Boosting BCG with recombinant modified vaccinia ankara expressing antigen 85A: Different boosting intervals and implications for efficacy trials

Objectives. To investigate the safety and immunogenicity of boosting BCG with modified vaccinia Ankara expressing antigen 85A (MVA85A), shortly after BCG vaccination, and to compare this first with the immunogenicity of BCG vaccination alone and second with a previous clinical trial where MVA85A was administered more than 10 years after BCG vaccination. Design. There are two clinical trials reported here: a Phase I observational trial with MVA85A; and a Phase IV observational trial with BCG. These clinical trials were all conducted in the UK in healthy, HIV negative, BCG naı¨ve adults. Subjects were vaccinated with BCG alone; or BCG and then subsequently boosted with MVA85A four weeks later (short interval). The outcome measures, safety and immunogenicity, were monitored for six months. The immunogenicity results from this short interval BCG prime–MVA85A boost trial were compared first with the BCG alone trial and second with a previous clinical trial where MVA85A vaccination was administered many years after vaccination with BCG. Results. MVA85A was safe and highly immunogenic when administered to subjects who had recently received BCG vaccination. When the short interval trial data presented here were compared with the previous long interval trial data, there were no significant differences in the magnitude of immune responses generated when MVA85A was administered shortly after, or many years after BCG vaccination. Conclusions. The clinical trial data presented here provides further evidence of the ability of MVA85A to boost BCG primed immune responses. This boosting potential is not influenced by the time interval between prior BCG vaccination and boosting with MVA85A. These findings have important implications for the design of efficacy trials with MVA85A. Boosting BCG induced anti-mycobacterial immunity in either infancy or adolescence are both potential applications for this vaccine, given the immunological data presented here. Trial Registration. ClinicalTrials.Oxford University was the sponsor for all the clinical trials reported here

Criteria for the use of omics-based predictors in clinical trials.

The US National Cancer Institute (NCI), in collaboration with scientists representing multiple areas of expertise relevant to 'omics'-based test development, has developed a checklist of criteria that can be used to determine the readiness of omics-based tests for guiding patient care in clinical trials. The checklist criteria cover issues relating to specimens, assays, mathematical modelling, clinical trial design, and ethical, legal and regulatory aspects. Funding bodies and journals are encouraged to consider the checklist, which they may find useful for assessing study quality and evidence strength. The checklist will be used to evaluate proposals for NCI-sponsored clinical trials in which omics tests will be used to guide therapy

NCI-MATCH Arms N & P: Phase II study of PI3K beta inhibitor GSK2636771 in patients (pts) with cancers (ca) with PTEN mutation/deletion (mut/del) or PTEN protein loss

Background: The NCI-MATCH trial is the largest national study (1173 sites) for ptswith relapsed/ refractory solid tumors, lymphomas and myeloma, which assigns tar-geted therapies based on individual tumor molecular alterations detected using theadapted Oncomine AmpliSeq panel (143 genes) and immunohistochemistry (IHC).We hypothesized that patients with PTEN-deficient cancers enrolled to Arms N and Pmay benefit from treatment with the PI3K beta-selective inhibitor GSK2636771. Methods: Eligibility: relapsed/refractory ca, good end-organ function, and ECOG PS ≤ 1. Pts were screened for molecular alterations by centralized testing on fresh tumor biopsy and had deleterious PTEN mut/del without loss of expression (Arm N) or complete loss of cytoplasmic and nuclear PTEN staining on IHC (Arm P), and no other aberrations activating the PI3K/MTOR and MAPK pathways (mut in PIK3CA, PIK3R1, BRAF, KRAS, AKT1, TSC1/2, mTOR, RHEB, NF2, NRAS, HRAS). Pts received GSK2636771 400mg/day (28-days cycles). RECIST 1.1 overall response rate (ORR) was the primary endpoint. Results: Of 59 enrolled pts, 56 were eligible and received treatment. Of 22 pts with PTEN mut/del (Arm N: 6 uterine, 2 breast, 2 prostate, 2 head/neck ca, 10 other), all are off treatment as of analysis (14 disease progression, 4 for adverse events [AEs], 4 other). One pt (4.5%) with prostate ca (PTEN deletion, MPRSS2-ERG fusion) attained a partial response (-42%). Of 7 (32%) pts with stable disease (SD), 2 had SD \u3e 6 months (uterine leiomyosarcoma; endometrial carcinoma). Of 34 pts with loss of PTEN protein by IHC (Arm P: 7 prostate, 6 breast, 3 squamous anal ca, 2 cholangiocarcinoma, 16 other), all are off treatment as of analysis (26 disease progression, 4 for AE, 4 other). Of 9 (37.5%) pts with SD, 3 had SD \u3e 6 months (prostate cancer; squamous bladder cancer, squamous anal cancer). Median progression-free survival was 1.8 months for both arms. Gr ≥ 3 treatment-related (tr) reversible toxicities were experienced by 30% (7) and 20% (7) of pts in arms N and P, respectively. No tr Gr 5 toxicities were observed in either arm. Conclusions: Single agent GSK2636771 has very modest activity in ca with PTEN gene mutation/deletion and/or PTEN protein loss

