Cell-Penetrating Peptides as a Tool for the Cellular Uptake of a Genetically Modified Nitroreductase for use in Directed Enzyme Prodrug Therapy

Directed enzyme prodrug therapy (DEPT) involves the delivery of a prodrug-activating enzyme to a solid tumour site, followed by the subsequent activation of an administered prodrug. One of the most studied enzyme–prodrug combinations is the nitroreductase from Escherichia coli (NfnB) with the prodrug CB1954 [5-(aziridin-1-yl)-2,4-dinitro-benzamide]. One of the major issues faced by DEPT is the ability to successfully internalize the enzyme into the target cells. NfnB has previously been genetically modified to contain cysteine residues (NfnB-Cys) which bind to gold nanoparticles for a novel DEPT therapy called magnetic nanoparticle directed enzyme prodrug therapy (MNDEPT). One cellular internalisation method is the use of cell-penetrating peptides (CPPs), which aid cellular internalization of cargo. Here the cell-penetrating peptides: HR9 and Pep-1 were tested for their ability to conjugate with NfnB-Cys. The conjugates were further tested for their potential use in MNDEPT, as well as conjugating with the delivery vector intended for use in MNDEPT and tested for the vectors capability to penetrate into cells

Who wants to be involved in health care decisions? Comparing preferences for individual and collective involvement in England and Sweden

Background: Patient and public involvement (PPI) is framed as positive for individuals, the health system, public health, as well as for communities and society as a whole. We investigated whether preferences for PPI differed between two countries with Beveridge type health systems-Sweden and England. We measured willingness to be involved in individual treatment decisions and in decisions about the organization and provision of local health and social care services. Methods: This was a comparative cross-sectional study of the general population's preferences. Together, the two samples included 3125 respondents; 1625 in England and 1500 in Sweden. Country differences were analysed in a multinomial regression model controlling for gender, age and educational attainment. Results: Overall, 68% of respondents wanted a passive patient role and 44% wanted to be involved in local decisions about organization and provision of services. In comparison with in Sweden, they were in England less likely to want a health professional such as a GP or consultant to make decisions about their treatment and also more likely to want to make their own decisions. They were also less likely to want to be involved in local service development decisions. An increased likelihood of wanting to be involved in organizational decision-making was associated with individuals wanting to make their own treatment decisions. Women were less likely to want health professionals to make decisions and more likely to want to be involved in organizational decisions. Conclusions: An effective health system that ensures public health must integrate an effective approach to PPI both in individual treatment decisions and shaping local health and social care priorities. To be effective, involvement activities must take in to account the variation in the desire for involvement and the implications that this has for equity. More work is needed to understand the relationship between the desire to be involved and actually being involved, but both appear related to judgements of the impact of involvement on health care decisions

Landsat 9 Thermal Infrared Sensor 2 Architecture and Design

The Thermal Infrared Sensor 2 (TIRS-2) will fly aboard the Landsat 9 spacecraft and leverages the Thermal Infrared Sensor (TIRS) design currently flying on Landsat 8. TIRS-2 will provide similar science data as TIRS, but is not a buildto-print rebuild due to changes in requirements and improvements in absolute accuracy. The heritage TIRS design has been modified to reduce the influence of stray light and to add redundancy for higher reliability over a longer mission life. The TIRS-2 development context differs from the TIRS scenario, adding to the changes. The TIRS-2 team has also learned some lessons along the way

Flight of the Bumblebee: the Early Excess Flux of Type Ia Supernova 2023bee revealed by TESSTESS, SwiftSwift and Young Supernova Experiment Observations

