Prolonged intralymphatic delivery of dendritic cells through implantable lymphatic ports in patients with advanced cancer

Background: The currently-used modes of administration of immunotherapeutic agents result in their limited delivery to the lymph nodes and/or require repetitive ultrasound-guided nodal injections or microsurgical lymphatic injections, limiting their feasibility. Here, we report on the feasibility and safety of a new method of long-term repetitive intralymphatic (IL) infusion of immune cells, using implantable delivery ports. Methods: Nine patients with stage IV recurrent colorectal cancer underwent complete resection and received autologous dendritic cells (DCs) loaded with killed autologous tumor cells, KLH and PADRE, for up to four monthly cycles. Leg lymphatic vessels were cannulated, connected to 6.6Fr low-profile implantable subcutaneous delivery ports, and used to infuse 12 doses of DC over each 72 h-long cycle (every 6 h), followed by heparin flushes of the cannula-port system (one 72 h-long cycle per month). The patients who opted for alternative route of vaccine administration (2 patients) or whose ports became non-functional between cycles, continued treatment via intranodal (one injection/cycle) or intradermal (four injections/cycle) routes. Results: A total of nine lymphatic cannulations and implantations of subcutaneous delivery ports were attempted in seven patients, with a success rate of eight out of nine (89 %). The average patency of the IL delivery system was 7.5 (±3.2) weeks. All six patients with IL ports successfully completed at least one complete 72 h-long DC infusion cycle (12 injections). Five patients (56 %) completed two full IL cycles (24 IL injections). No patients received more than two IL cycles without replacement of the IL port, due to catheter occlusion and/or local side effects: cellulitis and hematoma. Intranodal and intradermal backup options were used in, respectively, one and two patients. Overall cohort survival was >28 (±25) months. One patient with aggressive recurrent carcinomatosis, who received DC vaccines by intranodal route is alive at > 90 months, without evidence of disease. Conclusions: We conclude that an intermediate-duration IL delivery of multiple doses of immunotherapeutic factors using implantable delivery ports is feasible, highly-tolerable and can be reproducibly performed in cancer patients to administer immune cells, or potentially, other immune factors. However, long-term IL port placement (>7.5 weeks), is not a currently-feasible option. Trial registration:NCT00558051 , registered Nov. 13, 2007

Likelihood inference for exponential-trawl processes

Integer-valued trawl processes are a class of serially correlated, stationary and infinitely divisible processes that Ole E. Barndorff-Nielsen has been working on in recent years. In this Chapter, we provide the first analysis of likelihood inference for trawl processes by focusing on the so-called exponential-trawl process, which is also a continuous time hidden Markov process with countable state space. The core ideas include prediction decomposition, filtering and smoothing, complete-data analysis and EM algorithm. These can be easily scaled up to adapt to more general trawl processes but with increasing computation efforts.Comment: 29 pages, 6 figures, forthcoming in: "A Fascinating Journey through Probability, Statistics and Applications: In Honour of Ole E. Barndorff-Nielsen's 80th Birthday", Springer, New Yor

Review of biorthogonal coupled cluster representations for electronic excitation

Single reference coupled-cluster (CC) methods for electronic excitation are based on a biorthogonal representation (bCC) of the (shifted) Hamiltonian in terms of excited CC states, also referred to as correlated excited (CE) states, and an associated set of states biorthogonal to the CE states, the latter being essentially configuration interaction (CI) configurations. The bCC representation generates a non-hermitian secular matrix, the eigenvalues representing excitation energies, while the corresponding spectral intensities are to be derived from both the left and right eigenvectors. Using the perspective of the bCC representation, a systematic and comprehensive analysis of the excited-state CC methods is given, extending and generalizing previous such studies. Here, the essential topics are the truncation error characteristics and the separability properties, the latter being crucial for designing size-consistent approximation schemes. Based on the general order relations for the bCC secular matrix and the (left and right) eigenvector matrices, formulas for the perturbation-theoretical (PT) order of the truncation errors (TEO) are derived for energies, transition moments, and property matrix elements of arbitrary excitation classes and truncation levels. In the analysis of the separability properties of the transition moments, the decisive role of the so-called dual ground state is revealed. Due to the use of CE states the bCC approach can be compared to so-called intermediate state representation (ISR) methods based exclusively on suitably orthonormalized CE states. As the present analysis shows, the bCC approach has decisive advantages over the conventional CI treatment, but also distinctly weaker TEO and separability properties in comparison with a full (and hermitian) ISR method

