A phase II study of raltitrexed and gemcitabine in patients with advanced pancreatic carcinoma

Advanced adenocarcinoma of the pancreas has a very poor prognosis. The aim of this study was to assess the efficacy and tolerability of a combination of the chemotherapeutic agents gemcitabine and raltitrexed. Chemonaïve patients with advanced adenocarcinoma of the pancreas were treated with a combination of raltitrexed (3.5 mg m−2 on day 1 of a 21-day treatment cycle) and gemcitabine (800 mg m−2 intravenously (i.v.) on days 1 and 8 of a 21-day cycle). Between April 2000 and February 2003, 27 patients were enrolled onto the study. The mean duration of treatment was 11 weeks. Four of 27 patients experienced at least one episode of grade 3 or 4 neutropenia. One patient with grade 4 neutropenia died due to sepsis. Four of 27 patients experienced grade 4 diarrhoea. There was one partial remission (4%) and 12 patients experienced disease stabilisation (44%). The 6-month and 1-year survival rates were 37 and 11%, respectively. Symptomatic benefit occurred in seven (26%) patients. We conclude that a combination of raltitrexed and gemcitabine, using the schedule and doses in this study, cannot be recommended for patients with advanced pancreatic cancer

Assumptions behind grammatical approaches to code-switching: when the blueprint is a red herring

Many of the so-called ‘grammars’ of code-switching are based on various underlying assumptions, e.g. that informal speech can be adequately or appropriately described in terms of ‘‘grammar’’; that deep, rather than surface, structures are involved in code-switching; that one ‘language’ is the ‘base’ or ‘matrix’; and that constraints derived from existing data are universal and predictive. We question these assumptions on several grounds. First, ‘grammar’ is arguably distinct from the processes driving speech production. Second, the role of grammar is mediated by the variable, poly-idiolectal repertoires of bilingual speakers. Third, in many instances of CS the notion of a ‘base’ system is either irrelevant, or fails to explain the facts. Fourth, sociolinguistic factors frequently override ‘grammatical’ factors, as evidence from the same language pairs in different settings has shown. No principles proposed to date account for all the facts, and it seems unlikely that ‘grammar’, as conventionally conceived, can provide definitive answers. We conclude that rather than seeking universal, predictive grammatical rules, research on CS should focus on the variability of bilingual grammars

Active PD-L1 incorporation within HIV virions functionally impairs T follicular helper cells.

The limited development of broadly neutralizing antibodies (BnAbs) during HIV infection is classically attributed to an inadequate B-cell help brought by functionally impaired T follicular helper (Tfh) cells. However, the determinants of Tfh-cell functional impairment and the signals contributing to this condition remain elusive. In the present study, we showed that PD-L1 is incorporated within HIV virions through an active mechanism involving p17 HIV matrix protein. We subsequently showed that in vitro produced PD-L1high but not PD-L1low HIV virions, significantly reduced Tfh-cell proliferation and IL-21 production, ultimately leading to a decreased of IgG1 secretion from GC B cells. Interestingly, Tfh-cell functions were fully restored in presence of anti-PD-L1/2 blocking mAbs treatment, demonstrating that the incorporated PD-L1 proteins were functionally active. Taken together, the present study unveils an immunovirological mechanism by which HIV specifically exploits the regulatory potential of PD-L1 to suppress the immune system during the course of HIV infection

57Co Production using RbCl/RbCl/58Ni Target Stacks at the Los Alamos Isotope Production Facility: LA-UR-14-22122