Generating and measuring the anisotropic elastic behaviour of Co thin films with oriented surface nano-strings on micro-cantilevers

In this research, the elastic behaviour of two Co thin films simultaneously deposited in an off-normal angle method was studied. Towards this end, two Si micro-cantilevers were simultaneously coated using pulsed laser deposition at an oblique angle, creating a Co nano-string surface morphology with a predetermined orientation. The selected position of each micro-cantilever during the coating process created longitudinal or transverse nano-strings. The anisotropic elastic behaviour of these Co films was determined by measuring the changes that took place in the resonant frequency of each micro-cantilever after this process of creating differently oriented plasma coatings had been completed. This differential procedure allowed us to determine the difference between the Young's modulus of the different films based on the different direction of the nano-strings. This difference was determined to be, at least, the 20% of the Young's modulus of the bulk Co

Now or never: perceptions of uniqueness induce acceptance of price increases for experiences more than for objects

Seven studies test and support the prediction that consumers are more willing to accept a price increase for an experiential versus a material purchase; an effect explained by the greater uniqueness of experiences. Critically, the uniqueness model advanced here is found to be independent of the happiness consumers derive from the purchase. To gain a deeper understanding of the uniqueness mechanism, this investigation then advances and tests a four-facet framework of uniqueness (unique opportunity, unique purchase, unique identity, and counterconformity). Together, the findings converge on the conclusion that consumers perceive the opportunity to have a particular experience (vs. object) as more unique, and this unique opportunity increases their willingness to accept a price increase. Overall, this work extends the experiential versus material purchases literature into a new domain—that of pricing; identifies the dimension—uniqueness—and its precise facet responsible for the effect—unique opportunity; and demonstrates that this model unfolds in a pattern distinct from the oft researched model centered on consumer happiness. Theoretical and practical implications are discussed.info:eu-repo/semantics/acceptedVersio

Geometric Approach to Pontryagin's Maximum Principle

Since the second half of the 20th century, Pontryagin's Maximum Principle has been widely discussed and used as a method to solve optimal control problems in medicine, robotics, finance, engineering, astronomy. Here, we focus on the proof and on the understanding of this Principle, using as much geometric ideas and geometric tools as possible. This approach provides a better and clearer understanding of the Principle and, in particular, of the role of the abnormal extremals. These extremals are interesting because they do not depend on the cost function, but only on the control system. Moreover, they were discarded as solutions until the nineties, when examples of strict abnormal optimal curves were found. In order to give a detailed exposition of the proof, the paper is mostly self\textendash{}contained, which forces us to consider different areas in mathematics such as algebra, analysis, geometry.Comment: Final version. Minors changes have been made. 56 page

HAGE (DDX43) is a biomarker for poor prognosis and a predictor of chemotherapy response in breast cancer

Background: HAGE protein is a known immunogenic cancer-specific antigen. Methods: The biological, prognostic and predictive values of HAGE expression was studied using immunohistochemistry in three cohorts of patients with BC (n=2147): early primary (EP-BC; n=1676); primary oestrogen receptor-negative (PER-BC; n=275) treated with adjuvant anthracycline-combination therapies (Adjuvant-ACT); and primary locally advanced disease (PLA-BC) who received neo-adjuvant anthracycline-combination therapies (Neo-adjuvant-ACT; n=196). The relationship between HAGE expression and the tumour-infiltrating lymphocytes (TILs) in matched prechemotherapy and postchemotherapy samples were investigated. Results: Eight percent of patients with EP-BC exhibited high HAGE expression (HAGEþ) and was associated with aggressive clinico-pathological features (Ps<0.01). Furthermore, HAGEþexpression was associated with poor prognosis in both univariate and multivariate analysis (Ps<0.001). Patients with HAGE+ did not benefit from hormonal therapy in high-risk ER-positive disease. HAGE+ and TILs were found to be independent predictors for pathological complete response to neoadjuvant-ACT; P<0.001. A statistically significant loss of HAGE expression following neoadjuvant-ACT was found (P=0.000001), and progression-free survival was worse in those patients who had HAGE+ residual disease (P=0.0003). Conclusions: This is the first report to show HAGE to be a potential prognostic marker and a predictor of response to ACT in patients with BC

