Cancer resistance of SR/CR mice in the genetic knockout backgrounds of leukocyte effector mechanisms: determinations for functional requirements

<p>Abstract</p> <p>Background</p> <p>Spontaneous Regression/Complete Resistant (SR/CR) mice are a colony of cancer-resistant mice that can detect and rapidly destroy malignant cells with innate cellular immunity, predominately mediated by granulocytes. Our previous studies suggest that several effector mechanisms, such as perforin, granzymes, or complements, may be involved in the killing of cancer cells. However, none of these effector mechanisms is known as critical for granulocytes. Additionally, it is unclear which effector mechanisms are required for the cancer killing activity of specific leukocyte populations and the survival of SR/CR mice against the challenges of lethal cancer cells. We hypothesized that if any of these effector mechanisms was required for the resistance to cancer cells, its functional knockout in SR/CR mice should render them sensitive to cancer challenges. This was tested by cross breeding SR/CR mice into the individual genetic knockout backgrounds of perforin (Prf^-/-), superoxide (Cybb^-/), or inducible nitric oxide (Nos2^-/).</p> <p>Methods</p> <p>SR/CR mice were bred into individual Prf^-/-, Cybb^-/-, or Nos2^-/-genetic backgrounds and then challenged with sarcoma 180 (S180). Their overall survival was compared to controls. The cancer killing efficiency of purified populations of macrophages and neutrophils from these immunodeficient mice was also examined.</p> <p>Results</p> <p>When these genetically engineered mice were challenged with cancer cells, the knockout backgrounds of Prf^-/-, Cybb^-/-, or Nos2^-/-did not completely abolish the SR/CR cancer resistant phenotype. However, the Nos2^-/-background did appear to weaken the resistance. Incidentally, it was also observed that the male mice in these immunocompromised backgrounds tended to be less cancer-resistant than SR/CR controls.</p> <p>Conclusion</p> <p>Despite the previously known roles of perforin, superoxide or nitric oxide in the effector mechanisms of innate immune responses, these effector mechanisms were not required for cancer-resistance in SR/CR mice. The resistance was functional when any one of these effector mechanisms was completely absent, except some noticeably reduced penetrance, but not abolishment, of the phenotype in the male background in comparison to female background. These results also indicate that some other effector mechanism(s) of granulocytes may be involved in the killing of cancer cells in SR/CR mice.</p

Impact of sex, MHC, and age of recipients on the therapeutic effect of transferred leukocytes from cancer-resistant SR/CR mice

<p>Abstract</p> <p>Background</p> <p>Spontaneous Regression/Complete Resistant (SR/CR) mice are resistant to cancer through a mechanism that is mediated entirely by leukocytes of innate immunity. Transfer of leukocytes from SR/CR mice can confer cancer resistance in wild-type (WT) recipients in both preventative and therapeutic settings. In the current studies, we investigated factors that may impact the efficacy and functionality of SR/CR donor leukocytes in recipients.</p> <p>Results</p> <p>In sex-mismatched transfers, functionality of female donor leukocytes was not affected in male recipients. In contrast, male donor leukocytes were greatly affected in the female recipients. In MHC-mismatches, recipients of different MHC backgrounds, or mice of different strains, showed a greater negative impact on donor leukocytes than sex-mismatches. The negative effects of sex-mismatch and MHC-mismatch on donor leukocytes were additive. Old donor leukocytes performed worse than young donor leukocytes in all settings including in young recipients. Young recipients were not able to revive the declining function of old donor leukocytes. However, the function of young donor leukocytes declined gradually in old recipients, suggesting that an aged environment may contain factors that are deleterious to cellular functions. The irradiation of donor leukocytes prior to transfers had a profound suppressive effect on donor leukocyte functions, possibly as a result of impaired transcription. The cryopreserving of donor leukocytes in liquid nitrogen had no apparent effect on donor leukocyte functions, except for a small loss of cell number after revival from freezing.</p> <p>Conclusion</p> <p>Despite the functional suppression of donor leukocytes in sex- and MHC-mismatched recipients, as well as old recipients, there was a therapeutic time period during the initial few weeks during which donor leukocytes were functional before their eventual rejection or functional decline. The eventual rejection of donor leukocytes will likely prevent donor leukocyte engraftment which would help minimize the risk of transfusion-associated graft-versus-host disease. Therefore, using leukocytes from healthy donors with high anti-cancer activity may be a feasible therapeutic concept for treating malignant diseases.</p

Active Brownian Particles. From Individual to Collective Stochastic Dynamics

We review theoretical models of individual motility as well as collective dynamics and pattern formation of active particles. We focus on simple models of active dynamics with a particular emphasis on nonlinear and stochastic dynamics of such self-propelled entities in the framework of statistical mechanics. Examples of such active units in complex physico-chemical and biological systems are chemically powered nano-rods, localized patterns in reaction-diffusion system, motile cells or macroscopic animals. Based on the description of individual motion of point-like active particles by stochastic differential equations, we discuss different velocity-dependent friction functions, the impact of various types of fluctuations and calculate characteristic observables such as stationary velocity distributions or diffusion coefficients. Finally, we consider not only the free and confined individual active dynamics but also different types of interaction between active particles. The resulting collective dynamical behavior of large assemblies and aggregates of active units is discussed and an overview over some recent results on spatiotemporal pattern formation in such systems is given.Comment: 161 pages, Review, Eur Phys J Special-Topics, accepte

Search for the Higgs boson in events with missing transverse energy and b quark jets produced in proton-antiproton collisions at s**(1/2)=1.96 TeV

