In vitro culture with gemcitabine augments death receptor and NKG2D ligand expression on tumour cells

Much effort has been made to try to understand the relationship between chemotherapeutic treatment of cancer and the immune system. Whereas much of that focus has been on the direct effect of chemotherapy drugs on immune cells and the release of antigens and danger signals by malignant cells killed by chemotherapy, the effect of chemotherapy on cells surviving treatment has often been overlooked. In the present study, tumour cell lines: A549 (lung), HCT116 (colon) and MCF-7 (breast), were treated with various concentrations of the chemotherapeutic drugs cyclophosphamide, gemcitabine (GEM) and oxaliplatin (OXP) for 24 hours in vitro. In line with other reports, GEM and OXP upregulated expression of the death receptor CD95 (fas) on live cells even at sub-cytotoxic concentrations. Further investigation revealed that the increase in CD95 in response to GEM sensitised the cells to fas ligand treatment, was associated with increased phosphorylation of stress activated protein kinase/c-Jun N-terminal kinase and that other death receptors and activatory immune receptors were co-ordinately upregulated with CD95 in certain cell lines. The upregulation of death receptors and NKG2D ligands together on cells after chemotherapy suggest that although the cells have survived preliminary treatment with chemotherapy they may now be more susceptible to immune cell-mediated challenge. This re-enforces the idea that chemotherapy-immunotherapy combinations may be useful clinically and has implications for the make-up and scheduling of such treatments

Sustainability and management of groundwater resources in the Minchin Basin, Gansu Province

This project is concerned with a study of the sustainability of irrigation agriculture in the Minqin Basin in Gansu Province, China. In this region agriculture is dependent on water supply from groundwater resources. However, recharge rates from precipitation are very low and surface flow from the Tibetan Plateau is intercepted upstream to provide water for the city ofWuwei and its region. Future climate change may further decrease supply. Already many shallow wells have been exhausted or abandoned because of salinity problems, and new wells are now being drilled to pump water from depths up to 300m

Antimicrobial Nodule-Specific Cysteine-Rich Peptides Induce Membrane Depolarization-Associated Changes in the Transcriptome of Sinorhizobium meliloti.

Leguminous plants establish symbiosis with nitrogen-fixing alpha- and betaproteobacteria, collectively called rhizobia, which provide combined nitrogen to support plant growth. Members of the inverted repeat-lacking clade of legumes impose terminal differentiation on their endosymbiotic bacterium partners with the help of the nodule-specific cysteine-rich (NCR) peptide family composed of close to 600 members. Among the few tested NCR peptides, cationic ones had antirhizobial activity measured by reduction or elimination of the CFU and uptake of the membrane-impermeable dye propidium iodide. Here, the antimicrobial spectrum of two of these peptides, NCR247 and NCR335, was investigated, and their effect on the transcriptome of the natural target Sinorhizobium meliloti was characterized. Both peptides were able to kill quickly a wide range of Gram-negative and Gram-positive bacteria; however, their spectra were only partially overlapping, and differences were found also in their efficacy on given strains, indicating that the actions of NCR247 and NCR335 might be similar though not identical. Treatment of S. meliloti cultures with either peptide resulted in a quick downregulation of genes involved in basic cellular functions, such as transcription-translation and energy production, as well as upregulation of genes involved in stress and oxidative stress responses and membrane transport. Similar changes provoked mainly in Gram-positive bacteria by antimicrobial agents were coupled with the destruction of membrane potential, indicating that it might also be a common step in the bactericidal actions of NCR247 and NCR335

Membranes by the Numbers

Many of the most important processes in cells take place on and across membranes. With the rise of an impressive array of powerful quantitative methods for characterizing these membranes, it is an opportune time to reflect on the structure and function of membranes from the point of view of biological numeracy. To that end, in this article, I review the quantitative parameters that characterize the mechanical, electrical and transport properties of membranes and carry out a number of corresponding order of magnitude estimates that help us understand the values of those parameters.Comment: 27 pages, 12 figure

Salvage for cervical recurrences of head and neck cancer with dissection and interstitial high dose rate brachytherapy

Salvage therapy in head and neck cancer (HNC) is a controversy issue and the literature is scarce regarding the use of interstitial high-dose rate brachytherapy (I-HDR) in HNC. We evaluated the long-term results of a treatment policy combining salvage surgery and I-HDR for cervical recurrences of HNC. Charts of 21 patients treated from 1994 to 2004 were reviewed. The crude local control rate for all patients was 52.4%. The 5- and 8-years overall (OS) and local relapse-free survival (LRFS) rates were 50%, 42.9%, 42.5% and 28.6%, respectively. The only predictive factor associated to LFRS and OS was negative margin status (p = 0.0007 and p = 0.0002). We conclude that complete surgery is mandatory for long term control and the doses given by brachytherapy are not high enough to compensate for microscopic residual disease after surgery

A cross-national study on the antecedents of work–life balance from the fit and balance perspective

Drawing on the perceived work–family fit and balance perspective, this study investigates demands and resources as antecedents of work–life balance (WLB) across four countries (New Zealand, France, Italy and Spain), so as to provide empirical cross-national evidence. Using structural equation modelling analysis on a sample of 870 full time employees, we found that work demands, hours worked and family demands were negatively related to WLB, while job autonomy and supervisor support were positively related to WLB. We also found evidence that resources (job autonomy and supervisor support) moderated the relationships between demands and work–life balance, with high resources consistently buffering any detrimental influence of demands on WLB. Furthermore, our study identified additional predictors of WLB that were unique to some national contexts. For example, in France and Italy, overtime hours worked were negatively associated with WLB, while parental status was positively associated with WLB. Overall, the implications for theory and practice are discussed.Peer ReviewedPostprint (author's final draft

Local Difference Measures between Complex Networks for Dynamical System Model Evaluation

Acknowledgments We thank Reik V. Donner for inspiring suggestions that initialized the work presented herein. Jan H. Feldhoff is credited for providing us with the STARS simulation data and for his contributions to fruitful discussions. Comments by the anonymous reviewers are gratefully acknowledged as they led to substantial improvements of the manuscript.Peer reviewedPublisher PD

Early‐onset coenzyme Q10 deficiency associated with ataxia and respiratory chain dysfunction due to novel pathogenic COQ8A variants, including a large intragenic deletion

Coenzyme Q10 (CoQ10) deficiency is a clinically and genetically heterogeneous subtype of mitochondrial disease. We report two girls with ataxia and mitochondrial respiratory chain deficiency who were shown to have primary CoQ10 deficiency. Muscle histochemistry displayed signs of mitochondrial dysfunction—ragged red fibers, mitochondrial paracrystalline inclusions, and lipid deposits while biochemical analyses revealed complex II+III respiratory chain deficiencies. MRI brain demonstrated cerebral and cerebellar atrophy. Targeted molecular analysis identified a homozygous c.1015G>A, p.(Ala339Thr) COQ8A variant in subject 1, while subject 2 was found to harbor a single heterozygous c.1029_1030delinsCA variant predicting a p.Gln343_Val344delinsHisMet amino acid substitution. Subsequent investigations identified a large‐scale COQ8A deletion in trans to the c.1029_1030delinsCA allele. A skin biopsy facilitated cDNA studies that confirmed exon skipping in the fibroblast derived COQ8A mRNA transcript. This report expands the molecular genetic spectrum associated with COQ8A ‐related mitochondrial disease and highlights the importance of thorough investigation of candidate pathogenic variants to establish phase. Rapid diagnosis is of the utmost importance as patients may benefit from therapeutic CoQ10 supplementation