Is translational research compatible with preclinical publication strategies?

The term "translational research" is used to describe the transfer of basic biological knowledge into practical medicine, a process necessary for motivation of public spending. In the area of cancer therapeutics, it is becoming increasingly evident that results obtained in vitro and in animal models are difficult to translate into clinical medicine. We here argue that a number of factors contribute to making the translation process inefficient. These factors include the use of sensitive cell lines and fast growing experimental tumors as targets for novel therapies, and the use of unrealistic drug concentrations and radiation doses. We also argue that aggressive interpretation of data, successful in hypothesis-building biological research, does not form a solid base for development of clinically useful treatment modalities. We question whether "clean" results obtained in simplified models, expected for publication in high-impact journals, represent solid foundations for improved treatment of patients. Open-access journals such as Radiation Oncology have a large mission to fulfill by publishing relevant data to be used for making actual progress in translational cancer research

Charting calcium-regulated apoptosis pathways using chemical biology: role of calmodulin kinase II

<p>Abstract</p> <p>Background</p> <p>Intracellular free calcium ([Ca²⁺]_i) is a key element in apoptotic signaling and a number of calcium-dependent apoptosis pathways have been described. We here used a chemical biology strategy to elucidate the relative importance of such different pathways.</p> <p>Results</p> <p>A set of 40 agents ("bioprobes") that induce apoptosis was first identified by screening of a chemical library. Using p53, AP-1, NFAT and NF-κB reporter cell lines, these bioprobes were verified to induce different patterns of signaling. Experiments using the calcium chelator BAPTA-AM showed that Ca²⁺was involved in induction of apoptosis by the majority of the bioprobes and that Ca²⁺was in general required several hours into the apoptosis process. Further studies showed that the calmodulin pathway was an important mediator of the apoptotic response. Inhibition of calmodulin kinase II (CaMKII) resulted in more effective inhibition of apoptosis compared to inhibition of calpain, calcineurin/PP2B or DAP kinase. We used one of the bioprobes, the plant alkaloid helenalin, to study the role of CaMKII in apoptosis. Helenalin induced CaMKII, ASK1 and Jun-N-terminal kinase (JNK) activity, and inhibition of these kinases inhibited apoptosis.</p> <p>Conclusion</p> <p>Our study shows that calcium signaling is generally not an early event during the apoptosis process and suggests that a CaMKII/ASK1 signaling mechanism is important for sustained JNK activation and apoptosis by some types of stimuli.</p

Oxaliplatin retains HMGB1 intranuclearly and ameliorates collagen type II-induced arthritis

collagen type II-induced arthriti

Concentration Dependent Ion Selectivity in VDAC: A Molecular Dynamics Simulation Study

The voltage-dependent anion channel (VDAC) forms the major pore in the outer mitochondrial membrane. Its high conducting open state features a moderate anion selectivity. There is some evidence indicating that the electrophysiological properties of VDAC vary with the salt concentration. Using a theoretical approach the molecular basis for this concentration dependence was investigated. Molecular dynamics simulations and continuum electrostatic calculations performed on the mouse VDAC1 isoform clearly demonstrate that the distribution of fixed charges in the channel creates an electric field, which determines the anion preference of VDAC at low salt concentration. Increasing the salt concentration in the bulk results in a higher concentration of ions in the VDAC wide pore. This event induces a large electrostatic screening of the charged residues promoting a less anion selective channel. Residues that are responsible for the electrostatic pattern of the channel were identified using the molecular dynamics trajectories. Some of these residues are found to be conserved suggesting that ion permeation between different VDAC species occurs through a common mechanism. This inference is buttressed by electrophysiological experiments performed on bean VDAC32 protein akin to mouse VDAC

