IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines.

The use of lipid-formulated RNA vaccines for cancer or COVID-19 is associated with dose-limiting systemic inflammatory responses in humans that were not predicted from preclinical studies. Here, we show that the 'interleukin 1 (IL-1)-interleukin 1 receptor antagonist (IL-1ra)' axis regulates vaccine-mediated systemic inflammation in a host-specific manner. In human immune cells, RNA vaccines induce production of IL-1 cytokines, predominantly IL-1β, which is dependent on both the RNA and lipid formulation.

Dexamethasone premedication suppresses vaccine-induced immune responses against cancer.

Glucocorticosteroids (GCS) have an established role in oncology and are administered to cancer patients in routine clinical care and in drug development trials as co-medication. Given their strong immune-suppressive activity, GCS may interfere with immune-oncology drugs. We are developing a therapeutic cancer vaccine, which is based on a liposomal formulation of tumor-antigen encoding RNA (RNA-LPX) and induces a strong T-cell response both in mice as well as in humans.

Discovery of Potent and Selective Antibody-Drug Conjugates with Eg5 Inhibitors through Linker and Payload Optimization.

Targeted antimitotic agents are a promising class of anticancer therapies. Herein, we describe the development of a potent and selective antimitotic Eg5 inhibitor based antibody-drug conjugate (ADC). Preliminary studies were performed using proprietary Eg5 inhibitors which were conjugated onto a HER2-targeting antibody using maleimido caproyl valine-citrulline para-amino benzocarbamate, or MC-VC-PABC cleavable linker.

CSF1R inhibition delays cervical and mammary tumor growth in murine models by attenuating the turnover of tumor-associated macrophages and enhancing infiltration by CD8 T cells.

Increased numbers of tumor-infiltrating macrophages correlate with poor disease outcome in patients affected by several types of cancer, including breast and prostate carcinomas. The colony stimulating factor 1 receptor (CSF1R) signaling pathway drives the recruitment of tumor-associated macrophages (TAMs) to the neoplastic microenvironment and promotes the differentiation of TAMs toward a pro-tumorigenic phenotype. Twelve clinical trials are currently evaluating agents that target the CSF1/CSF1R signaling pathway as a treatment against multiple malignancies, including breast carcinoma, leukemia, and glioblastoma.

CSF-1R inhibition alters macrophage polarization and blocks glioma progression.

Glioblastoma multiforme (GBM) comprises several molecular subtypes, including proneural GBM. Most therapeutic approaches targeting glioma cells have failed. An alternative strategy is to target cells in the glioma microenvironment, such as tumor-associated macrophages and microglia (TAMs).

Analysis of hybrid mode-locking of two-section quantum dot lasers operating at 1.5 microm.

For the first time a detailed study of hybrid mode-locking in two-section InAs/InP quantum dot Fabry-Pérot-type lasers is presented. The output pulses have a typical upchirp of approximately 8 ps/nm, leading to very elongated pulses. The mechanism leading to this typical pulse shape and the phase noise is investigated by detailed radio-frequency and optical spectral studies as well as time-domain studies.

Lasing in metal-insulator-metal sub-wavelength plasmonic waveguides.

We demonstrate lasing in Metal-Insulator-Metal (MIM) waveguides filled with electrically pumped semiconductor cores, with core width dimensions below the diffraction limit. Furthermore these waveguides propagate a transverse magnetic (TM0) or so called gap plasmon mode [1-4]. Hence we show that losses in sub-wavelength MIM waveguides can be overcome to create small plasmon mode lasers at wavelengths near 1500 nm.

Observation of Q-switching and mode-locking in two-section InAs/InP (100) quantum dot lasers around 1.55 mum.

First observation of passive mode-locking in two-section quantum-dot lasers operating at wavelengths around 1.55 mum is reported. Pulse generation at 4.

Gain measurements of Fabry-Perot InP/InGaAsP lasers using an ultrahigh-resolution spectrometer.

