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

Measurement and Interpretation of Fermion-Pair Production at LEP energies above the Z Resonance

This paper presents DELPHI measurements and interpretations of cross-sections, forward-backward asymmetries, and angular distributions, for the e+e- -> ffbar process for centre-of-mass energies above the Z resonance, from sqrt(s) ~ 130 - 207 GeV at the LEP collider. The measurements are consistent with the predictions of the Standard Model and are used to study a variety of models including the S-Matrix ansatz for e+e- -> ffbar scattering and several models which include physics beyond the Standard Model: the exchange of Z' bosons, contact interactions between fermions, the exchange of gravitons in large extra dimensions and the exchange of sneutrino in R-parity violating supersymmetry.Comment: 79 pages, 16 figures, Accepted by Eur. Phys. J.

A Determination of the Centre-of-Mass Energy at LEP2 using Radiative 2-fermion Events

Using e+e- -> mu+mu-(gamma) and e+e- -> qqbar(gamma) events radiative to the Z pole, DELPHI has determined the centre-of-mass energy, sqrt{s}, using energy and momentum constraint methods. The results are expressed as deviations from the nominal LEP centre-of-mass energy, measured using other techniques. The results are found to be compatible with the LEP Energy Working Group estimates for a combination of the 1997 to 2000 data sets.Comment: 20 pages, 6 figures, Accepted by Eur. Phys. J.

A Measurement of the Tau Hadronic Branching Ratios

The exclusive and semi-exclusive branching ratios of the tau lepton hadronic decay modes (h- v_t, h- pi0 v_t, h- pi0 pi0 v_t, h- \geq 2pi0 v_t, h- \geq 3pi0 v_t, 2h- h+ v_t, 2h- h+ pi0 v_t, 2h- h+ \geq 2pi0 v_t, 3h- 2h+ v_t and 3h- 2h+ \geq 1pi0 v_t) were measured with data from the DELPHI detector at LEP.Comment: 53 pages, 18 figures, Accepted by Eur. Phys. J.

Molecular therapy for the treatment of hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Conventional cytotoxic chemotherapy has failed to show a substantial benefit for patients with HCC. Recently, a number of new drugs targeting molecular mechanisms involved in liver cell transformation have entered into clinical trials and led to encouraging results. In this review we summarise this data and point to a number of new compounds, which are currently being tested and can potentially broaden our therapeutic arsenal even further

Flow Residence Time and Regions of Intraluminal Thrombus Deposition in Intracranial Aneurysms

Thrombus formation in intracranial aneurysms, while sometimes stabilizing lesion growth, can present additional risk of thrombo-embolism. The role of hemodynamics in the progression of aneurysmal disease can be elucidated by patient-specific computational modeling. In our previous work, patient-specific computational fluid dynamics (CFD) models were constructed from MRI data for three patients who had fusiform basilar aneurysms that were thrombus-free and then proceeded to develop intraluminal thrombus. In this study, we investigated the effect of increased flow residence time (RT) by modeling passive scalar advection in the same aneurysmal geometries. Non-Newtonian pulsatile flow simulations were carried out in base-line geometries and a new postprocessing technique, referred to as “virtual ink” and based on the passive scalar distribution maps, was used to visualize the flow and estimate the flow RT. The virtual ink technique clearly depicted regions of flow separation. The flow RT at different locations adjacent to aneurysmal walls was calculated as the time the virtual ink scalar remained above a threshold value. The RT values obtained in different areas were then correlated with the location of intra-aneurysmal thrombus observed at a follow-up MR study. For each patient, the wall shear stress (WSS) distribution was also obtained from CFD simulations and correlated with thrombus location. The correlation analysis determined a significant relationship between regions where CFD predicted either an increased RT or low WSS and the regions where thrombus deposition was observed to occur in vivo. A model including both low WSS and increased RT predicted thrombus-prone regions significantly better than the models with RT or WSS alone

Search for supersymmetric particles in scenarios with a gravitino LSP and stau NLSP

Sleptons, neutralinos and charginos were searched for in the context of scenarios where the lightest supersymmetric particle is the gravitino. It was assumed that the stau is the next-to-lightest supersymmetric particle. Data collected with the DELPHI detector at a centre-of-mass energy near 189 GeV were analysed combining the methods developed in previous searches at lower energies. No evidence for the production of these supersymmetric particles was found. Hence, limits were derived at 95% confidence level.Comment: 31 pages, 14 figure

Congenital cardiovascular defects in children with intestinal malrotation

Intestinal malrotation (IM) and cardiovascular defects (CCVD) are both common congenital defects. We investigated the prevalence and types of CCVD in a 25-year IM population, and its association with post-IM-operative morbidity and mortality. Data on the type of CCVD, other congenital defects, syndromes, associations, post-IM-operative morbidity and mortality were retrospectively reviewed from the records of IM patients born between 1980 and 2005. Data were analyzed on (significant) differences between CCVD subgroups, and risk factors for both morbidity and mortality were calculated. Seventy-seven of 284 IM patients (27.1%) were diagnosed with a major or minor CCVD (37 and 40 patients, respectively). Syndromes and associations were more frequently diagnosed in patients with major than with a minor CCVD (67.6 vs. 40%, respectively). Post-IM-operative complications, although frequently observed (61%), did not differ between patients with major and minor CCVD. Physical CCVD signs before IM surgery increased post-IM-operative morbidity significantly (OR 4.0, 95% CI 1.4–11.0). Fifteen patients died (19.5%), seven due to cardiovascular cause. Mortality risk was increased by intestinal ischemia and post-IM-operative complications and by major CCVD after correction for age at weight at the time of IM operation. Congenital cardiovascular defects in children with intestinal malrotation are common, with high morbidity and mortality rates after IM operation. Elective IM surgery in young patients with CCVD should be performed in a centre with adequate paediatric cardiac care. Benefits of laparoscopic intervention need further study