Local therapy of cancer with free IL-2

This is a position paper about the therapeutic effects of locally applied free IL-2 in the treatment of cancer. Local therapy: IL-2 therapy of cancer was originally introduced as a systemic therapy. This therapy led to about 20% objective responses. Systemic therapy however was very toxic due to the vascular leakage syndrome. Nevertheless, this treatment was a break-through in cancer immunotherapy and stimulated some interesting questions: Supposing that the mechanism of IL-2 treatment is both proliferation and tumoricidal activity of the tumor infiltrating cells, then locally applied IL-2 should result in a much higher local IL-2 concentration than systemic IL-2 application. Consequently a greater beneficial effect could be expected after local IL-2 application (peritumoral = juxtatumoral, intratumoral, intra-arterial, intracavitary, or intratracheal = inhalation). Free IL-2: Many groups have tried to prepare a more effective IL-2 formulation than free IL-2. Examples are slow release systems, insertion of the IL-2 gene into a tumor cell causing prolonged IL-2 release. However, logistically free IL-2 is much easier to apply; hence we concentrated in this review and in most of our experiments on the use of free IL-2. Local therapy with free IL-2 may be effective against transplanted tumors in experimental animals, and against various spontaneous carcinomas, sarcomas, and melanoma in veterinary and human cancer patients. It may induce rejection of very large, metastasized tumor loads, for instance advanced clinical tumors. The effects of even a single IL-2 application may be impressive. Not each tumor or tumor type is sensitive to local IL-2 application. For instance transplanted EL4 lymphoma or TLX9 lymphoma were not sensitive in our hands. Also the extent of sensitivity differs: In Bovine Ocular Squamous Cell Carcinoma (BOSCC) often a complete regression is obtained, whereas with the Bovine Vulval Papilloma and Carcinoma Complex (BVPCC) mainly stable disease is attained. Analysis of the results of local IL-2 therapy in 288 cases of cancer in human patients shows that there were 27% Complete Regressions (CR), 23% Partial Regressions (PR), 18% Stable Disease (SD), and 32% Progressive Disease (PD). In all tumors analyzed, local IL-2 therapy was more effective than systemic IL-2 treatment. Intratumoral IL-2 applications are more effective than peritumoral application or application at a distant site. Tumor regression induced by intratumoral IL-2 application may be a fast process (requiring about a week) in the case of a highly vascular tumor since IL-2 induces vascular leakage/edema and consequently massive tumor necrosis. The latter then stimulates an immune response. In less vascular tumors or less vascular tumor sites, regression may require 9–20 months; this regression is mainly caused by a cytotoxic leukocyte reaction. Hence the disadvantageous vascular leakage syndrome complicating systemic treatment is however advantageous in local treatment, since local edema may initiate tumor necrosis. Thus the therapeutic effect of local IL-2 treatment is not primarily based on tumor immunity, but tumor immunity seems to be useful as a secondary component of the IL-2 induced local processes. If local IL-2 is combined with surgery, radiotherapy or local chemotherapy the therapeutic effect is usually greater than with either therapy alone. Hence local free IL-2 application can be recommended as an addition to standard treatment protocols. Local treatment with free IL-2 is straightforward and can readily be applied even during surgical interventions. Local IL-2 treatment is usually without serious side effects and besides minor complaints it is generally well supported. Only small quantities of IL-2 are required. Hence the therapy is relatively cheap. A single IL-2 application of 4.5 million U IL-2 costs about 70 Euros. Thus combined local treatment may offer an alternative in those circumstances when more expensive forms of treatment are not available, for instance in resource poor countries

Multi-Particle Collision Dynamics -- a Particle-Based Mesoscale Simulation Approach to the Hydrodynamics of Complex Fluids

