Cell cycle effects of fatty acid derivatives of cytarabine, CP-4055, and of gemcitabine, CP-4126, as basis for the interaction with oxaliplatin and docetaxel

To bypass resistance due to limited entry into the cell derivatives of cytarabine (CP-4055, elacytarabine) and gemcitabine (CP-4126) containing a fatty acid chain at the 5' position of the nucleoside were developed. CP-4055 showed an increased retention of the active metabolite, the triphosphate. This characteristic was supposed to favor combinations, such as with the tubulin antagonist docetaxel, the platinum oxaliplatin and the antifolate pemetrexed. The role of the cell cycle effects of CP-4055 and CP-4126 on the efficacy of the combination with docetaxel or pemetrexed was determined. The combination of CP-4055 with oxaliplatin and docetaxel was also evaluated in a mouse xenograft model. CP-4055 induced a G2/M and S phase accumulation and CP-4126 an S phase accumulation. Both analogs induced a dose-dependent cell kill (apoptosis and necrosis). None of the docetaxel combinations induced a synergistic effect. The combination of docetaxel with CP-4055 or CP-4126 induced a G2/M accumulation in the A549 (lung cancer) cell line, but a G0/G1 accumulation in the WiDR (colon cancer) cell line. Preincubation with docetaxel induced an increased cell kill in both cell lines. The combination with oxaliplatin showed a synergistic effect in both cell lines. Combinations with pemetrexed were antagonistic in both cell lines. In the A549 cell line pemetrexed with CP-4055 led to an increase of the G0/G1 phase and the S phase. In WiDR the combination of pemetrexed with CP-4055 increased the G0/G1 phase and increased the cell kill. Pemetrexed with CP-4126 induced an increase in the G0/G1 phase and the S phase in the A549 cell line. In the xenograft study, on a colon cancer and a lung metastasis model, the combination of CP-4055 with docetaxel showed the best results. Treatment with CP-4055 followed by docetaxel after 4 h resulted in a reduction in metastasis in a lung metastasis model, and a favorable toxicity profile was observed. In conclusion, the combinations with oxaliplatin showed a synergistic effect in the combination studies. Although the combinations with docetaxel did not show an enhanced effect in the in vitro studies, this combination revealed an increased effect in the xenograft model

Competencies: requirements and acquisition

Higher education is given the key task to prepare the highly talented among the young to fulfil highly qualified roles in the labour market. Successful labour market performance of graduates is generally associated with the acquisition of the correct competencies. Education as an individual investment in human capital is a viewpoint dating back to the 17th century and the writings of Sir William Petty (1662), and includes later work by Adam Smith (1776). The idea was formalized and brought into mainstream economics by Schultz (1961), Becker (1964) and Mincer (1970, 1974). The strong supply-side orientation of the human capital theory’s determination of labour productivity has also raised serious doubts. One of the first major competitors of the human capital theory was the job competition model (Thurow, 1975), in its most extreme form explaining productivity entirely by occupational characteristics. Both the human capital theory and the job competition model in their original versions seem to be too restricted to one side of the labour market. More recently, therefore, approaches that allow explicitly for an interaction between supply-side and demand-side characteristics (‘assignment models’) have been placed centrally in analyses of education-to-work stages. For a good overview of different assignment models and their distinctive features with respect to matching models, such as proposed by Mortensen (1986), or search theories (e.g. Jovanovic, 1979), see Dupuy (2004)

Characterization and comparison of smokeless powders by on-line two-dimensional liquid chromatography

Smokeless powders (SPs) are one of the most commonly used propellants for ammunition but can also be abused as energetic material in improvised explosive devices (IEDs) such as pipe bombs. After a shooting or explosion, unburnt or partially burnt particulates may be observed which can be used for forensic investigation. SPs comprise mainly nitrocellulose (NC) and additives. Therefore, the characterization of both NC and the additives is of significant forensic importance. Typically, the identification, classification, and chemical profiling of smokeless powders are based exclusively on the analysis of the additives. In this study, information regarding the NC base component was combined with the chemical analysis of the additives using two-dimensional liquid chromatography (2D-LC). The system combines size-exclusion chromatography (SEC) and reversed-phase liquid chromatography (RPLC) in an on-line heart-cut 2D-LC configuration. In the first dimension, the NC is characterized by its molecular-weight distribution (MWD) while being separated from the additives. The additives are then transferred to the second-dimension separation using a novel analyte-transfer system. In the second dimension, the additives are separated to obtain a detailed profile of the low-molecular-mass compounds in the SP. With this approach, the MWD of the NC and the composition of the additives in SP have been obtained within an hour. A discrimination power of 90.53% was obtained when studying exclusively the NC MWD, and 99.47% for the additive profile. This novel combination enables detailed forensic comparison of intact SPs. Additionally, no extensive sample preparation is required, making the developed method less labor intensive

Immunogenicity does not influence treatment with etanercept in patients with ankylosing spondylitis