We search for the standard model Higgs boson produced in association with an electroweak vector boson in events with no identified charged leptons, large imbalance in transverse momentum, and two jets where at least one contains a secondary vertex consistent with the decay of b hadrons. We use ~1 fb-1 integrated luminosity of proton-antiproton collisions at s**(1/2)=1.96 TeV recorded by the CDF II experiment at the Tevatron. We find 268 (16) single (double) b-tagged candidate events, where 248 +/- 43 (14.4 +/- 2.7) are expected from standard model background processes. We place 95% confidence level upper limits on the Higgs boson production cross section for several Higgs boson masses ranging from 110 GeV/c2 to 140 GeV/c2. For a mass of 115 GeV/c2 the observed (expected) limit is 20.4 (14.2) times the standard model prediction.Comment: 8 pages, 2 figures, submitted to Phys. Rev. Let

Observation and Mass Measurement of the Baryon Ξb−\Xi^-_b

We report the observation and measurement of the mass of the bottom, strange baryon $\Xi^-_b$ through the decay chain $\Xi^-_b \to J/\psi \Xi^-$, where $J/\psi \to \mu^+ \mu^-$, $\Xi^- \to \Lambda \pi^-$, and $\Lambda \to p \pi^-$. Evidence for observation is based on a signal whose probability of arising from the estimated background is 6.6 x 10^{-15}, or 7.7 Gaussian standard deviations. The $\Xi^-_b$ mass is measured to be $5792.9\pm 2.5$ (stat.) $\pm 1.7$ (syst.) MeV/$c^2$.Comment: Minor text changes for the second version. Accepted by Phys. Rev. Let

Polarizations of J/psi and psi(2S) Mesons Produced in ppbar Collisions at 1.96 TeV

We have measured the polarizations of \jpsi and \psiprime mesons as functions of their transverse momentum \pt when they are produced promptly in the rapidity range $|y|<0.6$ with \pt \geq 5 \pgev. The analysis is performed using a data sample with an integrated luminosity of about 800 \ipb collected by the CDF II detector. For both vector mesons, we find that the polarizations become increasingly longitudinal as \pt increases from 5 to 30 \pgev. These results are compared to the predictions of nonrelativistic quantum chromodynamics and other contemporary models. The effective polarizations of \jpsi and \psiprime mesons from $B$-hadron decays are also reported.Comment: 8 pages, 7 figures, published in Physical Review Letter

Search for New Particles Leading to Z+jets Final States in ppˉp\bar{p} Collisions at s=1.96\sqrt{s}=1.96 TeV

We present the results of a search for new particles that lead to a \Z boson plus jets in $p\bar{p}$ collisions at $\sqrt{s}=1.96$ TeV using the Collider Detector at Fermilab (CDF II). A data sample with a luminosity of 1.06 \ifb\ collected using \Z boson decays to $ee$ and $\mu\mu$ is used. We describe a completely data-based method to predict the dominant background from standard-model \Z+jet events. This method can be similarly applied to other analyses requiring background predictions in multi-jet environments, as shown when validating the method by predicting the background from $W$+jets in \ttbar production. No significant excess above the background prediction is observed, and a limit is set using a fourth generation quark model to quantify the acceptance. Assuming $BR(b' \to b\Z) = 100$ and using a leading-order calculation of the $b'$ cross section, $b'$ quark masses below 268 \gev/c^2 are excluded at 95% confidence level.Comment: To be submitted to PR

Precise measurement of the top quark mass in the lepton+jets topology at CDF II

We present a measurement of the mass of the top quark from proton-antiproton collisions recorded at the CDF experiment in Run II of the Fermilab Tevatron. We analyze events from the single lepton plus jets final state ($t\bar t\to W^+bW^-\bar b\to l\nu b q \bar q'\bar b$). The top quark mass is extracted using a direct calculation of the probability density that each event corresponds to the $t\bar t$ final state. The probability is a function of both the mass of the top quark and the energy scale of the calorimeter jets, which is constrained {\it in situ} by the hadronic $W$ boson mass. Using 167 events observed in 955 pb$^{{-}1}$ of integrated luminosity, we achieve the single most precise measurement of the top quark mass, 170.8 $\pm$ 2.2 (stat.) $\pm$ 1.4 (syst.) GeV/$c^2$.Comment: accepted by Phys. Rev. Let

First Measurement of the W Boson Mass in Run II of the Tevatron

We present a measurement of the W boson mass using 200/pb of data collected in pbar p collisions at sqrt(s) = 1.96 TeV by the CDF II detector at Run II of the Fermilab Tevatron. With a sample of 63964 W -> e nu candidates and 51128 W -> mu nu candidates, we measure M_W = (80413 +- 34 (stat) +- 34 (syst) = 80413 +- 48) MeV/c^2. This is the most precise single measurement of the W boson mass to date.Comment: published version in PR

Search for Third Generation Vector Leptoquarks in p anti-p Collisions at sqrt(s) = 1.96 TeV

We describe a search for a third generation vector leptoquark (VLQ3) that decays to a b quark and tau lepton using the CDF II detector and 322 pb^(-1) of integrated luminosity from the Fermilab Tevatron. Vector leptoquarks have been proposed in many extensions of the standard model (SM). Observing a number of events in agreement with SM expectations, assuming Yang-Mills (minimal) couplings, we obtain the most stringent upper limit on the VLQ3 pair production cross section of 344 fb (493 fb) and lower limit on the VLQ3 mass of 317 GeV/c^2 (251 GeV/c^2) at 95% C.L.Comment: 7 pages, 2 figures, submitted to PR