In this review, we describe and analyze a mesoscale simulation method for fluid flow, which was introduced by Malevanets and Kapral in 1999, and is now called multi-particle collision dynamics (MPC) or stochastic rotation dynamics (SRD). The method consists of alternating streaming and collision steps in an ensemble of point particles. The multi-particle collisions are performed by grouping particles in collision cells, and mass, momentum, and energy are locally conserved. This simulation technique captures both full hydrodynamic interactions and thermal fluctuations. The first part of the review begins with a description of several widely used MPC algorithms and then discusses important features of the original SRD algorithm and frequently used variations. Two complementary approaches for deriving the hydrodynamic equations and evaluating the transport coefficients are reviewed. It is then shown how MPC algorithms can be generalized to model non-ideal fluids, and binary mixtures with a consolute point. The importance of angular-momentum conservation for systems like phase-separated liquids with different viscosities is discussed. The second part of the review describes a number of recent applications of MPC algorithms to study colloid and polymer dynamics, the behavior of vesicles and cells in hydrodynamic flows, and the dynamics of viscoelastic fluids

First-Step Mutations for Adaptation at Elevated Temperature Increase Capsid Stability in a Virus

The relationship between mutation, protein stability and protein function plays a central role in molecular evolution. Mutations tend to be destabilizing, including those that would confer novel functions such as host-switching or antibiotic resistance. Elevated temperature may play an important role in preadapting a protein for such novel functions by selecting for stabilizing mutations. In this study, we test the stability change conferred by single mutations that arise in a G4-like bacteriophage adapting to elevated temperature. The vast majority of these mutations map to interfaces between viral coat proteins, suggesting they affect protein-protein interactions. We assess their effects by estimating thermodynamic stability using molecular dynamic simulations and measuring kinetic stability using experimental decay assays. The results indicate that most, though not all, of the observed mutations are stabilizing

Differential Interactions of Sex Pheromone and Plant Odour in the Olfactory Pathway of a Male Moth

Most animals rely on olfaction to find sexual partners, food or a habitat. The olfactory system faces the challenge of extracting meaningful information from a noisy odorous environment. In most moth species, males respond to sex pheromone emitted by females in an environment with abundant plant volatiles. Plant odours could either facilitate the localization of females (females calling on host plants), mask the female pheromone or they could be neutral without any effect on the pheromone. Here we studied how mixtures of a behaviourally-attractive floral odour, heptanal, and the sex pheromone are encoded at different levels of the olfactory pathway in males of the noctuid moth Agrotis ipsilon. In addition, we asked how interactions between the two odorants change as a function of the males' mating status. We investigated mixture detection in both the pheromone-specific and in the general odorant pathway. We used a) recordings from individual sensilla to study responses of olfactory receptor neurons, b) in vivo calcium imaging with a bath-applied dye to characterize the global input response in the primary olfactory centre, the antennal lobe and c) intracellular recordings of antennal lobe output neurons, projection neurons, in virgin and newly-mated males. Our results show that heptanal reduces pheromone sensitivity at the peripheral and central olfactory level independently of the mating status. Contrarily, heptanal-responding olfactory receptor neurons are not influenced by pheromone in a mixture, although some post-mating modulation occurs at the input of the sexually isomorphic ordinary glomeruli, where general odours are processed within the antennal lobe. The results are discussed in the context of mate localization

Incidence and Characterisation of Methicillin-Resistant Staphylococcus aureus (MRSA) from Nasal Colonisation in Participants Attending a Cattle Veterinary Conference in the UK

We sought to determine the prevalence of nasal colonisation with methicillin-resistant Staphylococcus aureus among cattle veterinarians in the UK. There was particular interest in examining the frequency of colonisation with MRSA harbouring mecC, as strains with this mecA homologue were originally identified in bovine milk and may represent a zoonotic risk to those in contact with dairy livestock. Three hundred and seven delegates at the British Cattle Veterinarian Association (BCVA) Congress 2011 in Southport, UK were screening for nasal colonisation with MRSA. Isolates were characterised by whole genome sequencing and antimicrobial susceptibility testing. Eight out of three hundred and seven delegates (2.6%) were positive for nasal colonisation with MRSA. All strains were positive for mecA and none possessed mecC. The time since a delegate’s last visit to a farm was significantly shorter in the MRSA-positive group than in MRSA-negative counterparts. BCVA delegates have an increased risk of MRSA colonisation compared to the general population but their frequency of colonisation is lower than that reported from other types of veterinarian conference, and from that seen in human healthcare workers. The results indicate that recent visitation to a farm is a risk factor for MRSA colonisation and that mecC-MRSA are rare among BCVA delegates (<1% based on sample size). Contact with livestock, including dairy cattle, may still be a risk factor for human colonisation with mecC-MRSA but occurs at a rate below the lower limit of detection available in this study

