Platelets for advanced drug delivery in cancer

Introduction: Cancer-related drug expenses are rising with the increasing cancer incidence and cost may represent a severe challenge for drug access for patients with cancer. Consequently, strategies for increasing therapeutic efficacy of already available drugs may be essential for the future health-care system. Areas covered: In this review, we have investigated the potential for the use of platelets as drug-delivery systems. We searched PubMed and Google Scholar to identify relevant papers written in English and published up to January 2023. Papers were included at the authors’ discretion to reflect an overview of state of the art. Expert opinion: It is known that cancer cells interact with platelets to gain functional advantages including immune evasion and metastasis development. This platelet-cancer interaction has been the inspiration for numerous platelet-based drug delivery systems using either drug-loaded or drug-bound platelets, or platelet membrane-containing hybrid vesicles combining platelet membranes with synthetic nanocarriers. Compared to treatment with free drug or synthetic drug vectors, these strategies may improve pharmacokinetics and selective cancer cell targeting. There are multiple studies showing improved therapeutic efficacy using animal models, however, no platelet-based drug delivery systems have been tested in humans, meaning the clinical relevance of this technology remains uncertain.publishedVersio

An Investigation of Aerosol Measurements from the Halogen Occultation Experiment: Validation, Size Distributions, Composition, and Relation to Other Chemical Species

The efforts envisioned within the original proposal (accepted February 1994) and the extension of this proposal (accepted February 1997) included measurement validations, the retrieval of aerosol size distributions and distribution moments, aerosol correction studies, and investigations of polar stratospheric clouds. A majority of the results from this grant have been published. The principal results from this grant are discussed

Quantitative relation between PMSE and ice mass density

Radar reflectivities associated with Polar Mesosphere Summer Echoes (PMSE) are compared with measurements of ice mass density in the mesopause region. The 54.5 MHz radar Moveable Atmospheric Radar for Antarctica (MARA), located at the Wasa/Aboa station in Antarctica (73° S, 13° W) provided PMSE measurements in December 2007 and January 2008. Ice mass density was measured by the Solar Occultation for Ice Experiment (SOFIE). The radar operated continuously during this period but only measurements close to local midnight are used for comparison, to coincide with the local time of the measurements of ice mass density. The radar location is at high geographic latitude but low geomagnetic latitude (61°) and the measurements were made during a period of very low solar activity. As a result, background electron densities can be modelled based on solar illumination alone. We find a close correlation between the time and height variations of radar reflectivity and ice mass density, at all PMSE heights, from 80 km up to 95 km. A quantitative expression relating radar reflectivities to ice mass density is found, including an empirical dependence on background electron density. Using this relation, we can use PMSE reflectivities as a proxy for ice mass density, and estimate the daily variation of ice mass density from the daily variation of PMSE reflectivities. According to this proxy, ice mass density is maximum around 05:00–07:00 LT, with lower values around local noon, in the afternoon and in the evening. This is consistent with the small number of previously published measurements and model predictions of the daily variation of noctilucent (mesospheric) clouds and in contrast to the daily variation of PMSE, which has a broad daytime maximum, extending from 05:00 LT to 15:00 LT, and an evening-midnight minimum

Dissociable and paradoxical roles of rat medial and lateral orbitofrontal cortex in visual serial reversal learning

Much evidence suggests that reversal learning is mediated by cortico-striatal circuitries with the orbitofrontal cortex (OFC) playing a prominent role. The OFC is a functionally heterogeneous region, but potential differential roles of lateral (lOFC) and medial (mOFC) portions in visual reversal learning have yet to be determined. We investigated the effects of pharmacological inactivation of mOFC and lOFC on a deterministic serial visual reversal learning task for rats. For reference, we also targeted other areas previously implicated in reversal learning: prelimbic (PrL) and infralimbic (IL) prefrontal cortex, and basolateral amygdala (BLA). Inactivating mOFC and lOFC produced opposite effects; lOFC impairing, and mOFC improving, performance in the early, perseverative phase specifically. Additionally, mOFC inactivation enhanced negative feedback sensitivity, while lOFC inactivation diminished feedback sensitivity in general. mOFC and lOFC inactivation also affected novel visual discrimination learning differently; lOFC inactivation paradoxically improved learning, and mOFC inactivation had no effect. We also observed dissociable roles of the OFC and the IL/PrL. Whereas the OFC inactivation affected only perseveration, IL/PrL inactivation improved learning overall. BLA inactivation did not affect perseveration, but improved the late phase of reversal learning. These results support opponent roles of the rodent mOFC and lOFC in deterministic visual reversal learning.Wellcome Trus

A Multi-Sims Investigation of Water Content and D/H Ratios in Roberts Massif 04262 with Insight to Sources of Hydrogen in Maskelynite

We want to define the H2O content ([H2O]) and hydrogen (H) isotope composition of meteoritic material from Mars [1-3] with motivation to understand Mars volatile history, constrain geochemical signatures of interior water reservoirs (i.e. the Martian mantle) and explore effects of planetary (e.g. planet formation, magma ocean degassing) and local (e.g. volcanic degassing, impact melting and degassing) processes on H incorporated in minerals. Secondary ion mass spectrometry (SIMS) allows multiple avenues to address these questions. However, application to (1) precious astromaterials and (2) low level H measurements, pose specific challenges that are further complicated when combined. We present preliminary data of a multi-approach (SIMS vs. NanoSIMS) study of H in Roberts Massif 04262 (RBT 04262), an enriched lherzolitic shergottite with nonpoikilitic (NP) and poikilitic (P) lithologies [4]. We analyze olivine, pyrox-ene, and melt inclusions to compare indigenous mantle water, with impact-generated maskelynite to investigate H signatures due to shock

