Biodistribution and pharmacokinetics of a telodendrimer micellar paclitaxel nanoformulation in a mouse xenograft model of ovarian cancer

Wenwu Xiao1, Juntao Luo2, Teesta Jain3, John Riggs3, Harry P Tseng1, Paul T Henderson3, Simon R Cherry4, Douglas Rowland4, Kit S Lam1,31Department of Biochemistry and Molecular Medicine, UC Davis Cancer Center, University of California Davis, Sacramento, CA; 2Department of Pharmacology, SUNY Upstate Cancer Research Institute, SUNY Upstate Medical University, Syracuse, NY; 3Department of Internal Medicine, Division of Hematology and Oncology, 4Department of Biomedical Engineering, UC Davis Cancer Center, University of California Davis, Davis, CABackground: A multifunctional telodendrimer-based micelle system was characterized for delivery of imaging and chemotherapy agents to mouse tumor xenografts. Previous optical imaging studies demonstrated qualitatively that these classes of nanoparticles, called nanomicelles, preferentially accumulate at tumor sites in mice. The research reported herein describes the detailed quantitative imaging and biodistribution profiling of nanomicelles loaded with a cargo of paclitaxel.Methods: The telodendrimer was covalently labeled with 125I and the nanomicelles were loaded with 14C-paclitaxel, which allowed measurement of pharmacokinetics and biodistribution in the mice using microSPECT/CT imaging and liquid scintillation counting, respectively.Results: The radio imaging data showed preferential accumulation of nanomicelles at the tumor site along with a slower clearance rate than paclitaxel formulated in Cremophor EL (Taxol®). Liquid scintillation counting confirmed that 14C-labeled paclitaxel sequestered in nanomicelles had increased uptake by tumor tissue and slower pharmacokinetics than Taxol.Conclusion: Overall, the results indicate that nanomicelle-formulated paclitaxel is a potentially superior formulation compared with Taxol in terms of water solubility, pharmacokinetics, and tumor accumulation, and may be clinically useful for both tumor imaging and improved chemotherapy applications.Keywords: telodendrimer, nanomicelle, paclitaxel, microSPECT/CT, imaging guided drug deliver

The nature of localization in graphene under quantum Hall conditions

Particle localization is an essential ingredient in quantum Hall physics [1,2]. In conventional high mobility two-dimensional electron systems Coulomb interactions were shown to compete with disorder and to play a central role in particle localization [3]. Here we address the nature of localization in graphene where the carrier mobility, quantifying the disorder, is two to four orders of magnitude smaller [4,5,6,7,8,9,10]. We image the electronic density of states and the localized state spectrum of a graphene flake in the quantum Hall regime with a scanning single electron transistor [11]. Our microscopic approach provides direct insight into the nature of localization. Surprisingly, despite strong disorder, our findings indicate that localization in graphene is not dominated by single particle physics, but rather by a competition between the underlying disorder potential and the repulsive Coulomb interaction responsible for screening.Comment: 18 pages, including 5 figure

Randomised, double-blind, placebo-controlled study investigating the effects of inorganic nitrate on vascular function, platelet reactivity and restenosis in stable angina: protocol of the NITRATE-OCT study

KSR and this work are funded by an NIHR Doctoral Fellowship (DRF-2014-07-008

Observation of the Fractional Quantum Hall Effect in Graphene

When electrons are confined in two dimensions and subjected to strong magnetic fields, the Coulomb interactions between them become dominant and can lead to novel states of matter such as fractional quantum Hall liquids. In these liquids electrons linked to magnetic flux quanta form complex composite quasipartices, which are manifested in the quantization of the Hall conductivity as rational fractions of the conductance quantum. The recent experimental discovery of an anomalous integer quantum Hall effect in graphene has opened up a new avenue in the study of correlated 2D electronic systems, in which the interacting electron wavefunctions are those of massless chiral fermions. However, due to the prevailing disorder, graphene has thus far exhibited only weak signatures of correlated electron phenomena, despite concerted experimental efforts and intense theoretical interest. Here, we report the observation of the fractional quantum Hall effect in ultraclean suspended graphene, supporting the existence of strongly correlated electron states in the presence of a magnetic field. In addition, at low carrier density graphene becomes an insulator with an energy gap tunable by magnetic field. These newly discovered quantum states offer the opportunity to study a new state of matter of strongly correlated Dirac fermions in the presence of large magnetic fields

COVID-19 and changes in activity and treatment of ST elevation MI from a UK cardiac centre.

