formation. Rodent models of PKD suggest that the multifunctional hormone insulin-like growth factor-1 (IGF-1) could play a pathogenic role in renal cyst formation. In order to test this possibility, conditionally immortalized renal epithelial cells were prepared from normal individuals and from ADPKD patients with known germline mutations in PKD1. All patient cell lines had a decreased or absence of polycystin-1 but not polycystin-2. These cells had an increased sensitivity to IGF-1 and to cyclic AMP, which required phosphatidylinositol-3 (PI3)-kinase and the mitogen-activated protein kinase, extracellular signal-regulated protein kinase (ERK) for enhanced growth. Inhibition of Ras or Raf abolished the stimulated cell proliferation. Our results suggest that haploinsufficiency of polycystin-1 lowers the activation threshold of the Ras/Raf signalling system leading to growth factor-induced hyperproliferation. Inhibition of Ras or Raf activity may be a therapeutic option for decreasing tubular cell proliferation in ADPKD

Leak Rate Quantification Method for Gas Pressure Seals with Controlled Pressure Differential

An enhancement to the pressure decay leak rate method with mass point analysis solved deficiencies in the standard method. By adding a control system, a constant gas pressure differential across the test article was maintained. As a result, the desired pressure condition was met at the onset of the test, and the mass leak rate and measurement uncertainty were computed in real-time. The data acquisition and control system were programmed to automatically stop when specified criteria were met. Typically, the test was stopped when a specified level of measurement uncertainty was attained. Using silicone O-ring test articles, the new method was compared with the standard method that permitted the downstream pressure to be non-constant atmospheric pressure. The two methods recorded comparable leak rates, but the new method recorded leak rates with significantly lower measurement uncertainty, statistical variance, and test duration. Utilizing this new method in leak rate quantification, projects will reduce cost and schedule, improve test results, and ease interpretation between data sets

A possible Reinterpretation of Einstein's Equations

In this paper, we first review Huei's formulation in which it is shown that the linearized Einstein equations can be written in the same form as the Maxwell equations. We eliminate some imperfections like the scalar potential which is ill linked to the electric-type field, the Lorentz-type force which is obtained with a time independence restriction and the undesired factor 4 which appears in the magnetic-type part. Second, from these results and in the light of a recent work by C.C. Barros, we propose an extension of the equivalence principle and we suggest a new interpretation for Einstein's equations by showing that the electromagnetic Maxwell equations can be derived from a new version of Einstein's ones.Comment: 11 pages, no figure

Prognostic value of B cells in cutaneous melanoma

Background: Measures of the adaptive immune response have prognostic and predictive associations in melanoma and other cancer types. Specifically, intratumoral T cell density and function have considerable prognostic and predictive value in skin cutaneous melanoma (SKCM). Less is known about the significance of tumor-infiltrating B cells in SKCM. Our goal was to understand the prognostic and predictive value of B cell phenotypic subsets in SKCM using RNA sequencing. Methods: We used our previously published algorithm, V'DJer, to assemble B cell receptor (BCR) repertoires and estimate diversity from short-read RNA sequencing (RNA-seq). We applied machine learning-based cellular phenotype classifiers to measure relative similarity of bulk tumor sample gene expression profiles and different B cell phenotypes. We assessed these aspects of B cell biology in 473 SKCM from the Cancer Genome Atlas Project (TCGA) as well as in RNA-seq data corresponding to tumor samples procured from patients who received CTLA-4 and PD-1 inhibitors for metastatic SKCM. Results: We found that the BCR repertoire was associated with different clinical factors, such as tumor tissue site and sex. However, increased clonality of the BCR repertoire was favorably prognostic in SKCM and was prognostic even after first conditioning on various clinical factors. Mutation burden was not correlated with any BCR measurement, and no specific mutation had an altered BCR repertoire. Lack of an assembled BCR in pre-treatment tumor tissues was associated with a lack of anti-tumor response to a CTLA-4 inhibitor in metastatic SKCM. Conclusions: These findings suggest an important prognostic and predictive role for B cell characteristics in SKCM. This has implications for melanoma immunobiology and potential development of immunogenomics features to predict survival and response to immunotherapy