Dall’Europa a Milano, da Milano all’Europa : a 250 anni da "Dei delitti e delle pene"

In occasione dei 250 anni dalla pubblicazione del trattato "Dei delitti e delle pene" , l'articolo ricostruisce alcuni momenti della vita dell'Accademia dei Pugni, anche in rapporto alle fasi di elaborazione del libro di Cesare Beccaria. Si propongono inoltre considerazioni sulla circolazione dell'opera e in particolare sulla diffusione che in Europa hanno avuto il trattato e, di conseguenza, le soluzioni espressive di quella prosa argomentativa

The metabolic significance of octulose phosphates in the photosynthetic carbon reduction cycle in spinach

(14)C-Labelled octulose phosphates were formed during photosynthetic (14)CO(2) fixation and were measured in spinach leaves and chloroplasts. Because mono- and bisphosphates of d-glycero-d-ido-octulose are the active 8-carbon ketosugar intermediates of the L-type pentose pathway, it was proposed that they may also be reactants in a modified Calvin–Benson–Bassham pathway reaction scheme. This investigation therefore initially focussed only on the ido-epimer of the octulose phosphates even though (14)C-labelled d-glycero-d-altro-octulose mono- and bisphosphates were also identified in chloroplasts and leaves. (14)CO(2) predominantly labelled positions 5 and 6 of d-glycero-d-ido-octulose 1,8-P(2) consistent with labelling predictions of the modified scheme. The kinetics of (14)CO(2) incorporation into ido-octulose was similar to its incorporation into some traditional intermediates of the path of carbon, while subsequent exposure to (12)CO(2) rapidly displaced the (14)C isotope label from octulose with the same kinetics of label loss as some of the confirmed Calvin pathway intermediates. This is consistent with octulose phosphates having the role of cyclic intermediates rather than synthesized storage products. (Storage products don’t rapidly exchange isotopically labelled carbons with unlabelled CO(2).) A spinach chloroplast extract, designated stromal enzyme preparation (SEP), catalysed and was used to measure rates of CO(2) assimilation with Calvin cycle intermediates and octulose and arabinose phosphates. Only pentose (but not arabinose) phosphates and sedoheptulose 7-phosphate supported CO(2) fixation at rates in excess of 120 μmol h(−1) mg(−1) Chl. Rates for octulose, sedoheptulose and fructose bisphosphates, octulose, hexose and triose monophosphates were all notably less than the above rate and arabinose 5-phosphate was inactive. Altro-octulose phosphates were more active than phosphate esters of the ido-epimer. The modified scheme proposed a specific phosphotransferase and SEP unequivocally catalysed reversible phosphate transfer between sedoheptulose bisphosphate and d-glycero-d-ido-octulose 8-phosphate. It was also initially hypothesized that arabinose 5-phosphate, an L-Type pentose pathway reactant, may have a role in a modified Calvin pathway. Arabinose 5-phosphate is present in spinach chloroplasts and leaves. Radiochromatography showed that (14)C-arabinose 5-phosphate with SEP, but only in the presence of an excess of unlabelled ribose 5-phosphate, lightly labelled ribulose 5-phosphate and more heavily labelled hexose and sedoheptulose mono- and bisphosphates. However, failure to demonstrate any CO(2) fixation by arabinose 5-phosphate as sole substrate suggested that the above labelling may have no metabolic significance. Despite this arabinose and ribose 5-phosphates are shown to exhibit active roles as enzyme co-factors in transaldolase and aldolase exchange reactions that catalyse the epimeric interconversions of the phosphate esters of ido- and altro-octulose. Arabinose 5-phosphate is presented as playing this role in a New Reaction Scheme for the path of carbon, where it is concluded that slow reacting ido-octulose 1,8 bisphosphate has no role. The more reactive altro-octulose phosphates, which are independent of the need for phosphotransferase processing, are presented as intermediates in the new scheme. Moreover, using the estimates of phosphotransferase activity with altro-octulose monophosphate as substrate allowed calculation of the contributions of the new scheme, that ranged from 11% based on the intact chloroplast carboxylation rate to 80% using the carboxylation rate required for the support of octulose phosphate synthesis and its role in the phosphotransferase reaction

