Biodegradable PLGA Based Nanoparticles for Sustained Regional Lymphatic Drug Delivery

The purpose of this work is to evaluate biodegradable drug carriers with defined size, hydrophobicity, and surface charge density for preferential lymphatic uptake and retention for sustained regional drug delivery. PLGA–PMA:PLA-PEG (PP) nanoparticles of defined size and relative hydrophobicity were prepared by nanoprecipitation method. These were compared with PS particles of similar sizes and higher hydrophobicity. PLGA–PMA:PLGA-COOH (PC) particles at 80:20, 50:50, and 20:80 ratios were prepared by nanoprecipitation for the charge study. Particle size and zeta potential were characterized by dynamic light scattering and laser doppler anemometry, respectively. Particles were administered in vivo to rats subcutaneously. Systemic and lymph node uptake was evaluated by marker recovery. Lymphatic uptake and node retention of PP nanoparticles was shown to be inversely related to size. Lymphatic uptake and node retention of PP particles, as compared to PS particles, was shown to be inversely related to hydrophobicity. Lastly, lymphatic uptake and node retention of PC nanoparticles were directly related to the anionic charge on the particles. In vivo lymphatic uptake and retention in a rat model indicates that the 50 nm PP particles are ideal for sustained regional delivery into the lymphatics for prevention/treatment of oligometastases

Diffusive Charge Transport in Graphene on SiO2

We review our recent work on the physical mechanisms limiting the mobility of graphene on SiO2. We have used intentional addition of charged scattering impurities and systematic variation of the dielectric environment to differentiate the effects of charged impurities and short-range scatterers. The results show that charged impurities indeed lead to a conductivity linear in density in graphene, with a scattering magnitude that agrees quantitatively with theoretical estimates [1]; increased dielectric screening reduces scattering from charged impurities, but increases scattering from short-range scatterers [2]. We evaluate the effects of the corrugations (ripples) of graphene on SiO2 on transport by measuring the height-height correlation function. The results show that the corrugations cannot mimic long-range (charged impurity) scattering effects, and have too small an amplitude-to-wavelength ratio to significantly affect the observed mobility via short-range scattering [3, 4]. Temperature-dependent measurements show that longitudinal acoustic phonons in graphene produce a resistivity linear in temperature and independent of carrier density [5]; at higher temperatures, polar optical phonons of the SiO2 substrate give rise to an activated, carrier density-dependent resistivity [5]. Together the results paint a complete picture of charge carrier transport in graphene on SiO2 in the diffusive regime.Comment: 28 pages, 7 figures, submitted to Graphene Week proceeding

Repeated clinical malaria episodes are associated with modification of the immune system in children

The study received funding from the UK Medical Research Council, (MRC Programme grant #: MR/M003906/1). MB and AR are supported by the Wellcome Trust (Grant #: WT 206194).Background There are over 200 million reported cases of malaria each year, and most children living in endemic areas will experience multiple episodes of clinical disease before puberty. We set out to understand how frequent clinical malaria, which elicits a strong inflammatory response, affects the immune system and whether these modifications are observable in the absence of detectable parasitaemia. Methods We used a multi-dimensional approach comprising whole blood transcriptomic, cellular and plasma cytokine analyses on a cohort of children living with endemic malaria, but uninfected at sampling, who had been under active surveillance for malaria for 8 years. Children were categorised into two groups depending on the cumulative number of episodes experienced: high (≥ 8) or low (< 5). Results We observe that multiple episodes of malaria are associated with modification of the immune system. Children who had experienced a large number of episodes demonstrated upregulation of interferon-inducible genes, a clear increase in circulating levels of the immunoregulatory cytokine IL-10 and enhanced activation of neutrophils, B cells and CD8+ T cells. Conclusion Transcriptomic analysis together with cytokine and immune cell profiling of peripheral blood can robustly detect immune differences between children with different numbers of prior malaria episodes. Multiple episodes of malaria are associated with modification of the immune system in children. Such immune modifications may have implications for the initiation of subsequent immune responses and the induction of vaccine-mediated protection.Publisher PDFPeer reviewe

Eocene extension in Idaho generated massive sediment floods into the Franciscan trench and into the Tyee, Great Valley, and Green River basins

The Franciscan Complex accretionary prism was assembled during an similar to 165-m.y.-long period of subduction of Pacific Ocean plates beneath the western margin of the North American plate. In such fossil subduction complexes, it is generally difficult to reconstruct details of the accretion of continent-derived sediments and to evaluate the factors that controlled accretion. New detrital zircon U-Pb ages indicate that much of the major Coastal belt subunit of the Franciscan Complex represents a massive, relatively brief, surge of near-trench deposition and accretion during Eocene time (ca. 53-49 Ma). Sediments were sourced mainly from the distant Idaho Batholith region rather than the nearby Sierra Nevada. Idaho detritus also fed the Great Valley forearc basin of California (ca. 53-37 Ma), the Tyee forearc basin of coastal Oregon (49 to ca. 36 Ma), and the greater Green River lake basin of Wyoming (50-47 Ma). Plutonism in the Idaho Batholith spanned 98-53 Ma in a contractional setting; it was abruptly superseded by major extension in the Bitterroot, Anaconda, Clearwater, and Priest River metamorphic core complexes (53-40 Ma) and by major volcanism in the Challis volcanic field (51-43 Ma). This extensional tectonism apparently deformed and uplifted a broad region, shedding voluminous sediments toward depocenters to the west and southeast. In the Franciscan Coastal belt, the major increase in sediment input apparently triggered a pulse of massive accretion, a pulse ultimately controlled by continental tectonism far within the interior of the North American plate, rather than by some tectonic event along the plate boundary itself.Keywords: Northern California, Oregon Coast Range, Subduction, Cordillera, Evolution, Erosion, Mountains, Provenance, Batholith, Constraint

