Elevated neoantigen levels in tumors with somatic mutations in the HLA-A, HLA-B, HLA-C and B2M genes.

BackgroundThe major histocompatibility complex class I (MHC-I) molecule is a protein complex that displays intracellular peptides to T cells, allowing the immune system to recognize and destroy infected or cancerous cells. MHC-I is composed of a highly polymorphic HLA-encoded alpha chain that binds the peptide and a Beta-2-microglobulin (B2M) protein that acts as a stabilizing scaffold. HLA mutations have been implicated as a mechanism of immune evasion during tumorigenesis, and B2M is considered a tumor suppressor gene. However, the implications of somatic HLA and B2M mutations have not been fully explored in the context of antigen presentation via the MHC-I molecule during tumor development. To understand the effect that B2M and HLA MHC-I molecule mutations have on mutagenesis, we analyzed the accumulation of mutations in patients from The Cancer Genome Atlas according to their MHC-I molecule mutation status.ResultsSomatic B2M and HLA mutations in microsatellite stable tumors were associated with higher overall mutation burden and a larger fraction of HLA-binding neoantigens when compared to B2M and HLA wild type tumors. B2M and HLA mutations were highly enriched in patients with microsatellite instability. B2M mutations tended to occur relatively early during patients' respective tumor development, whereas HLA mutations were either early or late events. In addition, B2M and HLA mutated patients had higher levels of immune infiltration by natural killer and CD8+ T cells and higher levels of cytotoxicity.ConclusionsOur findings add to a growing body of evidence that somatic B2M and HLA mutations are a mechanism of immune evasion by demonstrating that such mutations are associated with a higher load of neoantigens that should be presented via MHC-I

Glucose Enhances Leptin Signaling through Modulation of AMPK Activity

Leptin exerts its action by binding to and activating the long form of leptin receptors (LEPRb). LEPRb activates JAK2 that subsequently phosphorylates and activates STAT3. The JAK2/STAT3 pathway is required for leptin control of energy balance and body weight. Defects in leptin signaling lead to leptin resistance, a primary risk factor for obesity. Body weight is also regulated by nutrients, including glucose. Defects in glucose sensing also contribute to obesity. Here we report crosstalk between leptin and glucose. Glucose starvation blocked the ability of leptin to stimulate tyrosyl phosphorylation and activation of JAK2 and STAT3 in a variety of cell types. Glucose dose-dependently enhanced leptin signaling. In contrast, glucose did not enhance growth hormone-stimulated phosphorylation of JAK2 and STAT5. Glucose starvation or 2-deoxyglucose-induced inhibition of glycolysis activated AMPK and inhibited leptin signaling; pharmacological inhibition of AMPK restored the ability of leptin to stimulate STAT3 phosphorylation. Conversely, pharmacological activation of AMPK was sufficient to inhibit leptin signaling and to block the ability of glucose to enhance leptin signaling. These results suggest that glucose and/or its metabolites play a permissive role in leptin signaling, and that glucose enhances leptin sensitivity at least in part by attenuating the ability of AMPK to inhibit leptin signaling

On the nonlinear dynamics of the traveling-wave solutions of the Serre system

We numerically study nonlinear phenomena related to the dynamics of traveling wave solutions of the Serre equations including the stability, the persistence, the interactions and the breaking of solitary waves. The numerical method utilizes a high-order finite-element method with smooth, periodic splines in space and explicit Runge-Kutta methods in time. Other forms of solutions such as cnoidal waves and dispersive shock waves are also considered. The differences between solutions of the Serre equations and the Euler equations are also studied.Comment: 28 pages, 20 figures, 3 tables, 33 references. Other author's papers can be downloaded at http://www.denys-dutykh.com

Voltage-controlled wavelength conversion by terahertz electro-optic modulation in double quantum wells

An undoped double quantum well (DQW) was driven with a terahertz (THz) electric field of frequency \omega_{THz} polarized in the growth direction, while simultaneously illuminated with a near-infrared (NIR) laser at frequency \omega_{NIR}. The intensity of NIR upconverted sidebands \omega_{sideband}=\omega_{NIR} + \omega_{THz} was maximized when a dc voltage applied in the growth direction tuned the excitonic states into resonance with both the THz and NIR fields. There was no detectable upconversion far from resonance. The results demonstrate the possibility of using gated DQW devices for all-optical wavelength shifting between optical communication channels separated by up to a few THz.Comment: 3 pages, 6 figures. Figures 5 and 6 are JPEG files, figures/fig5.jpg and fig6.jp

Energy Complexity for Sorting Algorithms in Java

This study extends the concept of time complexity to energy, i.e., energy complexity, by showing a strong correlation between time complexity and energy consumption for sorting algorithms: Bubble Sort, Counting Sort, Merge Sort and Quick Sort, written in Java and run on single kernels. We investigate the correlation between wall time and time complexity, as well as the correlation between energy consumption and wall time. The primary finding is that time complexity can be used as a guideline to estimate the energy consumption of O(n*n), O(nlog(n)) and O(n + k) sorting algorithms. The secondary finding is that the inputs producing the theoretical worst cases for Merge Sort and Bubble Sort did not produce the worst case wall time nor the worst case energy consumption

