Targeted delivery of platinum-based anticancer complexes

The most widely used anticancer drugs are platinum-based. Their efficacy might be improved by carriers which can transport large numbers of Pt centres, shield the drug from premature activation, and/or deliver Pt specifically to cancer cells using vectors which recognise specific targets. We describe recent progress using functionalized carbon nanotubes (CNTs) and nanorods, hollow Prussian blue (HPB), magnetic iron oxide and gold nanoparticles, liposomes, nanogels and polymers, as well as active targeting by conjugation to biodegradable proteins and peptides (e.g. EGF, heparin, herceptin, somatostatin and TAT). Spatially targeted activation of PtIV prodrugs using light is also a promising approach. Interestingly, use of these new delivery and targeting systems for platinum drugs can lead to species with unusual reactivity which can kill cancer cells by new mechanisms

Visual-Vestibular Integration During Self-Motion Perception in Younger and Older Adults

Younger adults integrate visual and vestibular cues to self-motion in a manner consistent with optimal integration; however, little is currently known about whether this process changes with older age. Our objective was to determine whether older adults, like younger adults, display evidence of optimal visual-vestibular integration, including reductions in bimodal variance (visual-vestibular) compared with unimodal variance (visual or vestibular alone), and reliability-based cue weighting. We used a motion simulator and a head-mounted display to introduce a 2-interval forced-choice heading estimation task. Older (65+ years) and younger adults (18–35 years) judged which of two movements was more rightward. Movements consisted of vestibular cues (passive movement in darkness), visual cues (optic flow), or both cues combined. The combined condition contained either congruent cues or incongruent cues (either a subtle 5° or larger 20° conflict). Results demonstrated that older adults had less reliable visual heading estimates than younger adults but comparable vestibular heading estimates. During combined, congruent conditions, both age groups exhibited reductions in combined variance, consistent with predicted optimal integration. During subtle cue conflicts, only younger adults exhibited combined variance consistent with predicted optimal integration, but both age groups displayed reliability-based cue weighting. During larger spatial conflicts, neither group demonstrated optimal reductions in variance. Younger adults displayed reliability-based cue weighting but older adults’ heading estimates were biased toward the less reliable visual estimate. Older adults’ tendency to incorporate spatially conflicting and unreliable visual cues into their self-motion percept may affect their performance on mobility-related tasks like walking and driving

Photodecomposition pathways for photoactivatable platinum(IV) diazido anticancer complexes