Introduction The Los Alamos Isotope Production Program commonly irradiates target stacks consisting of high, medium and low-energy targets in the “A-”, “B-”, and “C-slots”, respectively, with a 100MeV proton beam. The Program has recently considered the production of 57Co (t1/2 = 271.74 d, 100% EC) from 58Ni using the low-energy posi-tion of the Isotope Production Facility, down-stream of two RbCl salt targets. Initial MCNPX/ CINDER’90 studies predicted 57Co radioisotopic purities >90% depending on time allotted for decay. But these studies do not account for broadening of the proton beam’s energy distribution caused by density changes in molten, potentially boiling RbCl targets upstream of the 58Ni (see e.g., [1]). During a typical production with 230 µA average proton intensity, the RbCl targets’ temperature is expected to produce beam energy changes of several MeV and commensurate effects on the yield and purity of any radioisotope irradiated in the low-energy posi-tion of the target stack. An experiment was designed to investigate both the potential for 57Co’s large-scale production and the 2-dimensional proton beam energy distribution. Material and Methods Two aluminum targets holders were fabricated to each contain 31 58Ni discs (99.48%, Isoflex, CA), 4.76 mm (Φ) x 0.127 mm (thickness). Each foil was indexed with a unique cut pattern by EDM with a 0.254 mm brass wire to allow their position in the target to be tracked through hot cell disassembly and assay (see FIG. 1). Brass residue from EDM was removed with HNO3/HCl solution. The holders’ front windows were 2.87 and 1.37 mm thick, corresponding to predicted average incident energies of 17.9 and 24.8 MeV on the Ni [2]. Each target was irradiated with protons for 1 h with an average beam current of 218 ± 3 µA to ensure an upstream RbCl target temperature and density that would mimic routine production. Following irradiation, targets were disassembled and each disc was assayed by HPGe γ-spectroscopy. Residuals 56Co (t1/2 = 77.2 d, 100% EC) and 57Co have inversely varying measured nuclear formation cross sections between approximately 15 and 40 MeV. Results and Conclusion Distributions of 56,57,58,60Co were tracked as described in both irradiated targets. The distribution of activities matched expectations, with radioisotopes produced by proton interactions with the 58Ni target (56Co and 57Co) concentrated in the area struck by IPF’s rastered, annulus-shaped proton beam, and the distribution of radioisotopes produced by neutron-induced reactions (58Co and 60Co) relatively uniform across all irradiated foils. The potential range of such temperature variations predicted by thermal modeling (approx. ± 200 °C) corre-sponds to a density variation of nearly 0.2 g.cm−3, and a change in the average energy of protons incident on the low-energy “C-slot” of approximately 5 MeV, well-matched to the indi-rectly measured energy variation plotted in FIG. 3. No energy distribution in the plane per-pendicular to the beam axis has previously been assumed in the design of IPF targets. The effective incident energy measured by yields of 57Co and 56Co is, however, almost 5 MeV higher than those predicted using Anderson and Ziegler’s well-known formalism [2]. This discrepancy is supported by previous reports [3] and likely exacerbated compared to these reports by the large magnitude of energy degradation (from 100 MeV down to 30 MeV) in the IPF target stack. For more detailed discussion, refer to Marus et al.’s abstract, also reported at this meeting. While the experiments reported do confirm the potential for many Ci-scale yields of 57Co from months-long irradiations at the IPF, the level radioisotopic impurities 56Co and 58Co are concerning. Commercial radioisotope producers using U-150 (23 MeV) and RIC-14 (14 MeV) cyclotrons in Obninsk, Russia specify 56/58Co activities at levels <0.2% of available 57C

Cancer and renal insufficiency results of the BIRMA study

Background: Half of anticancer drugs are predominantly excreted in urine. Dosage adjustment in renal insufficiency (RI) is, therefore, a crucial issue. Moreover, patients with abnormal renal function are at high risk for drug-induced nephrotoxicity. The Belgian Renal Insufficiency and Anticancer Medications (BIRMA) study investigated the prevalence of RI in cancer patients, and the profile/dosing of anticancer drugs prescribed. Methods:Primary end point: to estimate the prevalence of abnormal glomerular filtration rate (GFR; estimated with the abbreviated Modification of Diet in Renal Disease formula) and RI in cancer patient. Secondary end point: to describe the profile of anticancer drugs prescribed (dose reduction/nephrotoxicity). Data were collected for patients presenting at one of the seven Belgian BIRMA centres in March 2006. Results: A total of 1218 patients were included. The prevalence of elevated SCR (1.2 mg per 100 ml) was 14.9%, but 64.0% had a GFR90 ml min 1 per 1.73 m 2. In all, 78.6% of treated patients (n1087) were receiving at least one drug needing dosage adjustment and 78.1% received at least one nephrotoxic drug. In all, 56.5% of RI patients receiving chemotherapy requiring dose reduction in case of RI did not receive dose adjustment. Conclusions: The RI is highly frequent in cancer patients. In all, 80% of the patients receive potentially nephrotoxic drugs and/or for which dosage must be adjusted in RI. Oncologists should check the appropriate dose of chemotherapeutic drugs in relation to renal function before prescribing. © 2010 Cancer Research UK.SCOPUS: ar.jinfo:eu-repo/semantics/publishe