Background: The international healthcare response to COVID-19 has been driven by epidemiological data related to case numbers and case fatality rate. Second order effects have been less well studied. This study aimed to characterise the changes in emergency activity of a high-volume cardiac catheterisation centre and to cautiously model any excess indirect morbidity and mortality. Method: Retrospective cohort study of patients admitted with acute coronary syndrome fulfilling criteria for the heart attack centre (HAC) pathway at St. Bartholomew's hospital, UK. Electronic data were collected for the study period March 16th - May 16th 2020 inclusive and stored on a dedicated research server. Standard governance procedures were observed in line with the British Cardiovascular Intervention Society audit. Results: There was a 28% fall in the number of primary percutaneous coronary interventions (PCIs) for ST elevation myocardial infarction (STEMI) during the study period (111 vs. 154) and 36% fewer activations of the HAC pathway (312 vs. 485), compared to the same time period averaged across three preceding years. In the context of 'missing STEMIs', the excess harm attributable to COVID-19 could result in an absolute increase of 1.3% in mortality, 1.9% in nonfatal MI and 4.5% in recurrent ischemia. Conclusions: The emergency activity of a high-volume PCI centre was significantly reduced for STEMI during the peak of the first wave of COVID-19. Our data can be used as an exemplar to help future modelling within cardiovascular workstreams to refine aggregate estimates of the impact of COVID-19 and inform targeted policy action

Spectroscopic investigation of quantum confinement effects in ion implanted silicon-on-sapphire films

Crystalline Silicon-on-Sapphire (SOS) films were implanted with boron (B$^+$) and phosphorous (P$^+$) ions. Different samples, prepared by varying the ion dose in the range $10^{14}$ to 5 x $10^{15}$ and ion energy in the range 150-350 keV, were investigated by the Raman spectroscopy, photoluminescence (PL) spectroscopy and glancing angle x-ray diffraction (GAXRD). The Raman results from dose dependent B$^+$ implanted samples show red-shifted and asymmetrically broadened Raman line-shape for B$^+$ dose greater than $10^{14}$ ions cm$^{-2}$. The asymmetry and red shift in the Raman line-shape is explained in terms of quantum confinement of phonons in silicon nanostructures formed as a result of ion implantation. PL spectra shows size dependent visible luminescence at $\sim$ 1.9 eV at room temperature, which confirms the presence of silicon nanostructures. Raman studies on P$^+$ implanted samples were also done as a function of ion energy. The Raman results show an amorphous top SOS surface for sample implanted with 150 keV P$^+$ ions of dose 5 x $10^{15}$ ions cm$^{-2}$. The nanostructures are formed when the P$^+$ energy is increased to 350 keV by keeping the ion dose fixed. The GAXRD results show consistency with the Raman results.Comment: 9 Pages, 6 Figures and 1 Table, \LaTex format To appear in SILICON(SPRINGER

Prior Coronary Artery Bypass Graft Surgery and Outcome After Percutaneous Coronary Intervention: An Observational Study From the Pan-London Percutaneous Coronary Intervention Registry.

