Therapeutic limitations in tumor-specific CD8+ memory T cell engraftment

BACKGROUND: Adoptive immunotherapy with cytotoxic T lymphocytes (CTL) represents an alternative approach to treating solid tumors. Ideally, this would confer long-term protection against tumor. We previously demonstrated that in vitro-generated tumor-specific CTL from the ovalbumin (OVA)-specific OT-I T cell receptor transgenic mouse persisted long after adoptive transfer as memory T cells. When recipient mice were challenged with the OVA-expressing E.G7 thymoma, tumor growth was delayed and sometimes prevented. The reasons for therapeutic failures were not clear. METHODS: OT-I CTL were adoptively transferred to C57BL/6 mice 21 – 28 days prior to tumor challenge. At this time, the donor cells had the phenotypical and functional characteristics of memory CD8+ T cells. Recipients which developed tumor despite adoptive immunotherapy were analyzed to evaluate the reason(s) for therapeutic failure. RESULTS: Dose-response studies demonstrated that the degree of tumor protection was directly proportional to the number of OT-I CTL adoptively transferred. At a low dose of OT-I CTL, therapeutic failure was attributed to insufficient numbers of OT-I T cells that persisted in vivo, rather than mechanisms that actively suppressed or anergized the OT-I T cells. In recipients of high numbers of OT-I CTL, the E.G7 tumor that developed was shown to be resistant to fresh OT-I CTL when examined ex vivo. Furthermore, these same tumor cells no longer secreted a detectable level of OVA. In this case, resistance to immunotherapy was secondary to selection of clones of E.G7 that expressed a lower level of tumor antigen. CONCLUSIONS: Memory engraftment with tumor-specific CTL provides long-term protection against tumor. However, there are several limitations to this immunotherapeutic strategy, especially when targeting a single antigen. This study illustrates the importance of administering large numbers of effectors to engraft sufficiently efficacious immunologic memory. It also demonstrates the importance of targeting several antigens when developing vaccine strategies for cancer

In vitro culture with gemcitabine augments death receptor and NKG2D ligand expression on tumour cells

Much effort has been made to try to understand the relationship between chemotherapeutic treatment of cancer and the immune system. Whereas much of that focus has been on the direct effect of chemotherapy drugs on immune cells and the release of antigens and danger signals by malignant cells killed by chemotherapy, the effect of chemotherapy on cells surviving treatment has often been overlooked. In the present study, tumour cell lines: A549 (lung), HCT116 (colon) and MCF-7 (breast), were treated with various concentrations of the chemotherapeutic drugs cyclophosphamide, gemcitabine (GEM) and oxaliplatin (OXP) for 24 hours in vitro. In line with other reports, GEM and OXP upregulated expression of the death receptor CD95 (fas) on live cells even at sub-cytotoxic concentrations. Further investigation revealed that the increase in CD95 in response to GEM sensitised the cells to fas ligand treatment, was associated with increased phosphorylation of stress activated protein kinase/c-Jun N-terminal kinase and that other death receptors and activatory immune receptors were co-ordinately upregulated with CD95 in certain cell lines. The upregulation of death receptors and NKG2D ligands together on cells after chemotherapy suggest that although the cells have survived preliminary treatment with chemotherapy they may now be more susceptible to immune cell-mediated challenge. This re-enforces the idea that chemotherapy-immunotherapy combinations may be useful clinically and has implications for the make-up and scheduling of such treatments

Herbicidal Activities of Essential Oils from Pine, Nut Pine, Larch and Khingan Fir in Korea

ABSTRACT. The objective of this research was to understand herbicidal activity of essential oils isolated from leaves of pine (Pinus densiflora), nut pine (Pinus koraiensis), larch (Larix kaempferi) and khingan fir (Abies nephrolepsis) in Korea. In a seed bioassay, essential oils of nut pine, larch and khingan fir inhibited the growth of rapeseed (Brassica napus) seedlings by 50% at 4,766, 1,865, 5,934 µg ml , respectively, however, that of pine did not show any herbicidal effect. In a green house experiment, fall panicum, Southern crabgrass, sorghum, barnyardgrass, quackgrass, black nightshade, Indian jointvetch, velvet leaf, and Japanese morningglory were controlled in 24 hours by the foliar application of 10% essential oils from pine, nut pine, larch and khingan fir. The treated plant parts showed burndown effect, however, new shoots appeared 3 days after treatment. Results of GC-MS analysis showed that essential oils from pine, nut pine, larch and khingan fir contained 16, 25, 25, and 16 compounds, respectively, with hydrocarbons, alcohols, ketones, and esters. The major compounds of the essential oils were 3-carene, bornyl acetate, camphene, limonene, α-pinene, β-pinene and β-phellandrene

