The chemical evolution of the solar neighbourhood

Recent models of galactic chemical evolution account for updated evolutionary models of massive stars (with special emphasis on stellar winds) and for the effects of intermediate mass and massive binaries. The results are summarised. We also present a critical discussion on possible effects of stellar rotation on overall galactic chemical evolutionary simulations.Comment: 12 pages, 3 figures, Pacific Rim Conference, Xi'an, China, 11-17 July 200

Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

BackgroundT cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.MethodsPatients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.ResultsFourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.ConclusionThese findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity

Alpha-particle-induced complex chromosome exchanges transmitted through extra-thymic lymphopoiesis in vitro show evidence of emerging genomic instability

Human exposure to high-linear energy transfer α-particles includes environmental (e.g. radon gas and its decay progeny), medical (e.g. radiopharmaceuticals) and occupational (nuclear industry) sources. The associated health risks of α-particle exposure for lung cancer are well documented however the risk estimates for leukaemia remain uncertain. To further our understanding of α-particle effects in target cells for leukaemogenesis and also to seek general markers of individual exposure to α-particles, this study assessed the transmission of chromosomal damage initially-induced in human haemopoietic stem and progenitor cells after exposure to high-LET α-particles. Cells surviving exposure were differentiated into mature T-cells by extra-thymic T-cell differentiation in vitro. Multiplex fluorescence in situ hybridisation (M-FISH) analysis of naïve T-cell populations showed the occurrence of stable (clonal) complex chromosome aberrations consistent with those that are characteristically induced in spherical cells by the traversal of a single α-particle track. Additionally, complex chromosome exchanges were observed in the progeny of irradiated mature T-cell populations. In addition to this, newly arising de novo chromosome aberrations were detected in cells which possessed clonal markers of α-particle exposure and also in cells which did not show any evidence of previous exposure, suggesting ongoing genomic instability in these populations. Our findings support the usefulness and reliability of employing complex chromosome exchanges as indicators of past or ongoing exposure to high-LET radiation and demonstrate the potential applicability to evaluate health risks associated with α-particle exposure.This work was supported by the Department of Health, UK. Contract RRX95 (RMA NSDTG)

Generation of an ultrabroadband supercontinuum in the mid-infrared region using dispersion-engineered GeAsSe photonic crystal fiber

An ultrabroadband mid-infrared (MIR) region supercontinuum (SC) is demonstrated numerically through dispersion-engineered traditional chalcogenide (ChG) photonic crystal fiber (PCF). By varying structural parameters pitch (hole to hole spacing) and air-hole diameter to pitch ratio, a number of 10-mm-long hexagonal PCFs made employing GeAsSe ChG glass as a core and air-holes of hexagonal lattice running through their lengths as a cladding are optimized to predict an efficient mid-infrared region SC spectral emission by pumping them using a tunable pump source between 2.9 and 3.3 µm. Simulations are carried out using an ultrashort pump pulse of 100-fs duration with a low pulse peak powers of between 3 and 4 kW into the optimized designs. It is found through numerical analysis that efficient SC spectral broadening with flattened output can be obtained by increasing the PCF pitch rather than increasing the PCF cladding containing air-hole diameter although a larger nonlinear coefficient could be obtained through increasing air-hole diameter of an optimized design. Simulation results show that the SC spectra can be broadened up to 12.2 µm for a certain design with a peak power of 3 kW. Using a peak power of 4 kW, it is possible to obtain SC spectral broadening beyond 14 µm with an optimized design spanning the wavelength range from 1.8 to 14 µm which covers the electromagnetic spectrum required for MIR molecular fingerprint region applications such as sensing and biological imaging