Measurements of the optical gain in a semiconductor laser using a 20 MHz resolution optical spectrum analyzer are presented for what is believed to be the first time. The high resolution allows for accurate gain measurements close to the lasing threshold. This is demonstrated by gain measurements on a bulk InGaAsP 1.

Characterization of a 15 GHz integrated bulk InGaAsP passively modelocked ring laser at 1.53microm.

We report on an extensive characterization of a 15GHz integrated bulk InGaAsP passively modelocked ring laser at 1530 nm. The laser is modelocked for a wide range of amplifier currents and reverse bias voltages on the saturable absorber. We have measured a timing jitter of 7.

Novel robust hepatitis C virus mouse efficacy model.

The lack of a robust small-animal model for hepatitis C virus (HCV) has hindered the discovery and development of novel drug treatments for HCV infections. We developed a reproducible and easily accessible xenograft mouse efficacy model in which HCV RNA replication is accurately monitored in vivo by real-time, noninvasive whole-body imaging of gamma-irradiated SCID mice implanted with a mouse-adapted luciferase replicon-containing Huh-7 cell line (T7-11). The model was validated by demonstrating that both a small-molecule NS3/4A protease inhibitor (BILN 2061) and human alpha interferon (IFN-alpha) decreased HCV RNA replication and that treatment withdrawal resulted in a rebound in replication, which paralleled clinical outcomes in humans.

CHIR-258 is efficacious in a newly developed fibroblast growth factor receptor 3-expressing orthotopic multiple myeloma model in mice.

Purpose: The ectopically expressed and deregulated fibroblast growth factor receptor 3 (FGFR3) results from a t(4;14) chromosomal translocation that occurs in approximately 15% of multiple myeloma (MM) patients and confers a particularly poor prognosis. This study assesses the antimyeloma activity of CHIR-258, a small-molecule inhibitor of multiple receptor tyrosine kinases that is currently in phase I trials, in a newly developed FGFR3-driven preclinical MM animal model.

Experimental Design: We developed an orthotopic MM model in mice using a luciferase-expressing human KMS-11-luc line that expresses mutant FGFR3 (Y373C).

Coupled Mach-Zehnder interferometer memory element.

Two active Mach-Zehnder interferometers are integrated in a monolithic InP/InGaAsP photonic integrated circuit. Together they form a crucial component for optical signal processing: an optical memory element or set-reset flip-flop. The switching time for this initial device is approximately 200 ps.

CHIR-258: a potent inhibitor of FLT3 kinase in experimental tumor xenograft models of human acute myelogenous leukemia.

Purpose: Fms-like tyrosine kinase 3 (FLT3) encodes a receptor tyrosine kinase (RTK) for which activating mutations have been identified in a proportion of acute myelogenous leukemia (AML) patients and associated with poor clinical prognosis. Given the relevance of FLT3 mutations in AML, we investigated the activity of CHIR-258, an orally active, multitargeted small molecule, with potent activity against FLT3 kinase and class III, IV, and V RTKs involved in endothelial and tumor cell proliferation in AML models.

Experimental Design: CHIR-258 was tested on two human leukemic cell lines in vitro and in vivo with differing FLT3 mutational status [MV4;11 cells express FLT3 internal tandem duplications (ITD) versus RS4;11 cells with wild-type (WT) FLT3].

Bioluminescent human breast cancer cell lines that permit rapid and sensitive in vivo detection of mammary tumors and multiple metastases in immune deficient mice.

Introduction: Our goal was to generate xenograft mouse models of human breast cancer based on luciferase-expressing MDA-MB-231 tumor cells that would provide rapid mammary tumor growth; produce metastasis to clinically relevant tissues such as lymph nodes, lung, and bone; and permit sensitive in vivo detection of both primary and secondary tumor sites by bioluminescent imaging.

Method: Two clonal cell sublines of human MDA-MB-231 cells that stably expressed firefly luciferase were isolated following transfection of the parental cells with luciferase cDNA. Each subline was passaged once or twice in vivo to enhance primary tumor growth and to increase metastasis.