Photo-activatable platinum(IV) diazido complexes with the general formula of trans,trans,trans-[Pt(N3)2(OH)(X)(py)(am1)] (X is a hydroxide or carboxylate and am1 is an aliphatic/aromatic amine) show dark-stability under physiological conditions but can induce a photo-cytotoxic effect in cancer cells after irradiation with UVA, blue and/or green light. These platinum(IV) diazido complexes can platinate DNA and induce different lesions that are distinctly different from those generated by the anticancer drug cis-platin. Through the use of EPR, multinuclear NMR, and UV-visible absorption spectroscopy, as well as mass spectrometry and some cell studies, this thesis aims to investigate the pathways of photochemical decomposition and in particular the release of azidyl ligands and their subsequent involvement in photo-cytotoxicity. Firstly, the irradiation of trans,trans,trans-[Pt(N3)2(OH)2(py)2] (40, py = pyridine) with blue light in the presence of the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) led to the detection of a characteristic quartet-of-triplets EPR spectrum, assigned to the azidyl radical adduct, DMPO-14N3. Irradiation of 15N-40, led to the detection of a quartet-of-doublets EPR spectrum as assigned to the DMPO-15N3 spin adduct. This confirmed that the ●N3 radicals arose from the platinum(IV)- bound azide. The DMPO-N3 spin adduct was also detected from the photoirradiation of trans,trans,trans-[Pt(N3)2(OH)2(MA)(py)] (44, MA = methylamine) with blue light. A greater yield in the DMPO-N3 spin adduct was formed in PBS/D2O. This effect was attributed to the Brownian motion of the ●N3 radicals. Interestingly, photoirradiation in the cell culture medium-, RPMI-1640 led to a reduction in the DMPO-N3 spin adduct. This reduction was accredited to the variety of components present in the cell culture medium which could behave as radical quenchers. Alternative nitrone spin traps, -4-pyridyl-1-oxide-N-tert-butylnitrone (4-POBN) and 5-diethoxyphosphoryl-5-methyl-1-pyrroline-N-oxide (DEPMPO) also led to the trapping of the azidyl radicals from irradiated 40, forming the 4-POBN-N3 (triplet-of-quartets) and DEPMPO-N3 (octet-of-triplets) spin adducts EPR spectra, respectively. DEPMPO was the most efficient azidyl radical trap; with the DEPMPO-N3 spin adduct possessing the longest lifetime in aqueous media. Extending the wavelength of activation to green light (517 nm), also led to the detection of DMPO-N3 from the photo-irradiation of 40 in RPMI-1640, trans,trans,trans-[Pt(N3)2(OH)(SAD)(py)2] (56,SAD=succinate), trans,trans,trans-[Pt(N3)2(OH)(ethyl-methyl-SAD)(py)2] (57) and trans,trans,trans-[Pt(N3)2(OH)(N-MI)(py)2] (58, N-MI = N-methylisatoate) in H2O/DMF. The DEPMPO-N3 was also detected from the gamma-ray irradiation of 40, which appears to be the first report of the activation of a platinum(IV) diazido anticancer complex with gamma-rays, a procedure which might be useful of clinical use. The azidyl radicals generated from irradiated 40 were unreactive towards both glycine and L-tyrosine. However, in the presence of L-tryptophan the azidyl radicals were quenched. Detection of free azide by 14N NMR spectroscopy confirmed that this quenching mechanism proceeded through a one-electron transfer pathway. The photo-cytotoxicity of 40 was supressed in the presence of low doses of L-tryptophan in A2780 ovarian cancer cells. From this study, it was deduced that the photo-cytotoxicity of 40 is comprised of both an acute (radical) and chronic (DNA platination) based mechanisms. Additionally, certain cancers have reported on the depleted serum levels of L-tryptophan, in particular ovarian cancer cells. This suggests the extent of the photo-cytotoxicity of 40 can be controlled in the presence of L-tryptophan. Photo-irradiation of 40 in the presence of melatonin, an analogue of L-tryptophan was also performed. Despite, the structural similarity between L-tryptophan and melatonin, the presence of the 5-methoxy substituent present in melatonin induced an alternative photo-decomposition pathway of 40. Photo-irradiation of 40 in the presence of melatonin with blue light also led to the detection of the quartet EPR spectrum assigned to the hydroxyl radical adduct, DMPO-OH. Through multinuclear NMR and mass spectrometry the quenching of both the azidyl and hydroxyl radicals by melatonin was determined. Additionally, mass spectrometry also detected a mass adduct attributed to a platinum(II)-melatonin complex. This dual antioxidant and metal-binding ability of melatonin was attributed to the observed photo-protective effect in A2780 ovarian cancer cells. Melatonin regulates circadian rhythms with a maximum concentration during dark hours. Consequently, treatment of antineoplastic tissue with 40 during the hours of melatonin production may be ineffective. Platinum accumulation and absorption has been suggested to be mediated by organic cation transporters (OCTs), in particular OCT2. Irradiation of 40 was monitored in the presence of cimetidine, an OCT2 inhibitor. A new strong absorption band at ca. 354 nm was assigned to an SPtII LMCT band. High resolution mass spectroscopy identified a mass adduct assigned to a novel platinum(II)-cimetidine species. The loss of coordinated pyridine from irradiated 40 as detected by 1H NMR spectroscopy and the quenching of the azidyl radical by cimetidine were correlated with the observed photo-protective effect in HaCaT keratinocytes cells