Electronic Coherence Dephasing in Excitonic Molecular Complexes: Role of Markov and Secular Approximations

We compare four different types of equations of motion for reduced density matrix of a system of molecular excitons interacting with thermodynamic bath. All four equations are of second order in the linear system-bath interaction Hamiltonian, with different approximations applied in their derivation. In particular we compare time-nonlocal equations obtained from so-called Nakajima-Zwanzig identity and the time-local equations resulting from the partial ordering prescription of the cummulant expansion. In each of these equations we alternatively apply secular approximation to decouple population and coherence dynamics from each other. We focus on the dynamics of intraband electronic coherences of the excitonic system which can be traced by coherent two-dimensional spectroscopy. We discuss the applicability of the four relaxation theories to simulations of population and coherence dynamics, and identify features of the two-dimensional coherent spectrum that allow us to distinguish time-nonlocal effects.Comment: 14 pages, 8 figure

The Impact of Flavour Changing Neutral Gauge Bosons on B->X_s gamma

The branching ratio of the rare decay B->X_s gamma provides potentially strong constraints on models beyond the Standard Model. Considering a general scenario with new heavy neutral gauge bosons, present in particular in Z' and gauge flavour models, we point out two new contributions to the B->X_s gamma decay. The first one originates from one-loop diagrams mediated by gauge bosons and heavy exotic quarks with electric charge -1/3. The second contribution stems from the QCD mixing of neutral current-current operators generated by heavy neutral gauge bosons and the dipole operators responsible for the B->X_s gamma decay. The latter mixing is calculated here for the first time. We discuss general sum rules which have to be satisfied in any model of this type. We emphasise that the neutral gauge bosons in question could also significantly affect other fermion radiative decays as well as non-leptonic two-body B decays, epsilon'/epsilon, anomalous (g-2)_mu and electric dipole moments.Comment: 31 pages, 5 figures; version published on JHEP; added magic QCD numbers for flavour-violating Z gauge boson contribution to B -> X_s gamm

Pirfenidone in idiopathic pulmonary fibrosis:expert panel discussion on the management of drug-related adverse events

Pirfenidone is currently the only approved therapy for idiopathic pulmonary fibrosis, following studies demonstrating that treatment reduces the decline in lung function and improves progression-free survival. Although generally well tolerated, a minority of patients discontinue therapy due to gastrointestinal and skin-related adverse events (AEs). This review summarizes recommendations based on existing guidelines, research evidence, and consensus opinions of expert authors, with the aim of providing practicing physicians with the specific clinical information needed to educate the patient and better manage pirfenidone-related AEs with continued pirfenidone treatment. The main recommendations to help prevent and/or mitigate gastrointestinal and skin-related AEs include taking pirfenidone during (or after) a meal, avoiding sun exposure, wearing protective clothing, and applying a broad-spectrum sunscreen with high ultraviolet (UV) A and UVB protection. These measures can help optimize AE management, which is key to maintaining patients on an optimal treatment dose.Correction in: Advances in Therapy, Volume 31, Issue 5, pp 575-576 , doi: 10.1007/s12325-014-0118-8</p

Firm-specific, country-specific and region-specific competitive advantages: the case of emerging economy MNEs - Thailand

Increasing levels of regional economic integration have created a new source of international competitiveness for MNEs from an emerging economy, Thailand, in the context of ASEAN economic integration. Building on the theoretical framework of firm-specific advantages (FSAs) and country-specific advantages (CSAs) grounded in internalization theory, we introduce region-specific advantages (RSAs) and advance a novel regional dual-double-diamond model to analyse regional competitiveness. Using both primary and secondary data we find that most Thai firms derive their international competitiveness from CSAs rather than FSAs, and will benefit from ASEAN RSAs. Our study significantly advances the literature on international competitiveness of emerging-economy MNEs