A fast low-power optical memory based on coupled micro-ring lasers.

The increasing speed of fibre-optic-based telecommunications has focused attention on high-speed optical processing of digital information. Complex optical processing requires a high-density, high-speed, low-power optical memory that can be integrated with planar semiconductor technology for buffering of decisions and telecommunication data. Recently, ring lasers with extremely small size and low operating power have been made, and we demonstrate here a memory element constructed by interconnecting these microscopic lasers.

Imaging of bioluminescent LNCaP-luc-M6 tumors: a new animal model for the study of metastatic human prostate cancer.

Background: Animal experiments examining hormone-sensitive metastatic prostate cancer using the human LNCaP cell line have been limited to endpoint analyses. To permit longitudinal studies, we generated a luciferase-expressing cell line and used bioluminescent imaging (BLI) to non-invasively monitor the in vivo growth of primary LNCaP tumors and metastasis.

Methods: LNCaP.

Bioluminescent imaging (BLI) to improve and refine traditional murine models of tumor growth and metastasis.

Bioluminescent imaging (BLI) permits sensitive in vivo detection and quantification of cells specifically engineered to emit visible light. Three stable human tumor cell lines engineered to express luciferase were assessed for their tumorigenicity in subcutaneous, intravenous and spontaneous metastasis models. Bioluminescent PC-3M-luc-C6 human prostate cancer cells were implanted subcutaneously into SCID-beige mice and were monitored for tumor growth and response to 5-FU and mitomycin C treatments.

Human endothelial cell life extension by telomerase expression.

Normal human endothelial cells, like other somatic cells in culture, divide a limited number of times before entering a nondividing state called replicative senescence. Expression of the catalytic component of human telomerase, human telomerase reverse transcriptase (hTERT), extends the life span of human fibroblasts and retinal pigment epithelial cells beyond senescence without causing neoplastic transformation (Bodnar, A. G.

Gains in life expectancy after elimination of major causes of death: revised estimates taking into account the effect of competing causes.

Background: It is generally acknowledged that conventional estimates of the potential number of life years to be gained by elimination of causes of death are too generous. This is because these estimates fail to take into account the fact that those who are saved from the cause are likely to have one or more other conditions ("competing" causes of death), which may increase their risks of dying. It is unknown to what extent this introduces bias in comparisons of life years to be gained between underlying causes of death.

Competing causes of death: a death certificate study.

Background: Despite the widespread interest in competing causes of death, empirical information on interrelationships between causes of death is scarce. We have used death certificate information to estimate the prevalence of competing causes of death at the moment of dying from specific underlying causes of death.

Materials And Methods: In a stratified sample of 5975 deaths occurring in The Netherlands in 1990, information contained in the death certificate was used to determine the presence of diseases which, in the hypothetical case of elimination of the underlying cause of death, could develop into a new underlying cause of death.

[Discrepancy between results of registration of perinatal cause of death by the CBS (Central Bureau of Statistics) and by personal studies in the Delft-Westland-Oostland region].

Objective: To determine the reliability of the Dutch registration of causes of perinatal death by the Centraal Bureau voor de Statistiek (CBS, Central Statistics Office).

Design: Prospective, descriptive.

Setting: Region Delft-Westland-Oostland, the Netherlands.

Competing causes of death: an analysis using multiple-cause-of-death data from The Netherlands.

The standard methodology for cause-elimination life tables assumes that the various causes of death are statistically unrelated to one another, so that the mortality risks of those who are saved from an eliminated cause equal the risks of dying from other causes which are observed for the general population. In the analysis reported in this paper, data on multiple causes of death for the year 1990 in the Netherlands were used to investigate whether this is likely to be a valid assumption. For four groups of underlying causes of death (malignant neoplasms, cardiovascular diseases, and external causes), the age-standardized prevalence at death of other conditions was calculated.