A 4-Planet System Orbiting the K0V Star HD 141399

We present precision radial velocity (RV) data sets from Keck-HIRES and from Lick Observatory's new Automated Planet Finder Telescope and Levy Spectrometer on Mt. Hamilton that reveal a multiple-planet system orbiting the nearby, slightly evolved, K-type star HD 141399. Our 91 observations over 10.5 years suggest the presence of four planets with orbital periods of 94.35, 202.08, 1070.35, and 3717.35 days and minimum masses of 0.46, 1.36, 1.22, and 0.69 Jupiter masses respectively. The orbital eccentricities of the three inner planets are small, and the phase curves are well sampled. The inner two planets lie just outside the 2:1 resonance, suggesting that the system may have experienced dissipative evolution during the protoplanetary disk phase. The fourth companion is a Jupiter-like planet with a Jupiter-like orbital period. Its orbital eccentricity is consistent with zero, but more data will be required for an accurate eccentricity determination.Comment: 11 pages, 13 figures, To appear in the Astrophysical Journa

The anti-civic effects of popular culture on American teenagers

Civic participation and civic awareness is essential to the maintenance of American democracy. Strong civic communities serve to promote prosperity, ensure the resolution of collective problems, and act as a check upon the power of the state. But in 2002, there is little doubt that, across a wide range of indicators, America’s civic culture is in decline. Voting rates have fallen rapidly over the past several decades, and so too has trust in government. Equally troubling Ec002 Massachusetts Department of Education [email protected] Massachusetts Department of Education Massachusetts Department of Education Massachusetts Department of Education [email protected] Anders Lewis Jennifer Butler Melanie Winklosky Sandra Stotsky ESE Nº002 2002 is the disconcerting dearth of civic knowledge among American youths and the drop in participation, among all Americans, in numerous civic organizations, from church-affiliated groups to voluntary and fraternal organizations as well as women’s auxiliaries and unions. There are many causes for these trends. This paper examines how popular culture affects civic participation and civic awareness among a group of particularly active teenagers in Massachusetts. We found that popular culture has a generally negative influence on civic life but that its effects are not one-sided and that it can be mitigated by strong families and quality schools committed to an academic and civic education

Patterns of Use of Human Papillomavirus and Other Adolescent Vaccines in the United States

AbstractPurposeThe purpose of the study was to describe the patterns of use of universally recommended adolescent vaccines in the United States.MethodsWe identified 11-year-olds using the MarketScan insurance claims database (2009–2014). Human papillomavirus (HPV), tetanus-diphtheria-acellular pertussis (Tdap), and meningococcal (MenACWY) vaccination claims were identified using diagnosis and procedure codes. Generalized linear models estimated vaccination incidence rates and correlates of adolescent vaccination and timely vaccination.ResultsAmong 1,691,223 adolescents, receipt of Tdap (52.1%) and MenACWY (45.8%) vaccinations exceeded receipt of HPV vaccination (18.4%). While both sexes had similar Tdap and MenACWY vaccination proportions, girls received HPV vaccination more frequently than boys (21.9% vs. 15.1%). Adolescents received HPV vaccination later (mean age: 11.8 years) than Tdap or MenACWY vaccination (mean age: 11.2 years for both). Half of vaccinated adolescents received Tdap and MenACWY vaccination only; however, coadministration with HPV vaccine increased with birth cohort. Western adolescents had the highest incidence rates of HPV vaccination, and Southern adolescents had the lowest. Rural adolescents were less likely than urban adolescents to receive each vaccination except in the Northeast, where they were more likely to receive HPV vaccination (incidence rate ratio: 1.09, 95% confidence interval: 1.2005–1.13). Timely HPV vaccination was associated with female sex, urbanicity, Western residence, and later birth cohort.ConclusionsHPV vaccination occurred later than Tdap or MenACWY vaccination and was less frequent in boys and rural adolescents. Girls, Western and urban residents, and younger birth cohorts were more likely to receive timely HPV vaccination. Vaccine coadministration increased over time and may encourage timely and complete vaccination coverage

