CXD101 and nivolumab in patients with metastatic microsatellite-stable colorectal cancer (CAROSELL): a multicentre, open-label, single-arm, phase II trial.

BACKGROUND: Patients with microsatellite stable (MSS) colorectal carcinoma (CRC) do not respond to immune checkpoint inhibitors. Preclinical models suggested synergistic anti-tumour activity combining CXD101 and anti-programmed cell death protein 1 treatment; therefore, we assessed the clinical combination of CXD101 and nivolumab in heavily pre-treated patients with MSS metastatic CRC (mCRC). PATIENTS AND METHODS: This single-arm, open-label study enrolled patients aged 18 years or older with biopsy-confirmed MSS CRC; at least two lines of systemic anticancer therapies (including oxaliplatin and irinotecan); at least one measurable lesion; Eastern Cooperative Oncology Group performance status of 0, 1 or 2; predicted life expectancy above 3 months; and adequate organ and bone marrow function. Nine patients were enrolled in a safety run-in study to define a tolerable combination schedule of CXD101 and nivolumab, followed by 46 patients in the efficacy assessment phase. Patients in the efficacy assessment cohort were treated orally with 20 mg CXD101 twice daily for 5 consecutive days every 3 weeks, and intravenously with 240 mg nivolumab every 2 weeks. The primary endpoint was immune disease control rate (iDCR). RESULTS: Between 2018 and 2020, 55 patients were treated with CXD101 and nivolumab. The combination therapy was well tolerated with the most frequent grade 3 or 4 adverse events being neutropenia (18%) and anaemia (7%). Immune-related adverse reactions commonly ascribed to checkpoint inhibitors were surprisingly rare although we did see single cases of pneumonitis, hypothyroidism and hypopituitarism. There were no treatment-related deaths. Of 46 patients assessable for efficacy, 4 (9%) achieved partial response and 18 (39%) achieved stable disease, translating to an immune disease control rate of 48%. The median overall survival (OS) was 7.0 months (95% confidence interval 5.13-10.22 months). CONCLUSIONS: The primary endpoint was met in this phase II study, which showed that the combination of CXD101 and nivolumab, at full individual doses in the treatment of advanced or metastatic MSS CRC, was both well tolerated and efficacious

Optical and Infrared Spectroscopy of the type IIn SN 1998S : Days 3-127

We present contemporary infrared and optical spectroscopic observations of the type IIn SN 1998S for the period between 3 and 127 days after discovery. In the first week the spectra are characterised by prominent broad emission lines with narrow peaks superimposed on a very blue continuum(T~24000K). In the following two weeks broad, blueshifted absorption components appeared in the spectra and the temperature dropped. By day 44, broad emission components in H and He reappeared in the spectra. These persisted to 100-130d, becoming increasingly asymmetric. We agree with Leonard et al. (2000) that the broad emission lines indicate interaction between the ejecta and circumstellar material (CSM) and deduce that progenitor of SN 1998S appears to have gone through at least two phases of mass loss, giving rise to two CSM zones. Examination of the spectra indicates that the inner zone extended to <90AU, while the outer CSM extended from 185AU to over 1800AU. Analysis of high resolution spectra shows that the outer CSM had a velocity of 40-50 km/s. Assuming a constant velocity, we can infer that the outer CSM wind commenced more than 170 years ago, and ceased about 20 years ago, while the inner CSM wind may have commenced less than 9 years ago. During the era of the outer CSM wind the outflow was high, >2x10^{-5}M_{\odot}/yr corresponding to a mass loss of at least 0.003M_{\odot} and suggesting a massive progenitor. We also model the CO emission observed in SN 1998S. We deduce a CO mass of ~10^{-3} M_{\odot} moving at ~2200km/s, and infer a mixed metal/He core of ~4M_{\odot}, again indicating a massive progenitor.Comment: 22 pages, 14 figures, accepted in MNRA

Collisionless shock acceleration of narrow energy spread ion beams from mixed species plasmas using 1 μ\mum lasers

Collisionless shock acceleration of protons and C$^{6+}$ ions has been achieved by the interaction of a 10$^{20}$ W/cm$^2$, 1 $\mu$m laser with a near-critical density plasma. Ablation of the initially solid density target by a secondary laser allowed for systematic control of the plasma profile. This enabled the production of beams with peaked spectra with energies of 10-18 MeV/a.m.u. and energy spreads of 10-20$\%$ with up to 3x10$^9$ particles within these narrow spectral features. The narrow energy spread and similar velocity of ion species with different charge-to-mass ratio are consistent with acceleration by the moving potential of a shock wave. Particle-in-cell simulations show shock accelerated beams of protons and C$^{6+}$ ions with energy distributions consistent with the experiments. Simulations further indicate the plasma profile determines the trade-off between the beam charge and energy and that with additional target optimization narrow energy spread beams exceeding 100 MeV/a.m.u. can be produced using the same laser conditions.Comment: Accepted for publication in Physical Review Accelerators and Beam