Microsoft Word - Change management for using a Project Website in team communication.doc

Abstract A Project Website (PWS) has been advocated as an important tool for design teams of construction projects, because the tool is supposed to greatly enhance team communication. This, finally, should result in improved team performance in terms of increase of efficiency and effectiveness. PWS vendors claim these results on expected better communication of teams who share and update their design information using a PWS together. The growing use of IT tools by design team members who electronically generate, collect and update design information increases the need for such an IT tool that allow fast and easy access and overview of the status of the latest changed and generated design information of the whole team. Also due to the growing complexity of building projects, the number of design partners and the number of electronic means for communication, the need for better collective communication is more important then it has ever been before. However, due to the expanding complexity and changes in design information, the redundancy of design information is growing too and the risk to failures. Team members need new skills for collective use of a PWS. The use of the tool might need radical changes in information flows to become effective. It might be experienced also that use of a PWS formalizes team communication too much, or might be threatening because of &apos;big brother effects&apos;. Within this view the change to collective use of a PWS by a design team is not an automatic change to an effective communication environment as vendors like us to believe and many pitfalls can be encountered. In this paper the most important aspects of change to collective use of a project website for team communication will be discussed, based on the results of a Dutch PhD research project. Keywords: Change promoters, project website, rivalry of tools, second-order change, technological frames. Communication aspects To communicate collectively it is important that all members of a group are involved actively in the group&apos;s communication. According to Ruler (1996) three concepts of communication can be identified: inter-active, effective and active. These communication concepts are mainly based on differences in communication processes regarding feedback (expected by the sender) of a receiver or group receivers. Feedback is a type of message that the receiver transmits to the sender in response to having received a message (Wiener, 1948). Shannon and Weaver&apos;s communication theory (1949) is the basis for this approach. Ruler&apos;s interactive concept is defined as a back and forth process between sender and receiver(s) with changing roles. In this process, feedback is essential for communication (for example: in a dialogue, telephone conversation or group meetings). Proceedings of the CIB W096 Architectural Management meeting, publication 307 Designing Value: New directions in Architectural Management Technical University of Denmark, Lyngby November 2005 The effective concept is defined as a one-way process with an active sender and passive receiver(s) with a predictable re-action. In this process, feedback is possible but not expected (for example: postal mail, facsimile). The active concept is defined as an active one-way process of a sender, for broadcasting or publishing of information to receivers. In this process, the same channel of communication usually cannot give feedback (for example: the Queen&apos;s Christmas message on television). A sender might use a specific communication means to send a message to receiver(s) depending on the sender&apos;s need for feedback, the available means and his preference for use of a specific means synchronous or asynchronous. Synchronous communication can be defined as the communication between senders and receivers at the same time, whether or not it is in the same place (Robbins, 2001) while asynchronous communication between senders and receivers takes place at different times and mostly at different places

Ageing processes of alkyl bonded phases in HPLC; a chromatographic and spectroscopic approach

Summary Laboratory use of HPLC columns packed with C8 and C18 bonded phases leads to changes in selectivities and retention volumes. FTI R, 1 H N M R of hydrolysed bonded phases and solid state 13C-and 29Si NMR were applied to characterize the materials. The results of the various techniques are in fair agreement except solid state NMR. Loss of silane and hydrolysis of surface siloxane groups have been observed for the C8 bondes phase, while for the C18 material the latter process seems to dominate. The solid state NMR results have been tentatively explained in terms of changing chain arrangements and mobilities