Tube leukocyte adherence inhibition assay : the assessment of tumor immunity in cancer patients and in rats

For the past two decades, intensive search has been made for the existence of tumor-specific antigens of human cancer. The recent succesful development of monoclonal antibodies against TAA on human cell membrane has not yet resulted in the identification of any tumor-specific determinant(s) on cancer cells. An alternative approach for the identification of tumor-specific antigens has been to study the immune response of the host to cancer. Cell-mediated cytotoxicity was initially investigated using microcytotoxicity assays (47). Specific cytotoxicity against a variety of cultured cells from human tumors was observed with lymphoid cells from tumor-bearers or individuals whose tumor had been resected. The whole concept of specific cell-mediated cytotoxicity in human cancer was doubted when natural cytotoxicity was discovered (18, 19). However, investigators working with the tumor extract-induced leukocyte adherence inhibition (LA I) phenomenon have successfully provided much of the existing evidence for specific anti-tumor immunity in animals and human cancers (81,82). The ultimate objective of the present study was to use the tube LA! assay to monitor the purification of human TAA from crude tumor extracts. On the assumption that T AA are foreign or modified human major histocompatibility complex antigens (HLA antigens) or are closely associated with these antigens, the biochemical techniques used to study the nature of HLA antigens could be applied to obtain an insight into the biochemical nature of TAA and their relation (if any) to HLA antigens. The tube LAI assay was chosen since it was claimed to be simple, rapid and reproducible. In the first instance it was necessary to develop a reliable tube LAI technique of high sensitivity. In the initial studies it was investigated whether this could be achieved by using partially purified tumor extracts. Since the amount of patient tumor material severely restricted the amount of crude extracts that could be chroma to graphed and purified further using other physico-chemical techniques, LAI studies in rats were also pursued

MITF links differentiation with cell cycle arrest in melanocytes by transcriptional activation of INK4A

Cell cycle exit is required for proper differentiation in most cells and is critical for normal development, tissue homeostasis, and tumor suppression. However, the mechanisms that link cell cycle exit with differentiation remain poorly understood. Here, we show that the master melanocyte differentiation factor, microphthalmia transcription factor (MITF), regulates cell cycle exit by activating the cell cycle inhibitor INK4A, a tumor suppressor that frequently is mutated in melanomas. MITF binds the INK4A promoter, activates p16Ink4a mRNA and protein expression, and induces retinoblastoma protein hypophosphorylation, thereby triggering cell cycle arrest. This activation of INK4A was required for efficient melanocyte differentiation. Interestingly, MITF was also required for maintaining INK4A expression in mature melanocytes, creating a selective pressure to escape growth inhibition by inactivating INK4A. These findings demonstrate that INK4A can be regulated by a differentiation factor, establish a mechanistic link between melanocyte differentiation and cell cycle exit, and potentially explain the tissue-specific tendency for INK4A mutations to occur in melanoma

Wave reflection, assessed by use of the ARCSolver Algorithm for pulse wave separation, is reduced under acute µg conditions in parabolic flight

Weightlessness during long-term space flight over 6-12 months leads to complex individual cardiovascular adaptation. The initial central blood volume expansion followed by a loss of plasma volume is accompanied by changes in vascular mechanoreceptor loads and responsive-ness, altered autonomic reflex control of heart rate and blood pressure, and hormonal changes in the long run. Hence, function and structure of the heart and blood vessels may change. Hemodynamic data obtained during short- and long-term space flight may indicate that the adaptation process resembles ageing of the cardiovascular system characterized by decreased diastolic blood pressure, increased central sympathetic nerve traffic and increased arterial pulse wave velocity. Experiments during parabolic flights in supine position suggest, that stroke volume does not change during transitions between µ-g and 1-g. We tested a novel method of pulse wave separation based on simple oscillometric brachial cuff waveform reading to investigate pulse wave reflection during acute weightlessness in healthy subjects. We hypothesized that the wave reflection magnitude (RM) remains unaltered during parabolic flights in supine position

Implementation research for the prevention of antimicrobial resistance and healthcare-associated infections; 2017 Geneva infection prevention and control (IPC)-think tank (part 1)

Background Around 5–15% of all hospital patients worldwide suffer from healthcare-associated infections (HAIs), and years of excessive antimicrobial use in human and animal medicine have created emerging antimicrobial resistance (AMR). A considerable amount of evidence-based measures have been published to address these challenges, but the largest challenge seems to be their implementation. Methods In June 2017, a total of 42 experts convened at the Geneva IPC-Think Tank to discuss four domains in implementation science: 1) teaching implementation skills; 2) fostering implementation of IPC and antimicrobial stewardship (AMS) by policy making; 3) national/international actions to foster implementation skills; and 4) translational research bridging social sciences and clinical research in infection prevention and control (IPC) and AMR. Results Although neglected in the past, implementation skills have become a priority in IPC and AMS. They should now be part of any curriculum in health care, and IPC career paths should be created. Guidelines and policies should be aligned with each other and evidence-based, each document providing a section on implementing elements of IPC and AMS in patient care. International organisations should be advocates for IPC and AMS, framing them as patient safety issues and emphasizing the importance of implementation skills. Healthcare authorities at the national level should adopt a similar approach and provide legal frameworks, guidelines, and resources to allow better implementation of patient safety measures in IPC and AMS. Rather than repeating effectiveness studies in every setting, we should invest in methods to improve the implementation of evidence-based measures in different healthcare contexts. For this, we need to encourage and financially support collaborations between social sciences and clinical IPC research. Conclusions Experts of the 2017 Geneva Think Tank on IPC and AMS, CDC, and WHO agreed that sustained efforts on implementation of IPC and AMS strategies are required at international, country, and hospital management levels, to provide an adequate multimodal framework that addresses (not exclusively) leadership, resources, education and training for implementing IPC and AMS. Future strategies can build on this agreement to make strategies on IPC and AMS more effective