Two Large HI Shells in the Outer Galaxy near l=279 degrees

As part of a survey of HI 21-cm emission in the Southern Milky Way, we have detected two large shells in the interstellar neutral hydrogen near l=279 deg. The center velocities are +36 and +59 km/s, which puts the shells at kinematic distances of 7 and 10 kpc. The larger shell is about 610 pc in diameter and very empty, with density contrast of at least 15 between the middle and the shell walls. It has expansion velocity of about 20 km/s and swept up mass of several million solar masses. The energy indicated by the expansion may be as high as 2.4 X 10^53 ergs. We estimate its age to be 15 to 20 million years. The smaller shell has diameter of about 400 pc, expansion velocity about 10 km/s and swept up mass of about 10^6 solar masses. Morphologically both regions appear to be shells, with high density regions mostly surrounding the voids, although the first appears to have channels of low density which connect with the halo above and below the HI layer. They lie on the edge of the Carina arm, which suggests that they may be expanding horizontally into the interarm region as well as vertically out of the disk. If this interpretation is correct, this is the first detection of an HI chimney which has blown out of both sides of the disk.Comment: 21 pages, 14 jpeg figures, accepted for publication in A

Comprehensive health assessments during de-institutionalization: An observational study

Background: People with intellectual disability (ID) leaving institutions pass through a transition stage that makes them vulnerable to inadequate health care. They enter into community care under general practitioners (GPs) who are often untrained and inexperienced in their needs. Specifically designed health reviews may be of assistance to both them and their new GPs as they go through that phase

Can low-carbon urban development be pro-poor? The case of Kolkata, India

Fast-growing cities in the Global South have an important role to play in climate change mitigation. However, city governments typically focus on more pressing socio-economic needs, such as reducing urban poverty. To what extent can social, economic and climate objectives be aligned? Focusing on Kolkata in India, we consider the economic case for low-carbon urban development, and assess whether these this pathway could support wider social goals. We find that Kolkata could reduce its energy bill by 8.5% and greenhouse gas emissions by 20.7% by 2025, relative to business-as-usual trends, by exploiting readily available, economically attractive mitigation options. Some of these measures offer significant social benefits, particularly in terms of public health; others jeopardise low-income urban residents’ livelihoods, housing and access to affordable services. Our findings demonstrate that municipal mitigation strategies need to be designed and delivered in collaboration with affected communities in order to minimise social costs and – possibly – achieve transformative change

Pleasure and pedagogy: the consumption of DVD add-ons among Irish teenagers

This article addresses the issue of young people and media use in the digital age, more specifically the interconnection between new media pleasures and pedagogy as they relate to the consumption of DVD add-ons. Arguing against the view of new media as having predominantly detrimental effects on young people, the authors claim that new media can enable young people to develop media literacy skills and are of the view that media literacy strategies must be based on an understanding and legitimating of young people's use patterns and pleasures. The discussion is based on a pilot research project on the use patterns and pleasures of use with a sample of Irish teenagers. They found that DVDs were used predominantly in the home context, and that, while there was variability in use between the groups, overall they developed critical literacy skills and competences which were interwoven into their social life and projects of identity construction. The authors suggest that these findings could be used to develop DVDs and their add-on features as a learning resource in the more formal educational setting and they go on to outline the potential teaching benefits of their use across a range of pedagogical areas

Timing analysis for 20 millisecond pulsars in the Parkes Pulsar Timing Array

We present timing models for 20 millisecond pulsars in the Parkes Pulsar Timing Array. The precision of the parameter measurements in these models has been improved over earlier results by using longer data sets and modelling the non-stationary noise. We describe a new noise modelling procedure and demonstrate its effectiveness using simulated data. Our methodology includes the addition of annual dispersion measure (DM) variations to the timing models of some pulsars. We present the first significant parallax measurements for PSRs J1024-0719, J1045-4509, J1600-3053, J1603-7202, and J1730-2304, as well as the first significant measurements of some post-Keplerian orbital parameters in six binary pulsars, caused by kinematic effects. Improved Shapiro delay measurements have resulted in much improved pulsar mass measurements, particularly for PSRs J0437-4715 and J1909-3744 with $M_p=1.44\pm0.07$ $M_\odot$ and $M_p=1.47\pm0.03$ $M_\odot$ respectively. The improved orbital period-derivative measurement for PSR J0437-4715 results in a derived distance measurement at the 0.16% level of precision, $D=156.79\pm0.25$ pc, one of the most fractionally precise distance measurements of any star to date.Comment: 21 pages, 5 figures, 7 tables. Accepted for publication in MNRA