Neoadjuvant pazopanib and molecular analysis of tissue response in renal cell carcinoma

BACKGROUND. Surgery remains the frontline therapy for patients with localized clear cell renal cell carcinoma (ccRCC); however, 20%–40% recur. Angiogenesis inhibitors have improved survival in metastatic patients and may result in responses in the neoadjuvant setting. The impact of these agents on the tumor genetic heterogeneity or the immune milieu is largely unknown. This phase II study was designed to evaluate safety, response, and effect on tumor tissue of neoadjuvant pazopanib. METHODS. ccRCC patients with localized disease received pazopanib (800 mg daily; median 8 weeks), followed by nephrectomy. Five tumors were examined for mutations by whole exome sequencing from samples collected before therapy and at nephrectomy. These samples underwent RNA sequencing; 17 samples were available for posttreatment assessment. RESULTS. Twenty-one patients were enrolled. The overall response rate was 8 of 21 (38%). No patients with progressive disease. At 1-year, response-free survival and overall survival was 83% and 89%, respectively. The most frequent grade 3 toxicity was hypertension (33%, 7 of 21). Sequencing revealed strong concordance between pre- and posttreatment samples within individual tumors, suggesting tumors harbor stable core profiles. However, a reduction in private mutations followed treatment, suggesting a selective process favoring enrichment of driver mutations. CONCLUSION. Neoadjuvant pazopanib is safe and active in ccRCC. Future genomic analyses may enable the segregation of driver and passenger mutations. Furthermore, tumor infiltrating immune cells persist during therapy, suggesting that pazopanib can be combined with immune checkpoint inhibitors without dampening the immune response. FUNDING. Support was provided by Novartis and GlaxoSmithKline as part of an investigator-initiated study

Experimental Study of the Shortest Reset Word of Random Automata

In this paper we describe an approach to finding the shortest reset word of a finite synchronizing automaton by using a SAT solver. We use this approach to perform an experimental study of the length of the shortest reset word of a finite synchronizing automaton. The largest automata we considered had 100 states. The results of the experiments allow us to formulate a hypothesis that the length of the shortest reset word of a random finite automaton with $n$ states and 2 input letters with high probability is sublinear with respect to $n$ and can be estimated as $1.95 n^{0.55}.

Two-proton correlations from 158 AGeV Pb+Pb central collisions

The two-proton correlation function at midrapidity from Pb+Pb central collisions at 158 AGeV has been measured by the NA49 experiment. The results are compared to model predictions from static thermal Gaussian proton source distributions and transport models RQMD and VENUS. An effective proton source size is determined by minimizing CHI-square/ndf between the correlation functions of the data and those calculated for the Gaussian sources, yielding 3.85 +-0.15(stat.) +0.60-0.25(syst.) fm. Both the RQMD and the VENUS model are consistent with the data within the error in the correlation peak region.Comment: RevTeX style, 6 pages, 4 figures, 1 table. More discussion are added about the structure on the tail of the correlation function. The systematic error is revised. To appear in Phys. Lett.

Event-by-event fluctuations of average transverse momentum in central Pb+Pb collisions at 158 GeV per nucleon

We present first data on event-by-event fluctuations in the average transverse momentum of charged particles produced in Pb+Pb collisions at the CERN SPS. This measurement provides previously unavailable information allowing sensitive tests of microscopic and thermodynamic collision models and to search for fluctuations expected to occur in the vicinity of the predicted QCD phase transition. We find that the observed variance of the event-by-event average transverse momentum is consistent with independent particle production modified by the known two-particle correlations due to quantum statistics and final state interactions and folded with the resolution of the NA49 apparatus. For two specific models of non-statistical fluctuations in transverse momentum limits are derived in terms of fluctuation amplitude. We show that a significant part of the parameter space for a model of isospin fluctuations predicted as a consequence of chiral symmetry restoration in a non-equilibrium scenario is excluded by our measurement.Comment: 6 pages, 2 figures, submitted to Phys. Lett.