Strong-field terahertz-optical mixing in excitons

Driving a double-quantum-well excitonic intersubband resonance with a terahertz (THz) electric field of frequency \omega_{THz} generated terahertz optical sidebands \omega=\omega_{THz}+\omega_{NIR} on a weak NIR probe. At high THz intensities, the intersubband dipole energy which coupled two excitons was comparable to the THz photon energy. In this strong-field regime the sideband intensity displayed a non-monotonic dependence on the THz field strength. The oscillating refractive index which gives rise to the sidebands may be understood by the formation of Floquet states, which oscillate with the same periodicity as the driving THz field.Comment: 4 pages, 6 figure

Role of the tyrosine kinase JAK2 in signal transduction by growth hormone

Chronic renal failure in children results in impaired body growth. This effect is so severe in some children that not only does it have a negative impact on their self-image, but it also affects their ability to carry out normal day-to-day functions. Yet the mechanism by which chronic renal failure causes short stature is not well understood. Growth hormone (GH) therapy increases body height in prepubertal children, suggesting that a better understanding of how GH promotes body growth may lead to better insight into the impaired body growth in chronic renal failure and therefore better therapies. This review discusses what is currently known about how GH acts at a cellular level. The review discusses how GH is known to bind to a membrane-bound receptor and activate a cytoplasmic tyrosine kinase called Janus kinase (JAK) 2. The activated JAK2 in turn phosphorylates tyrosines within itself and the associated GH receptor, forming high-affinity binding sites for a variety of signaling molecules. Examples of such signaling molecules include signal transducers and activators of transcription (Stats), which regulate the expression of a variety of GH-dependent genes, and the adapter protein Shc, which leads to activation of the Ras-Raf-MEK-MAP kinase pathway. In response to GH, JAK2 is also known to phosphorylate the insulin receptor substrates, leading to activation of phosphatidyl inositol 3’ kinase and most likely other molecules that have been implicated in the regulation of metabolism. Finally, the ability of JAK2 to bind and activate the presumed adapter protein SH2-B is discussed. SH2-B has been shown to be a potent activator of GH-promoted JAK2 activity and downstream signaling events. Presumably these and other pathways initiated by GH combine to result in its ability to regulate body growth and metabolism.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/42301/1/467-14-7-550_00140550.pd

IP-10/CXCL10 induction in human pancreatic cancer stroma influences lymphocytes recruitment and correlates with poor survival

Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs) that contributes to tumor progression. Here we sought to characterize the interactions between pancreatic cancer cells (PCCs) and PSCs that affect the inflammatory and immune response in pancreatic tumors. Conditioned media from mono- and cocultures of PSCs and PCCs were assayed for expression of cytokines and growth factors. IP-10/CXCL10 was the most highly induced chemokine in coculture of PSCs and PCCs. Its expression was induced in the PSCs by PCCs. IP-10 was elevated in human PDAC specimens, and positively correlated with high stroma content. Furthermore, gene expression of IP-10 and its receptor CXCR3 were significantly associated with the intratumoral presence of regulatory T cells (Tregs). In an independent cohort of 48 patients with resectable pancreatic ductal adenocarcinoma, high IP-10 expression levels correlated with decreased median overall survival. Finally, IP-10 stimulated the ex vivo recruitment of CXCR3+ effector T cells as well as CXCR3+ Tregs derived from patients with PDAC. Our findings suggest that, in pancreatic cancer, CXCR3+ Tregs can be recruited by IP-10 expressed by PSCs in the tumor stroma, leading to immunosuppressive and tumor-promoting effects

Transformation of Cs-IONSIV® into a ceramic wasteform by hot isostatic pressing

A simple method to directly convert Cs-exchanged IONSIV® IE-911 into a ceramic wasteform by hot isostatic pressing (1100 °C/190 MPa/2 hr) is presented. Two major Cs-containing phases, Cs2TiNb6O18 and Cs2ZrSi6O15, and a series of mixed oxides form. The microstructure and phase assemblage of the samples as a function of Cs content were examined using XRD, XRF, SEM and TEM/EDX. The chemical aqueous durability of the materials was investigated using the MCC-1 and PCT-B standard test methods. For HIPed Cs-IONSIV® samples, the MCC-1 normalised release rates of Cs were <1.57 × 10−1 g m−2 d−1 at 0–28 days, and <3.78 × 10−2 g m−2 d−1 for PCT-B at 7 days. The low rates are indicative of a safe long-term immobilisation matrix for Cs formed directly from spent IONSIV®. It was also demonstrated that the phase formation can be altered by adding Ti metal due to a controlled redox environment