Engineering T cell immunity by TCR gene transfer

T cell responses against tumor-antigens are frequently observed for some human malignancies, in particular melanoma. However, the spontaneous development of T cell responses of a sufficient strength to eradicate human malignancies is rare. The transfer of T cell receptor (TCR) __ genes into autologous T cells, a process called TCR gene transfer, allows one to engineer antigen-specific T cell responses of interest. Over the last decade, TCR gene transfer has progressed to the stage of clinical evaluation as a strategy to engineer T cell responses against tumor-antigens, in order to treat metastatic melanoma and other malignancies. The scope of the work in this thesis is to advance the development of TCR gene transfer as an engineering strategy for T cell immunity against cancer. This involves the assessment of the safety of TCR gene transfer, the evaluation of strategies to enhance the function of TCR-modified T cells in vivo, and the development of technologies to identify tumor-reactive TCR__ genesUBL - phd migration 201

Currency Unions and Trade: A PPML Re-Assessment with High-Dimensional Fixed Effects

Recent work on the effects of currency unions (CUs) on trade stresses the importance of using many countries and years in order to obtain reliable estimates. However, for large samples, computational issues associated with the three-way (exporter-time, importer-time, and country-pair) fixed effects currently recommended in the gravity literature have heretofore limited the choice of estimator, leaving an important methodological gap. To address this gap, we introduce an iterative Poisson Pseudo-Maximum Likelihood (PPML) estimation procedure that facilitates the inclusion of these fixed effects for large data sets and also allows for correlated errors across countries and time. When applied to a comprehensive sample with more than 200 countries trading over 65 years, these innovations flip the conclusions of an otherwise rigorously-specified linear model. Most importantly, our estimates for both the overall CU effect and the Euro effect specifically are economically small and statistically insignificant. We also document that linear and PPML estimates of the Euro effect increasingly diverge as the sample size grows

Identification of mixed-symmetry states in an odd-mass nearly-spherical nucleus

The low-spin structure of 93Nb has been studied using the (n,n' gamma) reaction at neutron energies ranging from 1.5 to 3.0 MeV and the 94Zr(p,2n gamma)93Nb reaction at bombarding energies from 11.5 to 19 MeV. States at 1779.7 and 1840.6 keV, respectively, are proposed as mixed-symmetry states associated with the coupling of a proton hole in the p_1/2 orbit to the 2+_1,ms state in 94Mo. These assignments are derived from the observed M1 and E2 transition strengths to the symmetric one-phonon states, energy systematics, spins and parities, and comparison with shell model calculations.Comment: 5 pages, 3 figure

The Intrinsic Origin of Spin Echoes in Dipolar Solids Generated by Strong Pi Pulses

In spectroscopy, it is conventional to treat pulses much stronger than the linewidth as delta-functions. In NMR, this assumption leads to the prediction that pi pulses do not refocus the dipolar coupling. However, NMR spin echo measurements in dipolar solids defy these conventional expectations when more than one pi pulse is used. Observed effects include a long tail in the CPMG echo train for short delays between pi pulses, an even-odd asymmetry in the echo amplitudes for long delays, an unusual fingerprint pattern for intermediate delays, and a strong sensitivity to pi-pulse phase. Experiments that set limits on possible extrinsic causes for the phenomena are reported. We find that the action of the system's internal Hamiltonian during any real pulse is sufficient to cause the effects. Exact numerical calculations, combined with average Hamiltonian theory, identify novel terms that are sensitive to parameters such as pulse phase, dipolar coupling, and system size. Visualization of the entire density matrix shows a unique flow of quantum coherence from non-observable to observable channels when applying repeated pi pulses.Comment: 24 pages, 27 figures. Revised from helpful referee comments. Added new Table IV, new paragraphs on pages 3 and 1

Allergen immunotherapy on the way to product-based evaluation - a WAO statement

Allergen immunotherapy (AIT) is widely used in clinical practice for patients with moderate to severe allergic rhinitis due to inhalant allergens and may be delivered via subcutaneous (SCIT) and sublingual routes (SLIT). However, the quality of evidence for individual AIT products is very heterogeneous, and extensions of overall conclusions ("class effects") on the efficacy and disease-modifying effects to all AIT products are unjustified. In contrast, each product needs to be evaluated individually, based on available study results, to justify efficacy and specific claims on sustained and disease modifying effects per allergen and targeted patient group (children vs. adults, allergic rhinitis vs. asthma). WAO intends to support the current development to evidence-based AIT, which ultimately will lead to a more efficacious treatment of allergic patients and the appropriate recognition of AIT

Tumour-infiltrating lymphocyte scores effectively stratify outcomes over and above p16 post chemo-radiotherapy in anal cancer

Background: The majority (90%) of anal cancers are human papillomavirus (HPV)-driven, identified using immunochemistry for p16. Compared with HPV? patients, those with HPV+ disease generally show improved survival, although relapse rates around 25% indicate a need for further stratification of this group.Methods: Using two cohorts of anal cancer, previously characterised for p16, we assessed the prognostic value of tumour-infiltrating lymphocytes (TILs).Results: Tumour-infiltrating lymphocyte scores were used to stratify p16+ cases, where tumours with absent/low levels of TIL had a relapse-free rate of 63%, as opposed to 92% with high levels of TIL (log rank P=0.006).Conclusions: Assessment of TIL adds to p16 status in the prognosis of anal cancer following chemo-radiotherapy and provides evidence of the clinical importance of the immune response

TeV Gamma-Ray Sources from a Survey of the Galactic Plane with Milagro

A survey of Galactic gamma-ray sources at a median energy of ~20 TeV has been performed using the Milagro Gamma Ray Observatory. Eight candidate sources of TeV emission are detected with pre-trials significance $>4.5\sigma$ in the region of Galactic longitude $l\in[30^\circ,220^\circ]$ and latitude $b\in[-10^\circ,10^\circ]$. Four of these sources, including the Crab nebula and the recently published MGRO J2019+37, are observed with significances $>4\sigma$ after accounting for the trials involved in searching the 3800 square degree region. All four of these sources are also coincident with EGRET sources. Two of the lower significance sources are coincident with EGRET sources and one of these sources is Geminga. The other two candidates are in the Cygnus region of the Galaxy. Several of the sources appear to be spatially extended. The fluxes of the sources at 20 TeV range from ~25% of the Crab flux to nearly as bright as the Crab.Comment: Submitted to Ap