Molecular and clinical characterization of a claudin-low subtype of gastric cancer

Purpose Claudin-low molecular subtypes have been identified in breast and bladder cancers and are characterized by low expression of claudins, enrichment for epithelial-to-mesenchymal transition (EMT), and tumor-initiating cell (TIC) features. We evaluated whether the claudin-low subtype also exists in gastric cancer. Materials and Methods Four hundred fifteen tumors from The Cancer Genome Atlas (TCGA) gastric cancer mRNA data set were clustered on the claudin, EMT, and TIC gene sets to identify claudin-low tumors. We derived a 24-gene predictor that classifies gastric cancer into claudin-low and non-claudin-low subtypes. This predictor was validated with the Asian Cancer Research Group(ACRG)data set. We characterized molecular and clinical features of claudin-low tumors. Results We identified 46 tumors that had consensus enrichment for claudin-low features in TCGA data set. Claudin-low tumors were most commonly diffuse histologic type (82%) and originally classified as TCGA genomically stable(GS)subtype (78%). Compared with GS subtype, claudin-low subtype had significant activation in Rho family of GTPases signaling, which appears to play a key role in its EMT and TIC properties. In the ACRG data set, 28 of 300 samples were classified as claudin-low tumors by the 24-gene predictor and were phenotypically similar to the initially derived claudin-low tumors. Clinically, claudin-low subtype had the worst overall survival. Of note, the hazard ratios that compared claudin-low versus GS subtype were 2.10 (95% CI, 1.07 to 4.11) in TCGA and 2.32 (95% CI, 1.18 to 4.55) in the ACRG cohorts, with adjustment for age and pathologic stage. Conclusion We identified a gastric claudin-low subtype that carries a poor prognosis likely related to therapeutic resistance as a result of its EMT and TIC phenotypes

Fluxon Modeling of Low-Beta Plasmas

We have developed a new, quasi-Lagrangian approach for numerical modeling of magnetohydrodynamics in low to moderate $\beta$ plasmas such as the solar corona. We introduce the concept of a ``fluxon'', a discretized field line. Fluxon models represent the magnetic field as a skeleton of such discrete field lines, and interpolate field values from the geometry of the skeleton where needed, reversing the usual direction of the field line transform. The fluxon skeleton forms the grid for a collection of 1-D Eulerian models of plasma along individual flux tubes. Fluxon models have no numerical resistivity, because they preserve topology explicitly. Our prototype code, \emph{FLUX}, is currently able to find 3-D nonlinear force-free field solutions with a specified field topology, and work is ongoing to validate and extend the code to full magnetohydrodynamics. FLUX has significant scaling advantages over conventional models: for ``magnetic carpet'' models, with photospheric line-tied boundary conditions, FLUX simulations scale in complexity like a conventional 2-D grid although the full 3-D field is represented. The code is free software and is available online. In this current paper we introduce fluxons and our prototype code, and describe the course of future work with the code.Comment: 14 pages, 11 figures; also in press for JAST

The Magnetic Sun: Reversals and Long-Term Variations

A didactic introduction to current thinking on some aspects of the solar dynamo is given for geophysicists and planetary scientists.Comment: 17 pages, 9 figures; Space Science Rev., in pres

Machine-learning prediction of tumor antigen immunogenicity in the selection of therapeutic epitopes