We present high-cadence ultraviolet through near-infrared observations of the Type Ia supernova (SN Ia) 2023bee in NGC~2708 ($D = 32 \pm 3$ Mpc), finding excess flux in the first days after explosion relative to the expected power-law rise from an expanding fireball. This deviation from typical behavior for SNe Ia is particularly obvious in our 10-minute cadence $TESS$ light curve and $Swift$ UV data. Compared to a few other normal SNe Ia with detected early excess flux, the excess flux in SN 2023bee is redder in the UV and less luminous. We present optical spectra of SN 2023bee, including two spectra during the period where the flux excess is dominant. At this time, the spectra are similar to those of other SNe Ia but with weaker Si II, C II and Ca II absorption lines, perhaps because the excess flux creates a stronger continuum. We compare the data to several theoretical models that have been proposed to explain the early flux excess in SNe Ia. Interaction with either a nearby companion star or close-in circumstellar material is expected to produce a faster evolution than seen in the data. Radioactive material in the outer layers of the ejecta, either from a double detonation explosion or simply an explosion with a $^{56}$Ni clump near the surface, can not fully reproduce the evolution either, likely due to the sensitivity of early UV observable to the treatment of the outer part of ejecta in simulation. We conclude that no current model can adequately explain the full set of observations. We find that a relatively large fraction of nearby, bright SNe Ia with high-cadence observations have some amount of excess flux within a few days of explosion. Considering potential asymmetric emission, the physical cause of this excess flux may be ubiquitous in normal SNe Ia.Comment: 21 pages, 12 figures. Accepted by the astrophysical journa

The management and outcome for patients with chronic subdural hematoma: a prospective, multicenter, observational cohort study in the United Kingdom

Symptomatic chronic subdural hematoma (CSDH) will become an increasingly common presentation in neurosurgical practice as the population ages, but quality evidence is still lacking to guide the optimal management for these patients. The British Neurosurgical Trainee Research Collaborative (BNTRC) was established by neurosurgical trainees in 2012 to improve research by combining the efforts of trainees in each of the United Kingdom (UK) and Ireland's neurosurgical units (NSUs). The authors present the first study by the BNTRC that describes current management and outcomes for patients with CSDH throughout the UK and Ireland. This provides a resource both for current clinical practice and future clinical research on CSDH

SN 2022oqm: A Multi-peaked Calcium-rich Transient from a White Dwarf Binary Progenitor System

We present the photometric and spectroscopic evolution of SN 2022oqm, a nearby multi-peaked hydrogen- and helium-weak calcium-rich transient (CaRT). SN 2022oqm was detected 19.9 kpc from its host galaxy, the face-on spiral galaxy NGC 5875. Extensive spectroscopic coverage reveals a hot (T >= 40,000 K) continuum and carbon features observed ~1 day after discovery, SN Ic-like photospheric-phase spectra, and strong forbidden calcium emission starting 38 days after discovery. SN 2022oqm has a relatively high peak luminosity (MB = -17 mag) for CaRTs, making it an outlier in the population. We determine that three power sources are necessary to explain SN 2022oqm's light curve, with each power source corresponding to a distinct peak in its light curve. The first peak of the light curve is powered by an expanding blackbody with a power law luminosity, consistent with shock cooling by circumstellar material. Subsequent peaks are powered by a double radioactive decay model, consistent with two separate sources of photons diffusing through an optically thick ejecta. From the optical light curve, we derive an ejecta mass and 56Ni mass of ~0.89 solar masses and ~0.09 solar masses, respectively. Detailed spectroscopic modeling reveals ejecta that is dominated by intermediate-mass elements, with signs that Fe-peak elements have been well-mixed. We discuss several physical origins for SN 2022oqm and favor a white dwarf progenitor model. The inferred ejecta mass points to a surprisingly massive white dwarf, challenging models of CaRT progenitors.Comment: 33 pages, 17 figures, 5 tables, Submitted to Ap

The Gravity Collective: A Search for the Electromagnetic Counterpart to the Neutron Star-Black Hole Merger GW190814