Azimuthal anisotropy and correlations in the hard scattering regime at RHIC

Azimuthal anisotropy ($v_2$) and two-particle angular correlations of high $p_T$ charged hadrons have been measured in Au+Au collisions at $\sqrt{s_{NN}}$=130 GeV for transverse momenta up to 6 GeV/c, where hard processes are expected to contribute significantly. The two-particle angular correlations exhibit elliptic flow and a structure suggestive of fragmentation of high $p_T$ partons. The monotonic rise of $v_2(p_T)$ for $p_T<2$ GeV/c is consistent with collective hydrodynamical flow calculations. At \pT>3 GeV/c a saturation of $v_2$ is observed which persists up to $p_T=6$ GeV/c.Comment: As publishe

Disappearance of back-to-back high pTp_T hadron correlations in central Au+Au collisions at sNN\sqrt{s_{NN}} = 200 GeV

Azimuthal correlations for large transverse momentum charged hadrons have been measured over a wide pseudo-rapidity range and full azimuth in Au+Au and p+p collisions at $\sqrt{s_{NN}}$ = 200 GeV. The small-angle correlations observed in p+p collisions and at all centralities of Au+Au collisions are characteristic of hard-scattering processes already observed in elementary collisions. A strong back-to-back correlation exists for p+p and peripheral Au + Au. In contrast, the back-to-back correlations are reduced considerably in the most central Au+Au collisions, indicating substantial interaction as the hard-scattered partons or their fragmentation products traverse the medium.Comment: submitted to Phys. Rev. Let

Azimuthal anisotropy of K0S and Lambda + Lambda -bar production at midrapidity from Au+Au collisions at sqrt[sNN]=130 GeV