Current tumor neoantigen calling algorithms primarily rely on epitope/major histocompatibility complex (MHC) binding affinity predictions to rank and select for potential epitope targets. These algorithms do not predict for epitope immunogenicity using approaches modeled from tumor-specific antigen data. Here, we describe peptide-intrinsic biochemical features associated with neoantigen and minor histocompatibility mismatch antigen immunogenicity and present a gradient boosting algorithm for predicting tumor antigen immunogenicity. This algorithm was validated in two murine tumor models and demonstrated the capacity to select for therapeutically active antigens. Immune correlates of neoantigen immunogenicity were studied in a pan-cancer data set from The Cancer Genome Atlas and demonstrated an association between expression of immunogenic neoantigens and immunity in colon and lung adenocarcinomas. Lastly, we present evidence for expression of an out-of-frame neoantigen that was capable of driving antitumor cytotoxic T-cell responses. With the growing clinical importance of tumor vaccine therapies, our approach may allow for better selection of therapeutically relevant tumor-specific antigens, including nonclas-sic out-of-frame antigens capable of driving antitumor immunity

Particle creation, classicality and related issues in quantum field theory: I. Formalism and toy models

The quantum theory of a harmonic oscillator with a time dependent frequency arises in several important physical problems, especially in the study of quantum field theory in an external background. While the mathematics of this system is straightforward, several conceptual issues arise in such a study. We present a general formalism to address some of the conceptual issues like the emergence of classicality, definition of particle content, back reaction etc. In particular, we parametrize the wave function in terms of a complex number (which we call excitation parameter) and express all physically relevant quantities in terms it. Many of the notions -- like those of particle number density, effective Lagrangian etc., which are usually defined using asymptotic in-out states -- are generalized as time-dependent concepts and we show that these generalized definitions lead to useful and reasonable results. Having developed the general formalism we apply it to several examples. Exact analytic expressions are found for a particular toy model and approximate analytic solutions are obtained in the extreme cases of adiabatic and highly non-adiabatic evolution. We then work out the exact results numerically for a variety of models and compare them with the analytic results and approximations. The formalism is useful in addressing the question of emergence of classicality of the quantum state, its relation to particle production and to clarify several conceptual issues related to this. In Paper II (arXiv:0708.1237), which is a sequel to this, the formalism will be applied to analyze the corresponding issues in the context of quantum field theory in background cosmological models and electric fields.Comment: RevTeX 4; 32 pages; 28 figures; first of a series of two papers, the second being arXiv:0708.1237 [gr-qc]; high resolution figures available from the authors on reques

Meniscus treatment and age associated with narrower radiographic joint space width 2–3 years after ACL reconstruction: data from the MOON onsite cohort

SummaryObjectiveTo identify risk factors for radiographic signs of post-traumatic osteoarthritis (OA) 2–3 years after anterior cruciate ligament (ACL) reconstruction through multivariable analysis of minimum joint space width (mJSW) differences in a specially designed nested cohort.MethodsA nested cohort within the Multicenter Orthopaedic Outcomes Network (MOON) cohort included 262 patients (148 females, average age 20) injured in sport who underwent ACL reconstruction in a previously uninjured knee, were 35 or younger, and did not have ACL revision or contralateral knee surgery. mJSW on semi-flexed radiographs was measured in the medial compartment using a validated computerized method. A multivariable generalized linear model was constructed to assess mJSW difference between the ACL reconstructed and contralateral control knees while adjusting for potential confounding factors.ResultsUnexpectedly, we found the mean mJSW was 0.35 mm wider in ACL reconstructed than in control knees (5.06 mm (95% CI 4.96–5.15 mm) vs 4.71 mm (95% CI 4.62–4.80 mm), P < 0.001). However, ACL reconstructed knees with meniscectomy had narrower mJSW compared to contralateral normal knees by 0.64 mm (95% C.I. 0.38–0.90 mm) (P < 0.001). Age (P < 0.001) and meniscus repair (P = 0.001) were also significantly associated with mJSW difference.ConclusionSemi-flexed radiographs can detect differences in mJSW between ACL reconstructed and contralateral normal knees 2–3 years following ACL reconstruction, and the unexpected wider mJSW in ACL reconstructed knees may represent the earliest manifestation of post-traumatic osteoarthritis and warrants further study