Combination of Intensive Chemotherapy and Anticancer Vaccines in the Treatment of Human Malignancies: The Hematological Experience

In vitro studies have demonstrated that cancer-specific T cell cytotoxicity can be induced both ex vivo and in vivo, but this therapeutic strategy should probably be used as an integrated part of a cancer treatment regimen. Initial chemotherapy should be administered to reduce the cancer cell burden and disease-induced immune defects. This could be followed by autologous stem cell transplantation that is a safe procedure including both high-dose disease-directed chemotherapy and the possibility for ex vivo enrichment of the immunocompetent graft cells. The most intensive conventional chemotherapy and stem cell transplantation are used especially in the treatment of aggressive hematologic malignancies; both strategies induce T cell defects that may last for several months but cancer-specific T cell reactivity is maintained after both procedures. Enhancement of anticancer T cell cytotoxicity is possible but posttransplant vaccination therapy should probably be combined with optimalisation of immunoregulatory networks. Such combinatory regimens should be suitable for patients with aggressive hematological malignancies and probably also for other cancer patients

Platelet microparticles decrease daunorubicin‐induced dna damage and modulate intrinsic apoptosis in thp‐1 cells

Platelets can modulate cancer through budding of platelet microparticles (PMPs) that can transfer a plethora of bioactive molecules to cancer cells upon internalization. In acute myelogenous leukemia (AML) this can induce chemoresistance, partially through a decrease in cell activity. Here we investigated if the internalization of PMPs protected the monocytic AML cell line, THP-1, from apoptosis by decreasing the initial cellular damage inflicted by treatment with daunorubicin, or via direct modulation of the apoptotic response. We examined whether PMPs could protect against apoptosis after treatment with a selection of inducers, primarily associated with either the intrinsic or the extrinsic apoptotic pathway, and protection was restricted to the agents targeting intrinsic apoptosis. Furthermore, levels of daunorubicin-induced DNA damage, assessed by measuring gH2AX, were reduced in both 2N and 4N cells after PMP co-incubation. Measuring different BCL2-family proteins before and after treatment with daunorubicin revealed that PMPs downregulated the pro-apoptotic PUMA protein. Thus, our findings indicated that PMPs may protect AML cells against apoptosis by reducing DNA damage both dependent and independent of cell cycle phase, and via direct modulation of the intrinsic apoptotic pathway by downregulating PUMA. These findings further support the clinical relevance of platelets and PMPs in AML.publishedVersio

Impact of the January 2012 solar proton event on polar mesospheric clouds

We use data from the Aeronomy of Ice in the Mesosphere mission and simulations using the Whole Atmosphere Community Climate Model to determine the impact of the 23–30 January 2012 solar proton event (SPE) on polar mesospheric clouds (PMCs) and mesospheric water vapor. We see a small heating and loss of ice mass on 26 January that is consistent with prior results but is not statistically significant. We also find a previously unreported but statistically significant ~10% increase in ice mass and in water vapor in the sublimation area in the model that occurs in the 7 to 14 days following the start of the event. The magnitude of the response to the January 2012 SPE is small compared to other sources of variability like gravity waves and planetary waves; however, sensitivity tests suggest that with larger SPEs this delayed increase in ice mass will increase, while there is little change in the loss of ice mass early in the event. The PMC response to SPEs in models is dependent on the gravity wave parameterization, and temperature anomalies from SPEs may be useful in evaluating and tuning gravity wave parameterizations

Quasielastic neutron scattering and molecular dynamics simulation studies of the melting transition in butane and hexane monolayers adsorbed on graphite

Quasielastic neutron scattering experiments and molecular dynamics (MD) simulations have been used to investigate molecular diffusive motion near the melting transition of monolayers of flexible rod-shaped molecules. The experiments were conducted on butane and hexane monolayers adsorbed on an exfoliated graphite substrate, For butane, quasielastic scattering broader than the experimental energy resolution width of 70 mu eV appears abruptly at the monolayer melting point of T-m = 116 K, whereas, for the hexane monolayer, it appears 20 K below the melting transition (T-m = 170 K). To facilitate comparison with experiment, quasielastic spectra calculated from the MD simulations were analyzed using the same models and fitting algorithms as for the neutron spectra. This combination of techniques gives a microscopic picture of the melting process in these two monolayers which is consistent with earlier neutron diffraction experiments. Butane melts abruptly to a liquid phase where the molecules in the trans conformation translationally diffuse while rotating about their center of mass. In the case of the hexane monolayer, the MD simulations show that the appearance of quasielastic scattering below T-m coincides with transformation of Some molecules from trans to gauche conformations. Furthermore, if gauche molecules are prevented from forming in the simulation, the calculated incoherent scattering function contains no quasielastic component below T-m. Modeling of both the neutron and simulated hexane monolayer spectra below T-m favors a plastic phase in which there is nearly isotropic rotational diffusion of the gauche molecules about their center of mass, but no translational diffusion, The elastic scattering observed above T-m is consistent with the coexistence of solid monolayer clusters with a fluid phase, as predicted by the simulations. For T/T-m greater than or equal to 1.3, the elastic scattering vanishes from the neutron spectra where the simulation indicates the presence of a fluid phase alone, The qualitative similarities between the observed and simulated quasielastic spectra lend support to a previously proposed ''footprint reduction'' mechanism of melting in monolayers of flexible, rod-shaped molecules. (C) 1997 American Institute of Physics