We report STAR results on the azimuthal anisotropy parameter v2 for strange particles K0S, Lambda , and Lambda -bar at midrapidity in Au+Au collisions at sqrt[sNN]=130 GeV at the Relativistic Heavy Ion Collider. The value of v2 as a function of transverse momentum, pt, of the produced particle and collision centrality is presented for both particles up to pt~3.0 GeV/c. A strong pt dependence in v2 is observed up to 2.0 GeV/c. The v2 measurement is compared with hydrodynamic model calculations. The physics implications of the pt integrated v2 magnitude as a function of particle mass are also discussed.Alle Autoren: C. Adler, Z. Ahammed, C. Allgower, J. Amonett, B. D. Anderson, M. Anderson, G. S. Averichev, J. Balewski, O. Barannikova, L. S. Barnby, J. Baudot, S. Bekele, V. V. Belaga, R. Bellwied, J. Berger, H. Bichsel, A. Billmeier, L. C. Bland, C. O. Blyth, B. E. Bonner, A. Boucham, A. Brandin, A. Bravar, R. V. Cadman, H. Caines, M. Calderón de la Barca Sánchez, A. Cardenas, J. Carroll, J. Castillo, M. Castro, D. Cebra, P. Chaloupka, S. Chattopadhyay, Y. Chen, S. P. Chernenko, M. Cherney, A. Chikanian, B. Choi, W. Christie, J. P. Coffin, T. M. Cormier, J. G. Cramer, H. J. Crawford, W. S. Deng, A. A. Derevschikov, L. Didenko, T. Dietel, J. E. Draper, V. B. Dunin, J. C. Dunlop, V. Eckardt, L. G. Efimov, V. Emelianov, J. Engelage, G. Eppley, B. Erazmus, P. Fachini, V. Faine, K. Filimonov, E. Finch, Y. Fisyak, D. Flierl, K. J. Foley, J. Fu, C. A. Gagliardi, N. Gagunashvili, J. Gans, L. Gaudichet, M. Germain, F. Geurts, V. Ghazikhanian, O. Grachov, V. Grigoriev, M. Guedon, E. Gushin, T. J. Hallman, D. Hardtke, J. W. Harris, T. W. Henry, S. Heppelmann, T. Herston, B. Hippolyte, A. Hirsch, E. Hjort, G. W. Hoffmann, M. Horsley, H. Z. Huang, T. J. Humanic, G. Igo, A. Ishihara, Yu. I. Ivanshin, P. Jacobs, W. W. Jacobs, M. Janik, I. Johnson, P. G. Jones, E. G. Judd, M. Kaneta, M. Kaplan, D. Keane, J. Kiryluk, A. Kisiel, J. Klay, S. R. Klein, A. Klyachko, A. S. Konstantinov, M. Kopytine, L. Kotchenda, A. D. Kovalenko, M. Kramer, P. Kravtsov, K. Krueger, C. Kuhn, A. I. Kulikov, G. J. Kunde, C. L. Kunz, R. Kh. Kutuev, A. A. Kuznetsov, L. Lakehal-Ayat, M. A. C. Lamont, J. M. Landgraf, S. Lange, C. P. Lansdell, B. Lasiuk, F. Laue, A. Lebedev, R. Lednický, V. M. Leontiev, M. J. LeVine, Q. Li, S. J. Lindenbaum, M. A. Lisa, F. Liu, L. Liu, Z. Liu, Q. J. Liu, T. Ljubicic, W. J. Llope, G. LoCurto, H. Long, R. S. Longacre, M. Lopez-Noriega, W. A. Love, T. Ludlam, D. Lynn, J. Ma, R. Majka, S. Margetis, C. Markert, L. Martin, J. Marx, H. S. Matis, Yu. A. Matulenko, T. S. McShane, F. Meissner, Yu. Melnick, A. Meschanin, M. Messer, M. L. Miller, Z. Milosevich, N. G. Minaev, J. Mitchell, V. A. Moiseenko, C. F. Moore, V. Morozov, M. M. de Moura, M. G. Munhoz, J. M. Nelson, P. Nevski, V. A. Nikitin, L. V. Nogach, B. Norman, S. B. Nurushev, G. Odyniec, A. Ogawa, V. Okorokov, M. Oldenburg, D. Olson, G. Paic, S. U. Pandey, Y. Panebratsev, S. Y. Panitkin, A. I. Pavlinov, T. Pawlak, V. Perevoztchikov, W. Peryt, V. A Petrov, M. Planinic, J. Pluta, N. Porile, J. Porter, A. M. Poskanzer, E. Potrebenikova, D. Prindle, C. Pruneau, J. Putschke, G. Rai, G. Rakness, O. Ravel, R. L. Ray, S. V. Razin, D. Reichhold, J. G. Reid, F. Retiere, A. Ridiger, H. G. Ritter, J. B. Roberts, O. V. Rogachevski, J. L. Romero, A. Rose, C. Roy, V. Rykov, I. Sakrejda, S. Salur, J. Sandweiss, A. C. Saulys, I. Savin, J. Schambach, R. P. Scharenberg, N. Schmitz, L. S. Schroeder, A. Schüttauf, K. Schweda, J. Seger, D. Seliverstov, P. Seyboth, E. Shahaliev, K. E. Shestermanov, S. S. Shimanskii, V. S. Shvetcov, G. Skoro, N. Smirnov, R. Snellings, P. Sorensen, J. Sowinski, H. M. Spinka, B. Srivastava, E. J. Stephenson, R. Stock, A. Stolpovsky, M. Strikhanov, B. Stringfellow, C. Struck, A. A. P. Suaide, E. Sugarbaker, C. Suire, M. Šumbera, B. Surrow, T. J. M. Symons, A. Szanto de Toledo, P. Szarwas, A. Tai, J. Takahashi, A. H. Tang, J. H. Thomas, M. Thompson, V. Tikhomirov, M. Tokarev, M. B. Tonjes, T. A. Trainor, S. Trentalange, R. E. Tribble, V. Trofimov, O. Tsai, T. Ullrich, D. G. Underwood, G. Van Buren, A. M. VanderMolen, I. M. Vasilevski, A. N. Vasiliev, S. E. Vigdor, S. A. Voloshin, F. Wang, H. Ward, J. W. Watson, R. Wells, G. D. Westfall, C. Whitten, Jr., H. Wieman, R. Willson, S. W. Wissink, R. Witt, J. Wood, N. Xu, Z. Xu, A. E. Yakutin, E. Yamamoto, J. Yang, P. Yepes, V. I. Yurevich, Y. V. Zanevski, I. Zborovský, H. Zhang, W. M. Zhang, R. Zoulkarneev, and A. N. Zubarev (STAR Collaboration