Background Limited information exists regarding procedural success and clinical outcomes in patients with previous coronary artery bypass grafting (CABG) undergoing percutaneous coronary intervention (PCI). We sought to compare outcomes in patients undergoing PCI with or without CABG. Methods and Results This was an observational cohort study of 123 780 consecutive PCI procedures from the Pan-London (UK) PCI registry from 2005 to 2015. The primary end point was all-cause mortality at a median follow-up of 3.0 years (interquartile range, 1.2-4.6 years). A total of 12 641(10.2%) patients had a history of previous CABG, of whom 29.3% (n=3703) underwent PCI to native vessels and 70.7% (n=8938) to bypass grafts. There were significant differences in the demographic, clinical, and procedural characteristics of these groups. The risk of mortality during follow-up was significantly higher in patients with prior CABG (23.2%; P=0.0005) compared with patients with no prior CABG (12.1%) and was seen for patients who underwent either native vessel (20.1%) or bypass graft PCI (24.2%; P<0.0001). However, after adjustment for baseline characteristics, there was no significant difference in outcomes seen between the groups when PCI was performed in native vessels in patients with previous CABG (hazard ratio [HR],1.02; 95%CI, 0.77-1.34; P=0.89), but a significantly higher mortality was seen among patients with PCI to bypass grafts (HR,1.33; 95% CI, 1.03-1.71; P=0.026). This was seen after multivariate adjustment and propensity matching. Conclusions Patients with prior CABG were older with greater comorbidities and more complex procedural characteristics, but after adjustment for these differences, the clinical outcomes were similar to the patients undergoing PCI without prior CABG. In these patients, native-vessel PCI was associated with better outcomes compared with the treatment of vein grafts

The impact of COVID-19 on pulmonary, neurological, and cardiac outcomes: evidence from a Mendelian randomization study

BackgroundLong COVID is a clinical entity characterized by persistent health problems or development of new diseases, without an alternative diagnosis, following SARS-CoV-2 infection that affects a significant proportion of individuals globally. It can manifest with a wide range of symptoms due to dysfunction of multiple organ systems including but not limited to cardiovascular, hematologic, neurological, gastrointestinal, and renal organs, revealed by observational studies. However, a causal association between the genetic predisposition to COVID-19 and many post-infective abnormalities in long COVID remain unclear.MethodsHere we employed Mendelian randomization (MR), a robust genetic epidemiological approach, to investigate the potential causal associations between genetic predisposition to COVID-19 and long COVID symptoms, namely pulmonary (pneumonia and airway infections including bronchitis, emphysema, asthma, and rhinitis), neurological (headache, depression, and Parkinson’s disease), cardiac (heart failure and chest pain) diseases, and chronic fatigue. Using two-sample MR, we leveraged genetic data from a large COVID-19 genome-wide association study and various disorder-specific datasets.ResultsThis analysis revealed that a genetic predisposition to COVID-19 was significantly causally linked to an increased risk of developing pneumonia, airway infections, headache, and heart failure. It also showed a strong positive correlation with chronic fatigue, a frequently observed symptom in long COVID patients. However, our findings on Parkinson’s disease, depression, and chest pain were inconclusive.ConclusionOverall, these findings provide valuable insights into the genetic underpinnings of long COVID and its diverse range of symptoms. Understanding these causal associations may aid in better management and treatment of long COVID patients, thereby alleviating the substantial burden it poses on global health and socioeconomic systems

Singlet-doublet Higgs mixing and its implications on the Higgs mass in the PQ-NMSSM

We examine the implications of singlet-doublet Higgs mixing on the properties of a Standard Model (SM)-like Higgs boson within the Peccei-Quinn invariant extension of the NMSSM (PQ-NMSSM). The SM singlet added to the Higgs sector connects the PQ and visible sectors through a PQ-invariant non-renormalizable K\"ahler potential term, making the model free from the tadpole and domain-wall problems. For the case that the lightest Higgs boson is dominated by the singlet scalar, the Higgs mixing increases the mass of a SM-like Higgs boson while reducing its signal rate at collider experiments compared to the SM case. The Higgs mixing is important also in the region of parameter space where the NMSSM contribution to the Higgs mass is small, but its size is limited by the experimental constraints on the singlet-like Higgs boson and on the lightest neutralino constituted mainly by the singlino whose Majorana mass term is forbidden by the PQ symmetry. Nonetheless the Higgs mixing can increase the SM-like Higgs boson mass by a few GeV or more even when the Higgs signal rate is close to the SM prediction, and thus may be crucial for achieving a 125 GeV Higgs mass, as hinted by the recent ATLAS and CMS data. Such an effect can reduce the role of stop mixing.Comment: 26 pages, 3 figures; published in JHE