Measurements of the observed cross sections for e+e−→e^+e^-\to exclusive light hadrons containing π0π0\pi^0\pi^0 at s=3.773\sqrt s= 3.773, 3.650 and 3.6648 GeV

By analyzing the data sets of 17.3, 6.5 and 1.0 pb$^{-1}$ taken, respectively, at $\sqrt s= 3.773$, 3.650 and 3.6648 GeV with the BES-II detector at the BEPC collider, we measure the observed cross sections for $e^+e^-\to \pi^+\pi^-\pi^0\pi^0$, $K^+K^-\pi^0\pi^0$, $2(\pi^+\pi^-\pi^0)$, $K^+K^-\pi^+\pi^-\pi^0\pi^0$ and $3(\pi^+\pi^-)\pi^0\pi^0$ at the three energy points. Based on these cross sections we set the upper limits on the observed cross sections and the branching fractions for $\psi(3770)$ decay into these final states at 90% C.L..Comment: 7 pages, 2 figure

Direct Measurements of Absolute Branching Fractions for D0 and D+ Inclusive Semimuonic Decays

By analyzing about 33 $\rm pb^{-1}$ data sample collected at and around 3.773 GeV with the BES-II detector at the BEPC collider, we directly measure the branching fractions for the neutral and charged $D$ inclusive semimuonic decays to be $BF(D^0 \to \mu^+ X) =(6.8\pm 1.5\pm 0.7)$ and $BF(D^+ \to \mu^+ X) =(17.6 \pm 2.7 \pm 1.8)$, and determine the ratio of the two branching fractions to be $\frac{BF(D^+ \to \mu^+ X)}{BF(D^0 \to \mu^+ X)}=2.59\pm 0.70 \pm 0.25$

Measurements of the observed cross sections for exclusive light hadron production in e^+e^- annihilation at \sqrt{s}= 3.773 and 3.650 GeV

By analyzing the data sets of 17.3 pb$^{-1}$ taken at $\sqrt{s}=3.773$ GeV and 6.5 pb$^{-1}$ taken at $\sqrt{s}=3.650$ GeV with the BESII detector at the BEPC collider, we have measured the observed cross sections for 12 exclusive light hadron final states produced in $e^+e^-$ annihilation at the two energy points. We have also set the upper limits on the observed cross sections and the branching fractions for $\psi(3770)$ decay to these final states at 90% C.L.Comment: 8 pages, 5 figur

Delivery of hepato-pancreato-biliary surgery during the COVID-19 pandemic: an European-African Hepato-Pancreato-Biliary Association (E-AHPBA) cross-sectional survey

Background: The extent of the COVID-19 pandemic and the resulting response has varied globally. The European and African Hepato-Pancreato-Biliary Association (E-AHPBA), the premier representative body for practicing HPB surgeons in Europe and Africa, conducted this survey to assess the impact of COVID-19 on HPB surgery. Methods: An online survey was disseminated to all E-AHPBA members to assess the effects of the pandemic on unit capacity, management of HPB cancers, use of COVID-19 screening and other aspects of service delivery. Results: Overall, 145 (25%) members responded. Most units, particularly in COVID-high countries (>100,000 cases) reported insufficient critical care capacity and reduced HPB operating sessions compared to COVID-low countries. Delayed access to cancer surgery necessitated alternatives including increased neoadjuvant chemotherapy for pancreatic cancer and colorectal liver metastases, and locoregional treatments for hepatocellular carcinoma. Other aspects of service delivery including COVID-19 screening and personal protective equipment varied between units and countries. Conclusion: This study demonstrates that the COVID-19 pandemic has had a profound adverse impact on the delivery of HPB cancer care across the continents of Europe and Africa. The findings illustrate the need for safe resumption of cancer surgery in a “new” normal world with screening of patients and staff for COVID-19

A three-drug nanoscale drug delivery system designed for preferential lymphatic uptake for the treatment of metastatic melanoma

Metastatic melanoma has a high mortality rate due to lymphatic progression of the disease. Current treatment is surgery followed by radiation and intravenous chemotherapy. However, drawbacks for current chemotherapeutics lie in the fact that they develop resistance and do not achieve therapeutic concentrations in the lymphatic system. We hypothesize that a three-drug nanoscale drug delivery system, tailored for lymphatic uptake, administered subcutaneously, will have decreased drug resistance and therefore offer better therapeutic outcomes. We prepared and characterized nanoparticles (NPs) with docetaxel, everolimus, and LY294002 in polyethyleneglycol-block-poly(ε-caprolactone) (PEG-PCL) polymer with different charge distributions by modifying the ratio of anionic and neutral end groups on the PEG block. These NPs are similarly sized (~48nm), with neutral, partially charged, or fully charged surface. The NPs are able to load ~2mg/mL of each drug and are stable for 24h. The NPs are assessed for safety and efficacy in two transgenic metastatic melanoma mouse models. All the NPs were safe in both models based on general appearance, weight changes, death, and blood biochemical analyses. The partially charged NPs are most effective in decreasing the number of melanocytes at both the proximal (sentinel) lymph node (LN) and the distal LN from the injection site. The neutral NPs are efficacious at the proximal LN, while the fully charged NPs have no effect on either LNs. Thus, our data indicates that the NP surface charge and lymphatic efficacy are closely tied to each other and the partially charged NPs have the highest potential in treating metastatic melanoma