A Shifty Target: Tumor-Initiating Cells and Their Metabolism

Tumor-initiating cells (TICs), or cancer stem cells, constitute highly chemoresistant, asymmetrically dividing, and tumor-initiating populations in cancer and are thought to play a key role in metastatic and chemoresistant disease. Tumor-initiating cells are isolated from cell lines and clinical samples based on features such as sphere formation in stem cell medium and expression of TIC markers, typically a set of outer membrane proteins and certain transcription factors. Although both bulk tumor cells and TICs show an adaptive metabolic plasticity, TIC metabolism is thought to differ and likely in a tumor-specific and growth condition-dependent pattern. In the context of some common solid tumor diseases, we here review reports on how TIC isolation methods and markers associate with metabolic features, with some focus on oxidative metabolism, including fatty acid and lipid metabolism. These have emerged as significant factors in TIC phenotypes, and in tumor biology as a whole. Other sections address mitochondrial biogenesis and dynamics in TICs, and the influence of the tumor microenvironment. Further elucidation of the complex biology of TICs and their metabolism will require advanced methodologies

Does reality meet expectations? An analysis of medical students’ expectations and perceived learning during mandatory research projects

Abstract Background Although much has been written about structure and outcomes of medical students’ curricular research projects, less attention has been paid to the expectations on such projects. In order to foster students’ scientific understanding and improve the quality of mandatory research projects, we compared students’ pre-course expectations with their post-course insights regarding learning and transferable skills. Methods A prospective cross-sectional questionnaire study. All students registered on a mandatory 20-week research project course in 2011–2013 were e-mailed questionnaires in the beginning and after the course asking them to rate statements on expectations and perceived learning on a 5-point Likert scale. Of 652 students, 358 (mean age 26 years; range 21–49; 63% females) returned both questionnaires, corresponding to a response rate of 55%. Results The ratings for expectations as well as perceived learning were highest for learning to search and critically appraise literature. The greatest pre- and post-course differences were indicated for participation in scientific discussions and oral communication. Surprisingly, both pre- and post-course ratings were low for research ethics. The highest post-course ratings regarding skills for future working life were given to items pertaining to understanding the scientific basis of medicine, ability to follow the development of knowledge and to critically integrate knowledge. Female students had higher expectations than male students. Those with a previous university degree had lower ratings of expectations and perceived learning. Students with basic science projects reported higher expectations and higher learning compared to students with other projects. Previous research experience had no significant influence on expectations nor learning. The correlations between post-course ratings of learning and skills showed that problem-solving ability had a relatively high correlation with all skills. Conclusions Students had high expectations and perceived the course improved crucial practical skills. However, expectations were not quite met regarding aspects of scientific communication, and hypothesis formulation, likely because these require more extensive practice and feedback. Students should be actively involved in ethical discussions and oral communication should be trained repeatedly as it is an important task of doctors to communicate scientific information to patients and non-experts

PGC1\u3b1: Friend or Foe in Cancer?

The PGC1 family (Peroxisome proliferator-activated receptor \uce\ub3 (PPAR \uce\ub3) coactivators) of transcriptional coactivators are considered master regulators of mitochondrial biogenesis and function. The PGC1\uce\ub1 isoform is expressed especially in metabolically active tissues, such as the liver, kidneys and brain, and responds to energy-demanding situations. Given the altered and highly adaptable metabolism of tumor cells, it is of interest to investigate PGC1\uce\ub1 in cancer. Both high and low levels of PGC1\uce\ub1 expression have been reported to be associated with cancer and worse prognosis, and PGC1\uce\ub1 has been attributed with oncogenic as well as tumor suppressive features. Early in carcinogenesis PGC1\uce\ub1 may be downregulated due to a protective anticancer role, and low levels likely reflect a glycolytic phenotype. We suggest mechanisms of PGC1\uce\ub1 downregulation and how these might be connected to the increased cancer risk that obesity is now known to entail. Later in tumor progression PGC1\uce\ub1 is often upregulated and is reported to contribute to increased lipid and fatty acid metabolism and/or a tumor cell phenotype with an overall metabolic plasticity that likely supports drug resistance as well as metastasis. We conclude that in cancer PGC1\uce\ub1 is neither friend nor foe, but rather the obedient servant reacting to metabolic and environmental cues to benefit the tumor cell