Background: Immunogenicity, specifically the onset of antibodies against tumour necrosis factor (TNF) blocking agents, seems to play an important role in non-response to treatment with these drugs. Objectives: To assess the relation of clinical response of ankylosing spondylitis (AS) to etanercept with etanercept levels, and the presence of antibodies to etanercept. Methods: Patients with AS were treated with etanercept 25 mg twice weekly, according to the international Assessment in Ankylosing Spondylitis (ASAS) working group consensus statement. Sera were collected at baseline and after 3 and 6 months of treatment. Clinical response was defined as a 50% improvement or as an absolute improvement of 2 points on a (0-10 scale) Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score. Functional etanercept levels were measured by a newly developed ELISA, measuring the binding of etanercept to TNF. Antibodies against etanercept were measured with a two-site assay and antigen binding test. Clinical data were used to correlate disease activity with serum etanercept levels. Results: In all, 53 consecutive patients were included. After 3 months of treatment 40 patients (76%) fulfilled the response criteria. Mean etanercept levels were 2.7 mg/litre and 3.0 mg/litre after 3 and 6 months respectively. Characteristics and etanercept levels of responders and non-responders were similar. No antibodies to etanercept were detected with any of the assays. Conclusion: Etanercept levels of responders and non-responders were similar and no antibodies to etanercept were detected with any of the assays. This study indicates that etanercept is much less immunogenic compared with the other TNF-blocking agent

Folates provoke cellular efflux and drug resistance of substrates of the multidrug resistance protein 1 (MRP1)

Cellular folate concentration was earlier reported to be a critical factor in the activity and expression of the multidrug resistance protein MRP1 (ABCC1). Since MRP1 mediates resistance to a variety of therapeutic drugs, we investigated whether the cellular folate concentration inf

Ensuring organization-intervention fit for a participatory organizational intervention to improve food service workers’ health and wellbeing: Workplace organizational health study

Objective: Food-service workers’ health and wellbeing is impacted by their jobs and work environments. Formative research methods were used to explore working conditions impacting workers’ health to inform intervention planning and implementation and to enhance the intervention’s ‘fit’ to the organization. Methods: Four qualitative methods (worker focus groups; manager interviews; worksite observations; multi-stakeholder workshop) explored in-depth and then prioritized working conditions impacting workers’ health as targets for an intervention. Results: Prioritized working conditions included: ergonomics; work intensity; career development and job enrichment. Data revealed necessary intervention mechanisms to enhance intervention implementation: worker and management communication infrastructure; employee participation in intervention planning and implementation; tailored worksite strategies; and ensuring leadership commitment. Conclusions: These targeted, comprehensive methods move away from a typical focus on generic working conditions, e.g. job demands and physical work environment, to explore those conditions unique to an organization. Thereby, enhancing ‘intervention-fit’ at multiple levels within the company context

Lowering dietary phosphorus concentrations reduces kidney calcification, but does not adversely affect growth, mineral metabolism, and bone development in growing rabbits

New Zealand White rabbits were used to investigate the influence of increasing dietary P concentrations on growth performance, mineral balance, kidney calcification and bone development. The minimum dietary P requirement of 0.22% (National Research Council) is usually exceeded in commercial natural-ingredient chows, leading to undesirable kidney calcifications. In order to study the optimal dietary P level, rabbits were fed semi-purified diets with four different P levels (0.1, 0.2, 0.4, and 0.8 %; w/w) at a constant dietary Ca concentration (0.5 %) during an 8-week period. Body weight and growth were not influenced by the dietary P level. During two periods (days 20-23 and 48-51), faeces and urine were collected quantitatively for the analysis of Ca, Mg and P and balances were calculated. Increased dietary P intake caused increased urinary and faecal P excretion and P apparent absorption and retention. Faecal Ca excretion increased with higher dietary P levels, whereas urinary Ca excretion reacted inversely. The apparent absorption of Ca became reduced at higher dietary P concentrations, but Ca retention was unchanged. The response of Mg was in a similar direction to that of the Ca balance. Kidney mineral content increased with higher dietary P levels, indicating the presence of calcified deposits. Nephrocalcinosis became more severe in kidney cortex and medulla at increasing dietary P levels, as was confirmed by histological analysis. Femur bone length was not differentially influenced by dietary P. Bone density (g/cm(3)) of the femur diaphysis became significantly lower at the 0.8 % dietary P level as compared with the 0.2 % P group only. The bone Mg content was significantly increased on the 0.8 % P diet, both in the diaphysis and epiphysis. Plasma P concentration increased and plasma Ca decreased with higher dietary P levels, whereas plasma Mg levels were unaffected. The present study shows that the current recommended minimum dietary P level of 0.2 % for rabbits, as advised by the National Research Council in 1977, leads to a normal growth and bone development, but also causes some degree of kidney calcifications at a dietary Ca level of 0.5 %. As the dietary P level of 0.1 % virtually prevented kidney calcification and at the same time did not give evidence for any deleterious effects on growth and bone development, this indicates that the current recommended dietary P level for rabbits should be regarded as a maximum advisable concentration, and that a lower P level may be more optimal

TERAVOLT: Thoracic Cancers International COVID-19 Collaboration.

Prior publications on small subsets of cancer patients infected with SARS CoV-2 have shown an increased risk of mortality compared to the general population. Furthermore, patients with thoracic malignancies are thought to be at particularly high risk given their older age, smoking habits, and pre-existing cardio-pulmonary comorbidities. For this reason, physicians around the world have formed TERAVOLT, a global consortium dedicated to understanding the impact of COVID-19 on patients with thoracic malignancies

Supporting Clinical Decision-Making during the SARS-CoV-2 Pandemic through a Global Research Commitment: The TERAVOLT Experience.

To understand the real impact of COVID-19 on cancer patients, an entirely new data collection effort was initiated within the Thoracic Cancers International COVID-19 Collaboration (TERAVOLT). TERAVOLT reported high mortality related to COVID-19 infection in thoracic cancer patients and identified several negative prognostic factors. In this commentary, we discuss the importance and limits of patient registries to support decision-making in thoracic cancer during the SARS-CoV-2 pandemic