Stakeholder involvement in systematic reviews:a scoping review

Abstract Background There is increasing recognition that it is good practice to involve stakeholders (meaning patients, the public, health professionals and others) in systematic reviews, but limited evidence about how best to do this. We aimed to document the evidence-base relating to stakeholder involvement in systematic reviews and to use this evidence to describe how stakeholders have been involved in systematic reviews. Methods We carried out a scoping review, following a published protocol. We searched multiple electronic databases (2010–2016), using a stepwise searching approach, supplemented with hand searching. Two authors independently screened and discussed the first 500 abstracts and, after clarifying selection criteria, screened a further 500. Agreement on screening decisions was 97%, so screening was done by one reviewer only. Pre-planned data extraction was completed, and the comprehensiveness of the description of methods of involvement judged. Additional data extraction was completed for papers judged to have most comprehensive descriptions. Three stakeholder representatives were co-authors for this systematic review. Results We included 291 papers in which stakeholders were involved in a systematic review. Thirty percent involved patients and/or carers. Thirty-two percent were from the USA, 26% from the UK and 10% from Canada. Ten percent (32 reviews) were judged to provide a comprehensive description of methods of involving stakeholders. Sixty-nine percent (22/32) personally invited people to be involved; 22% (7/32) advertised opportunities to the general population. Eighty-one percent (26/32) had between 1 and 20 face-to-face meetings, with 83% of these holding ≤ 4 meetings. Meetings lasted 1 h to ½ day. Nineteen percent (6/32) used a Delphi method, most often involving three electronic rounds. Details of ethical approval were reported by 10/32. Expenses were reported to be paid to people involved in 8/32 systematic reviews. Discussion/conclusion We identified a relatively large number (291) of papers reporting stakeholder involvement in systematic reviews, but the quality of reporting was generally very poor. Information from a subset of papers judged to provide the best descriptions of stakeholder involvement in systematic reviews provide examples of different ways in which stakeholders have been involved in systematic reviews. These examples arguably currently provide the best available information to inform and guide decisions around the planning of stakeholder involvement within future systematic reviews. This evidence has been used to develop online learning resources. Systematic review registration The protocol for this systematic review was published on 21 April 2017. Publication reference: Pollock A, Campbell P, Struthers C, Synnot A, Nunn J, Hill S, Goodare H, Watts C, Morley R: Stakeholder involvement in systematic reviews: a protocol for a systematic review of methods, outcomes and effects. Research Involvement and Engagement 2017, 3:9. https://doi.org/10.1186/s40900-017-0060-4

Sub-lethal radiation enhances anti-tumor immunotherapy in a transgenic mouse model of pancreatic cancer

BACKGROUND: It is not uncommon to observe circulating tumor antigen-specific T lymphocytes in cancer patients despite a lack of significant infiltration and destruction of their tumors. Thus, an important goal for tumor immunotherapy is to identify ways to modulate in vivo anti-tumor immunity to achieve clinical efficacy. We investigate this proposition in a spontaneous mouse tumor model, Rip1-Tag2. METHODS: Experimental therapies were carried out in two distinctive trial designs, intended to either intervene in the explosive growth of small tumors, or regress bulky end-stage tumors. Rip1-Tag2 mice received a single transfer of splenocytes from Tag-specific, CD4(+) T cell receptor transgenic mice, a single sub-lethal radiation, or a combination therapy in which the lymphocyte transfer was preceded by the sub-lethal radiation. Tumor burden, the extent of lymphocyte infiltration into solid tumors and host survival were used to assess the efficacy of these therapeutic approaches. RESULTS: In either intervention or regression, the transfer of Tag-specific T cells alone did not result in significant lymphocyte infiltration into solid tumors, not did it affect tumor growth or host survival. In contrast, the combination therapy resulted in significant reduction in tumor burden, increase in lymphocyte infiltration into solid tumors, and extension of survival. CONCLUSIONS: The results indicate that certain types of solid tumors may be intrinsically resistant to infiltration and destruction by tumor-specific T lymphocytes. Our data suggest that such resistance can be disrupted by sub-lethal radiation. The combinatorial approach presented here merits consideration in the design of clinical trials aimed to achieve T cell-mediated anti-tumor immunity

Research Methodologies and Business Discourse Teaching

This chapter will:; ; ; Define English for specific purposes and indicate the specific ways in which it has been influential on business discourse teaching;; ; ; Discuss the most relevant approaches to genre analysis that have been used in business discourse teaching;; ; ; Explore the most relevant approaches to critical discourse analysis and organizational rhetoric for business discourse teaching;; ; ; Identify the most relevant aspects of multimodal discourse analysis for business discourse teaching;; ; ; Provide a case study that illustrates the use of one approach to business discourse teaching, showing how practitioners can incorporate it into their classroom- or consultancy-based ideas