Search for the glueball candidates f0(1500) and fJ(1710) in gamma gamma collisions

Data taken with the ALEPH detector at LEP1 have been used to search for gamma gamma production of the glueball candidates f0(1500) and fJ(1710) via their decay to pi+pi-. No signal is observed and upper limits to the product of gamma gamma width and pi+pi- branching ratio of the f0(1500) and the fJ(1710) have been measured to be Gamma_(gamma gamma -> f0(1500)). BR(f0(1500)->pi+pi-) < 0.31 keV and Gamma_(gamma gamma -> fJ(1710)). BR(fJ(1710)->pi+pi-) < 0.55 keV at 95% confidence level.Comment: 10 pages, 3 figure

Search for supersymmetry with a dominant R-parity violating LQDbar couplings in e+e- collisions at centre-of-mass energies of 130GeV to 172 GeV

A search for pair-production of supersymmetric particles under the assumption that R-parity is violated via a dominant LQDbar coupling has been performed using the data collected by ALEPH at centre-of-mass energies of 130-172 GeV. The observed candidate events in the data are in agreement with the Standard Model expectation. This result is translated into lower limits on the masses of charginos, neutralinos, sleptons, sneutrinos and squarks. For instance, for m_0=500 GeV/c^2 and tan(beta)=sqrt(2) charginos with masses smaller than 81 GeV/c^2 and neutralinos with masses smaller than 29 GeV/c^2 are excluded at the 95% confidence level for any generation structure of the LQDbar coupling.Comment: 32 pages, 30 figure

Study of Inclusive Strange-Baryon Production and Search for Pentaquarks in Two-Photon Collisions at LEP

Measurements of inclusive production of the Lambda, Xi- and Xi*(1530) baryons in two-photon collisions with the L3 detector at LEP are presented. The inclusive differential cross sections for Lambda and Xi- are measured as a function of the baryon transverse momentum, pt, and pseudo-rapidity, eta. The mean number of Lambda, Xi- and Xi*(1530) baryons per hadronic two-photon event is determined in the kinematic range 0.4 GeV < pt< 2.5 GeV, |eta| < 1.2. Overall agreement with the theoretical models and Monte Carlo predictions is observed. A search for inclusive production of the pentaquark theta+(1540) in two-photon collisions through the decay theta+ -> proton K0s is also presented. No evidence for production of this state is found

Accelerated SARS-CoV-2 intrahost evolution leading to distinct genotypes during chronic infection

The chronic infection hypothesis for novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant emergence is increasingly gaining credence following the appearance of Omicron. Here, we investigate intrahost evolution and genetic diversity of lineage B.1.517 during a SARS-CoV-2 chronic infection lasting for 471 days (and still ongoing) with consistently recovered infectious virus and high viral genome copies. During the infection, we find an accelerated virus evolutionary rate translating to 35 nucleotide substitutions per year, approximately 2-fold higher than the global SARS-CoV-2 evolutionary rate. This intrahost evolution results in the emergence and persistence of at least three genetically distinct genotypes, suggesting the establishment of spatially structured viral populations continually reseeding different genotypes into the nasopharynx. Finally, we track the temporal dynamics of genetic diversity to identify advantageous mutations and highlight hallmark changes for chronic infection. Our findings demonstrate that untreated chronic infections accelerate SARS-CoV-2 evolution, providing an opportunity for the emergence of genetically divergent variants

The exposure of the hybrid detector of the Pierre Auger Observatory

The Pierre Auger Observatory is a detector for ultra-high energy cosmic rays. It consists of a surface array to measure secondary particles at ground level and a fluorescence detector to measure the development of air showers in the atmosphere above the array. The "hybrid" detection mode combines the information from the two subsystems. We describe the determination of the hybrid exposure for events observed by the fluorescence telescopes in coincidence with at least one water-Cherenkov detector of the surface array. A detailed knowledge of the time dependence of the detection operations is crucial for an accurate evaluation of the exposure. We discuss the relevance of monitoring data collected during operations, such as the status of the fluorescence detector, background light and atmospheric conditions, that are used in both simulation and reconstruction.Comment: Paper accepted by Astroparticle Physic

Search for a W' boson decaying to a bottom quark and a top quark in pp collisions at sqrt(s) = 7 TeV

Results are presented from a search for a W' boson using a dataset corresponding to 5.0 inverse femtobarns of integrated luminosity collected during 2011 by the CMS experiment at the LHC in pp collisions at sqrt(s)=7 TeV. The W' boson is modeled as a heavy W boson, but different scenarios for the couplings to fermions are considered, involving both left-handed and right-handed chiral projections of the fermions, as well as an arbitrary mixture of the two. The search is performed in the decay channel W' to t b, leading to a final state signature with a single lepton (e, mu), missing transverse energy, and jets, at least one of which is tagged as a b-jet. A W' boson that couples to fermions with the same coupling constant as the W, but to the right-handed rather than left-handed chiral projections, is excluded for masses below 1.85 TeV at the 95% confidence level. For the first time using LHC data, constraints on the W' gauge coupling for a set of left- and right-handed coupling combinations have been placed. These results represent a significant improvement over previously published limits.Comment: Submitted to Physics Letters B. Replaced with version publishe