We present optical follow-up imaging obtained with the Katzman Automatic Imaging Telescope, Las Cumbres Observatory Global Telescope Network, Nickel Telescope, Swope Telescope, and Thacher Telescope of the LIGO/Virgo gravitational wave (GW) signal from the neutron star-black hole (NSBH) merger GW190814. We searched the GW190814 localization region (19 deg$^{2}$ for the 90th percentile best localization), covering a total of 51 deg$^{2}$ and 94.6% of the two-dimensional localization region. Analyzing the properties of 189 transients that we consider as candidate counterparts to the NSBH merger, including their localizations, discovery times from merger, optical spectra, likely host-galaxy redshifts, and photometric evolution, we conclude that none of these objects are likely to be associated with GW190814. Based on this finding, we consider the likely optical properties of an electromagnetic counterpart to GW190814, including possible kilonovae and short gamma-ray burst afterglows. Using the joint limits from our follow-up imaging, we conclude that a counterpart with an $r$-band decline rate of 0.68 mag day$^{-1}$, similar to the kilonova AT 2017gfo, could peak at an absolute magnitude of at most $-17.8$ mag (50% confidence). Our data are not constraining for ''red'' kilonovae and rule out ''blue'' kilonovae with $M>0.5 M_{\odot}$ (30% confidence). We strongly rule out all known types of short gamma-ray burst afterglows with viewing angles $<$17$^{\circ}$ assuming an initial jet opening angle of $\sim$$5.2^{\circ}$ and explosion energies and circumburst densities similar to afterglows explored in the literature. Finally, we explore the possibility that GW190814 merged in the disk of an active galactic nucleus, of which we find four in the localization region, but we do not find any candidate counterparts among these sources.Comment: 86 pages, 9 figure

Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease:results from the IMmunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study

BACKGROUND: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD).AIM: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab.RESULTS: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p &lt; 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p &lt; 0.001) and 1.99 (95%CI 1.34-2.99, p &lt; 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p &lt; 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure.CONCLUSION: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure

Implications for sequencing of biologic therapy and choice of second anti-TNF in patients with inflammatory bowel disease:results from the IMmunogenicity to Second Anti-TNF therapy (IMSAT) therapeutic drug monitoring study

BACKGROUND: Anti-drug antibodies are associated with treatment failure to anti-TNF agents in patients with inflammatory bowel disease (IBD).AIM: To assess whether immunogenicity to a patient's first anti-TNF agent would be associated with immunogenicity to the second, irrespective of drug sequence METHODS: We conducted a UK-wide, multicentre, retrospective cohort study to report rates of immunogenicity and treatment failure of second anti-TNF therapies in 1058 patients with IBD who underwent therapeutic drug monitoring for both infliximab and adalimumab. The primary outcome was immunogenicity to the second anti-TNF agent, defined at any timepoint as an anti-TNF antibody concentration ≥9 AU/ml for infliximab and ≥6 AU/ml for adalimumab.RESULTS: In patients treated with infliximab and then adalimumab, those who developed antibodies to infliximab were more likely to develop antibodies to adalimumab, than patients who did not develop antibodies to infliximab (OR 1.99, 95%CI 1.27-3.20, p = 0.002). Similarly, in patients treated with adalimumab and then infliximab, immunogenicity to adalimumab was associated with subsequent immunogenicity to infliximab (OR 2.63, 95%CI 1.46-4.80, p &lt; 0.001). For each 10-fold increase in anti-infliximab and anti-adalimumab antibody concentration, the odds of subsequently developing antibodies to adalimumab and infliximab increased by 1.73 (95% CI 1.38-2.17, p &lt; 0.001) and 1.99 (95%CI 1.34-2.99, p &lt; 0.001), respectively. Patients who developed immunogenicity with undetectable drug levels to infliximab were more likely to develop immunogenicity with undetectable drug levels to adalimumab (OR 2.37, 95% CI 1.39-4.19, p &lt; 0.001). Commencing an immunomodulator at the time of switching to the second anti-TNF was associated with improved drug persistence in patients with immunogenic, but not pharmacodynamic failure.CONCLUSION: Irrespective of drug sequence, immunogenicity to the first anti-TNF agent was associated with immunogenicity to the second, which was mitigated by the introduction of an immunomodulator in patients with immunogenic, but not pharmacodynamic treatment failure