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

Displaced but not replaced: the impact of e-learning on academic identities in higher education.

Challenges facing universities are leading many to implement institutional strategies to incorporate e-learning rather than leaving its adoption up to enthusiastic individuals. Although there is growing understanding about the impact of e-learning on the student experience, there is less understanding of academics’ perceptions of e-learning and its impact on their identities. This paper explores the changing nature of academic identities revealed through case study research into the implementation of e-learning at one UK university. By providing insight into the lived experiences of academics in a university in which technology is not only transforming access to knowledge but also influencing the balance of power between academic and student in knowledge production and use, it is suggested that academics may experience a jolt to their ‘trajectory of self’ when engaging with e-learning. The potential for e-learning to prompt loss of teacher presence and displacement as knowledge expert may appear to undermine the ontological security of their academic identity

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

Mitigation of Quantum Dot Cytotoxicity by Microencapsulation

When CdSe/ZnS-polyethyleneimine (PEI) quantum dots (QDs) are microencapsulated in polymeric microcapsules, human fibroblasts are protected from acute cytotoxic effects. Differences in cellular morphology, uptake, and viability were assessed after treatment with either microencapsulated or unencapsulated dots. Specifically, QDs contained in microcapsules terminated with polyethylene glycol (PEG) mitigate contact with and uptake by cells, thus providing a tool to retain particle luminescence for applications such as extracellular sensing and imaging. The microcapsule serves as the “first line of defense” for containing the QDs. This enables the individual QD coating to be designed primarily to enhance the function of the biosensor

Preclinical Development of an In Vivo BCG Challenge Model for Testing Candidate TB Vaccine Efficacy

There is an urgent need for an immunological correlate of protection against tuberculosis (TB) with which to evaluate candidate TB vaccines in clinical trials. Development of a human challenge model of Mycobacterium tuberculosis (M.tb) could facilitate the detection of such correlate(s). Here we propose a novel in vivo Bacille Calmette-Guérin (BCG) challenge model using BCG immunization as a surrogate for M.tb infection. Culture and quantitative PCR methods have been developed to quantify BCG in the skin, using the mouse ear as a surrogate for human skin. Candidate TB vaccines have been evaluated for their ability to protect against a BCG skin challenge, using this model, and the results indicate that protection against a BCG skin challenge is predictive of BCG vaccine efficacy against aerosol M.tb challenge. Translation of these findings to a human BCG challenge model could enable more rapid assessment and down selection of candidate TB vaccines and ultimately the identification of an immune correlate of protection

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

Pion interferometry in Au+Au collisions at sNN\sqrt{\mathrm{s}_{_{\mathrm{NN}}}} = 200 GeV

We present a systematic analysis of two-pion interferometry in Au+Au collisions at $\sqrt{s_{NN}}$ = 200 GeV using the STAR detector at RHIC. We extract the HBT radii and study their multiplicity, transverse momentum, and azimuthal angle dependence. The Gaussianess of the correlation function is studied. Estimates of the geometrical and dynamical structure of the freeze-out source are extracted by fits with blast wave parameterizations. The expansion of the source and its relation with the initial energy density distribution is studied.Comment: 21 pages, 30 figures. As published in Physics Review

Transverse-momentum dependent modification of dynamic texture in central Au+Au collisions at sqrt(S_NN)=200 GeV

Correlations in the hadron distributions produced in relativistic Au+Au collisions are studied in the discrete wavelet expansion method. The analysis is performed in the space of pseudorapidity (|eta| < 1) and azimuth (full 2 pi) in bins of transverse momentum (p_t) from 0.14 < p_t < 2.1 GeV/c. In peripheral Au+Au collisions a correlation structure ascribed to mini-jet fragmentation is observed. It evolves with collision centrality and p_t in a way not seen before which suggests strong dissipation of minijet fragmentation in the longitudinally-expanding medium.Comment: 6 pages, 3 figure, accepted as Phys.Rev.C Rapid Communication. This version fixes journal style issue

Pion interferometry in Au+Au collisions at sqrt[sNN]=200GeV

We present a systematic analysis of two-pion interferometry in Au+Au collisions at sqrt[sNN]=200GeV using the STAR detector at Relativistic Heavy Ion Collider. We extract the Hanbury-Brown and Twiss radii and study their multiplicity, transverse momentum, and azimuthal angle dependence. The Gaussianness of the correlation function is studied. Estimates of the geometrical and dynamical structure of the freeze-out source are extracted by fits with blast-wave parametrizations. The expansion of the source and its relation with the initial energy density distribution is studied

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