Reward devaluation disrupts latent inhibition in fear conditioning

Three experiments explored the link between reward shifts and latent inhibition (LI). Using consummatory procedures, rewards were either downshifted from 32% to 4% sucrose (Experiments 1–2), or upshifted from 4% to 32% sucrose (Experiment 3). In both cases, appropriate unshifted controls were also included. LI was implemented in terms of fear conditioning involving a single tone-shock pairing after extensive tone-only preexposure. Nonpreexposed controls were also included. Experiment 1 demonstrated a typical LI effect (i.e., disruption of fear conditioning after preexposure to the tone) in animals previously exposed only to 4% sucrose. However, the LI effect was eliminated by preexposure to a 32%-to-4% sucrose devaluation. Experiment 2 replicated this effect when the LI protocol was administered immediately after the reward devaluation event. However, LI was restored when preexposure was administered after a 60- min retention interval. Finally, Experiment 3 showed that a reward upshift did not affect LI. These results point to a significant role of negative emotion related to reward devaluation in the enhancement of stimulus processing despite extensive nonreinforced preexposure experience

Multicentre phase II studies evaluating imatinib plus hydroxyurea in patients with progressive glioblastoma

Contains fulltext : 79699.pdf (publisher's version ) (Closed access)BACKGROUND: We evaluated the efficacy of imatinib mesylate in addition to hydroxyurea in patients with recurrent glioblastoma (GBM) who were either on or not on enzyme-inducing anti-epileptic drugs (EIAEDs). METHODS: A total of 231 patients with GBM at first recurrence from 21 institutions in 10 countries were enrolled. All patients received 500 mg of hydroxyurea twice a day. Imatinib was administered at 600 mg per day for patients not on EIAEDs and at 500 mg twice a day if on EIAEDs. The primary end point was radiographic response rate and secondary end points were safety, progression-free survival at 6 months (PFS-6), and overall survival (OS). RESULTS: The radiographic response rate after centralised review was 3.4%. Progression-free survival at 6 months and median OS were 10.6% and 26.0 weeks, respectively. Outcome did not appear to differ based on EIAED status. The most common grade 3 or greater adverse events were fatigue (7%), neutropaenia (7%), and thrombocytopaenia (7%). CONCLUSIONS: Imatinib in addition to hydroxyurea was well tolerated among patients with recurrent GBM but did not show clinically meaningful anti-tumour activity

An 11-bp Insertion in Zea mays fatb Reduces the Palmitic Acid Content of Fatty Acids in Maize Grain

The ratio of saturated to unsaturated fatty acids in maize kernels strongly impacts human and livestock health, but is a complex trait that is difficult to select based on phenotype. Map-based cloning of quantitative trait loci (QTL) is a powerful but time-consuming method for the dissection of complex traits. Here, we combine linkage and association analyses to fine map QTL-Pal9, a QTL influencing levels of palmitic acid, an important class of saturated fatty acid. QTL-Pal9 was mapped to a 90-kb region, in which we identified a candidate gene, Zea mays fatb (Zmfatb), which encodes acyl-ACP thioesterase. An 11-bp insertion in the last exon of Zmfatb decreases palmitic acid content and concentration, leading to an optimization of the ratio of saturated to unsaturated fatty acids while having no effect on total oil content. We used three-dimensional structure analysis to explain the functional mechanism of the ZmFATB protein and confirmed the proposed model in vitro and in vivo. We measured the genetic effect of the functional site in 15 different genetic backgrounds and found a maximum change of 4.57 mg/g palmitic acid content, which accounts for ∼20–60% of the variation in the ratio of saturated to unsaturated fatty acids. A PCR-based marker for QTL-Pal9 was developed for marker-assisted selection of nutritionally healthier maize lines. The method presented here provides a new, efficient way to clone QTL, and the cloned palmitic acid QTL sheds lights on the genetic mechanism of oil biosynthesis and targeted maize molecular breeding