A Six-Planet System Around the Star HD 34445

We present a new precision radial velocity dataset that reveals a multi-planet system orbiting the G0V star HD 34445. Our 18-year span consists of 333 precision radial velocity observations, 56 of which were previously published, and 277 which are new data from Keck Observatory, Magellan at Las Campanas Observatory, and the Automated Planet Finder at Lick Observatory. These data indicate the presence of six planet candidates in Keplerian motion about the host star with periods of 1057, 215, 118, 49, 677, and 5700 days, and minimum masses of 0.63, 0.17, 0.1, 0.05, 0.12 and 0.38 Jupiter masses respectively. The HD 34445 planetary system, with its high degree of multiplicity, its long orbital periods, and its induced stellar radial velocity half-amplitudes in the range $2 \,{\rm m\, s^{-1}} \lesssim K \lesssim 5\,{\rm m\, s^{-1}}$ is fundamentally unlike either our own solar system (in which only Jupiter and Saturn induce significant reflex velocities for the Sun), or the Kepler multiple-transiting systems (which tend to have much more compact orbital configurations)Comment: 10 pages, 11 figure

Optimized modeling of Gaia-Hipparcos astrometry for the detection of the smallest cold Jupiter and confirmation of seven low mass companions

© 2021 The Author(s) Published by Oxford University Press on behalf of the Royal Astronomical Society. This is the accepted manuscript version of an article which has been published in final form at https://doi.org/10.1093/mnras/stab2225To fully constrain the orbits of low mass circumstellar companions, we conduct combined analyses of the radial velocity data as well as the Gaia and Hipparcos astrometric data for eight nearby systems. Our study shows that companion-induced position and proper motion differences between Gaia and Hipparcos are significant enough to constrain orbits of low mass companions to a precision comparable with previous combined analyses of direct imaging and radial velocity data. We find that our method is robust to whether we use Gaia DR2 or Gaia EDR3, as well as whether we use all of the data, or just proper motion differences. In particular, we fully characterize the orbits of HD 190360 b and HD 16160 C for the first time. With a mass of 1.8$\pm$0.2$m_{\rm Jup}$ and an effective temperature of 123-176 K and orbiting around a Sun-like star, HD 190360 b is the smallest Jupiter-like planet with well-constrained mass and orbit, belonging to a small sample of fully characterized Jupiter analogs. It is separated from its primary star by 0.25$''$ and thus may be suitable for direct imaging by the CGI instrument of the Roman Space Telescope.Peer reviewe

Further evidence for the involvement of EFL1 in a Shwachman-Diamond-like syndrome and expansion of the phenotypic features.

Recent evidence has implicated EFL1 in a phenotype overlapping Shwachman-Diamond syndrome (SDS), with the functional interplay between EFL1 and the previously known causative gene SBDS accounting for the similarity in clinical features. Relatively little is known about the phenotypes associated with pathogenic variants in the EFL1 gene, but the initial indication was that phenotypes may be more severe, when compared with SDS. We report a pediatric patient who presented with a metaphyseal dysplasia and was found to have biallelic variants in EFL1 on reanalysis of trio whole-exome sequencing data. The variant had not been initially reported because of the research laboratory's focus on de novo variants. Subsequent phenotyping revealed variability in her manifestations. Although her metaphyseal abnormalities were more severe than in the original reported cohort with EFL1 variants, the bone marrow abnormalities were generally mild, and there was equivocal evidence for pancreatic insufficiency. Despite the limited number of reported patients, variants in EFL1 appear to cause a broader spectrum of symptoms that overlap with those seen in SDS. Our report adds to the evidence of EFL1 being associated with an SDS-like phenotype and provides information adding to our understanding of the phenotypic variability of this disorder. Our report also highlights the value of exome data reanalysis when a diagnosis is not initially apparent