Phase I and pharmacokinetic (PK) study of MAG-CPT (PNU 166148): a polymeric derivative of camptothecin (CPT)

Polymeric cytotoxic conjugates are being developed with the aim of preferential delivery of the anticancer agent to tumour. MAG-CPT comprises the topoisomerase I inhibitor camptothecin linked to a water-soluble polymeric backbone methacryloylglycynamide ( average molecular weight 18 kDa, 10% CPT by weight). It was administered as a 30-min infusion once every 4 weeks to patients with advanced solid malignancies. The objectives of our study were to determine the maximum tolerated dose, dose-limiting toxicities, and the plasma and urine pharmacokinetics of MAG-CPT, and to document responses to this treatment. The starting dose was 30 mgm(-2) (dose expressed as mg equivalent camptothecin). In total, 23 patients received 47 courses at six dose levels, with a maximum dose of 240 mgm(-2). Dose-limiting toxicities were myelosuppression, neutropaenic sepsis, and diarrhoea. One patient died after cycle 1 MAG-CPT at the maximum dose. The maximum tolerated dose and dose recommended for further clinical study was 200 mgm(-2). The half-lives of both MAG-CPT and released CPT were prolonged (46 days) and measurable levels of MAG-CPT were retrieved from plasma and urine 4 weeks after treatment. However, subsequent pharmacodynamic studies of this agent have led to its withdrawal from clinical development

Geophysical studies with laser-beam detectors of gravitational waves

The existing high technology laser-beam detectors of gravitational waves may find very useful applications in an unexpected area - geophysics. To make possible the detection of weak gravitational waves in the region of high frequencies of astrophysical interest, ~ 30 - 10^3 Hz, control systems of laser interferometers must permanently monitor, record and compensate much larger external interventions that take place in the region of low frequencies of geophysical interest, ~ 10^{-5} - 3 X 10^{-3} Hz. Such phenomena as tidal perturbations of land and gravity, normal mode oscillations of Earth, oscillations of the inner core of Earth, etc. will inevitably affect the performance of the interferometers and, therefore, the information about them will be stored in the data of control systems. We specifically identify the low-frequency information contained in distances between the interferometer mirrors (deformation of Earth) and angles between the mirrors' suspensions (deviations of local gravity vectors and plumb lines). We show that the access to the angular information may require some modest amendments to the optical scheme of the interferometers, and we suggest the ways of doing that. The detailed evaluation of environmental and instrumental noises indicates that they will not prevent, even if only marginally, the detection of interesting geophysical phenomena. Gravitational-wave instruments seem to be capable of reaching, as a by-product of their continuous operation, very ambitious geophysical goals, such as observation of the Earth's inner core oscillations.Comment: 29 pages including 8 figures, modifications and clarifications in response to referees' comments, to be published in Class. Quant. Gra

Bifidobacterial ß-galactosidase-mediated production of galacto-oligosaccharides: structural and preliminary functional assessments

This work was sponsored by FrieslandCampina. DS, VA, and FB are members of APC Microbiome Ireland, which is a research center funded by Science Foundation Ireland (SFI), through the Irish Government’s National Development Plan. The authors and their work were supported by SFI (Grant SFI/12/RC/2273), FEMS Research Grant FEMS-RG-2016-0103 and project AGL2017-84614-C2-1-R funded by the Spanish Ministry of Economy, Industry and Competitiveness. OH-H has received funding from the European Union’s Horizon 2020 Research and Innovation Program under the Marie Skłodowska- Curie grant agreement no. 843950

CIRIR programs: drilling and research opportunities at the Rochechouart Impact Structure

International audienc

Cancer incidence and mortality in 23 000 patients with type 1 diabetes in the UK : long‐term follow‐up

Type 2 diabetes is associated with raised risk of several cancers, but for type 1 diabetes risk data are fewer and inconsistent We assembled a cohort of 23 473 UK patients with insulin‐treated diabetes diagnosed at ages <30, almost all of whom will have had type 1 diabetes, and for comparison 5058 diagnosed at ages 30 to 49, of whom we estimate two‐thirds will have had type 2, and followed them for an average of 30 years for cancer incidence and mortality compared with general population rates. Patients aged <30 at diabetes diagnosis had significantly raised risks only for ovarian (standardised incidence ratio = 1.58; 95% confidence interval 1.16‐2.11; P < .01) and vulval (3.55; 1.94‐5.96; P < .001) cancers, with greatest risk when diabetes was diagnosed at ages 10‐14. Risks of cancer overall (0.89; 0.84‐0.95; P < .001) and sites including lung and larynx were significantly diminished. Patients diagnosed with diabetes at ages 30 to 49 had significantly raised risks of liver (1.76;1.08‐2.72) and kidney (1.46;1.03‐2.00) cancers, and reduced risk of cancer overall (0.89; 0.84‐0.95). The raised ovarian and vulval cancer risks in patients with type 1 diabetes, especially with diabetes diagnosed around pubertal ages, suggest possible susceptibility of these organs at puberty to metabolic disruption at diabetes onset. Reduced risk of cancer overall, particularly smoking and alcohol‐related sites, might reflect adoption of a healthy lifestyle