Interpersonal and affective dimensions of psychopathic traits in adolescents : development and validation of a self-report instrument

We report the development and psychometric evaluations of a self-report instrument designed to screen for psychopathic traits among mainstream community adolescents. Tests of item functioning were initially conducted with 26 adolescents. In a second study the new instrument was administered to 150 high school adolescents, 73 of who had school records of suspension for antisocial behavior. Exploratory factor analysis yielded a 4-factor structure (Impulsivity α = .73, Self-Centredness α = .70, Callous-Unemotional α = .69, and Manipulativeness α = .83). In a third study involving 328 high school adolescents, 130 with records of suspension for antisocial behaviour, competing measurement models were evaluated using confirmatory factor analysis. The superiority of a first-order model represented by four correlated factors that was invariant across gender and age was confirmed. The findings provide researchers and clinicians with a psychometrically strong, self-report instrument and a greater understanding of psychopathic traits in mainstream adolescents

Complete experimental toolbox for alignment-free quantum communication

Quantum communication employs the counter-intuitive features of quantum physics to perform tasks that are im- possible in the classical world. It is crucial for testing the foundations of quantum theory and promises to rev- olutionize our information and communication technolo- gies. However, for two or more parties to execute even the simplest quantum transmission, they must establish, and maintain, a shared reference frame. This introduces a considerable overhead in communication resources, par- ticularly if the parties are in motion or rotating relative to each other. We experimentally demonstrate how to circumvent this problem with the efficient transmission of quantum information encoded in rotationally invariant states of single photons. By developing a complete toolbox for the efficient encoding and decoding of quantum infor- mation in such photonic qubits, we demonstrate the fea- sibility of alignment-free quantum key-distribution, and perform a proof-of-principle alignment-free entanglement distribution and violation of a Bell inequality. Our scheme should find applications in fundamental tests of quantum mechanics and satellite-based quantum communication.Comment: Main manuscript: 7 pages, 3 figures; Supplementary Information: 7 pages, 3 figure

A re-investigation of the path of carbon in photosynthesis utilizing GC/MS methodology. Unequivocal verification of the participation of octulose phosphates in the pathway

A GC/EIMS/SIM methodology has been developed to re-examine the path of carbon in photosynthesis. Exposing isolated spinach chloroplasts to (13)CO(2 )on a solid support for a defined period followed by quenching and work-up provided a mixture of labelled sugar phosphates. After enzymatic dephosphorylation and derivatization, the Mox-TMS sugars were analysed using the above method. The purpose of the study was to try to calculate the atom% enrichment of (13)C in as many of the individual carbons in each of the derivatized sugars as was practical using diagnostic fragment ions. In the event, only one 45 s experiment provided sufficient data to enable a range of enrichment values to be calculated. This confirmed that D-glycero-D-altro-octulose phosphate was present in the chloroplasts and was heavily labelled in the C4, C5 and C6 positions, in keeping with the hypothesis that it had an inclusive role and a labelling pattern consistent with a new modified pathway of carbon in photosynthesis

Random-phase approximation and its applications in computational chemistry and materials science

The random-phase approximation (RPA) as an approach for computing the electronic correlation energy is reviewed. After a brief account of its basic concept and historical development, the paper is devoted to the theoretical formulations of RPA, and its applications to realistic systems. With several illustrating applications, we discuss the implications of RPA for computational chemistry and materials science. The computational cost of RPA is also addressed which is critical for its widespread use in future applications. In addition, current correction schemes going beyond RPA and directions of further development will be discussed.Comment: 25 pages, 11 figures, published online in J. Mater. Sci. (2012