Increased sensitivity to gemcitabine of P-glycoprotein and multidrug resistance-associated protein-overexpressing human cancer cell lines

0.05), respectively. P-glycoprotein and MRP1 overexpression possibly caused a cellular stress resulting in increased gemcitabine metabolism and sensitivity, while reversal of collateral gemcitabine sensitivity by verapamil also suggests a direct relation between the presence of membrane efflux pumps and gemcitabine sensitivity

Chronic musculoskeletal pain predicted hospitalisation due to serious medical conditions in a 10 year follow up study

BACKGROUND: The aim was to examine if self reported chronic regional pain (CRP) and chronic widespread pain (CWP) predicted inpatient care due to serious medical conditions such as cerebrovascular diseases, ischemic heart diseases, neoplasms and infectious diseases in a general population cohort over a ten year follow-up period.METHODS: A ten-year follow up of a cohort from the general adult population in two health care districts with mixed urban and rural population in the south of Sweden, that in 1995 participated in a survey on health and musculoskeletal pain experience. Information on hospitalisation for each subject was taken from the regional health care register. Multiple logistic regression analyses were used to study the associations between chronic musculoskeletal pain and different medical conditions as causes of hospitalisation.RESULTS: A report of CRP (OR = 1.6; p < 0.001) or CWP ( OR = 2.1; p < 0.001) predicted at least one episode of inpatient care over a ten year period, with an increased risk in almost all diagnostic subgroups, including cerebrovascular diseases, ischemic heart diseases, and infectious diseases. There was however no increased risk of hospitalisation due to neoplasms.CONCLUSIONS: The presence of especially CWP was associated with hospital inpatient care due to several serious medical disorders. This may imply a general vulnerability to different medical conditions that has to be addressed in the assessment and management of subjects with chronic musculoskeletal pain

Inverse magnetic catalysis in dense holographic matter

We study the chiral phase transition in a magnetic field at finite temperature and chemical potential within the Sakai-Sugimoto model, a holographic top-down approach to (large-N_c) QCD. We consider the limit of a small separation of the flavor D8-branes, which corresponds to a dual field theory comparable to a Nambu-Jona Lasinio (NJL) model. Mapping out the surface of the chiral phase transition in the parameter space of magnetic field strength, quark chemical potential, and temperature, we find that for small temperatures the addition of a magnetic field decreases the critical chemical potential for chiral symmetry restoration - in contrast to the case of vanishing chemical potential where, in accordance with the familiar phenomenon of magnetic catalysis, the magnetic field favors the chirally broken phase. This "inverse magnetic catalysis" (IMC) appears to be associated with a previously found magnetic phase transition within the chirally symmetric phase that shows an intriguing similarity to a transition into the lowest Landau level. We estimate IMC to persist up to 10^{19} G at low temperatures.Comment: 42 pages, 11 figures, v3: extended discussion; new appendix D; references added; version to appear in JHE

Formation of regulatory modules by local sequence duplication

Turnover of regulatory sequence and function is an important part of molecular evolution. But what are the modes of sequence evolution leading to rapid formation and loss of regulatory sites? Here, we show that a large fraction of neighboring transcription factor binding sites in the fly genome have formed from a common sequence origin by local duplications. This mode of evolution is found to produce regulatory information: duplications can seed new sites in the neighborhood of existing sites. Duplicate seeds evolve subsequently by point mutations, often towards binding a different factor than their ancestral neighbor sites. These results are based on a statistical analysis of 346 cis-regulatory modules in the Drosophila melanogaster genome, and a comparison set of intergenic regulatory sequence in Saccharomyces cerevisiae. In fly regulatory modules, pairs of binding sites show significantly enhanced sequence similarity up to distances of about 50 bp. We analyze these data in terms of an evolutionary model with two distinct modes of site formation: (i) evolution from independent sequence origin and (ii) divergent evolution following duplication of a common ancestor sequence. Our results suggest that pervasive formation of binding sites by local sequence duplications distinguishes the complex regulatory architecture of higher eukaryotes from the simpler architecture of unicellular organisms

Experimental modulation of capsule size in Cryptococcus neoformans

Experimental modulation of capsule size is an important technique for the study of the virulence of the encapsulated pathogen Cryptococcus neoformans. In this paper, we summarize the techniques available for experimental modulation of capsule size in this yeast and describe improved methods to induce capsule size changes. The response of the yeast to the various stimuli is highly dependent on the cryptococcal strain. A high CO(2) atmosphere and a low iron concentration have been used classically to increase capsule size. Unfortunately, these stimuli are not reliable for inducing capsular enlargement in all strains. Recently we have identified new and simpler conditions for inducing capsule enlargement that consistently elicited this effect. Specifically, we noted that mammalian serum or diluted Sabouraud broth in MOPS buffer pH 7.3 efficiently induced capsule growth. Media that slowed the growth rate of the yeast correlated with an increase in capsule size. Finally, we summarize the most commonly used media that induce capsule growth in C. neoformans

Observer-Based State Feedback for Enhanced Insulin Control of Type ‘I’ Diabetic Patients

During the past few decades, biomedical modeling techniques have been applied to improve performance of a wide variety of medical systems that require monitoring and control. Diabetes is one of the most important medical problems. This paper focuses on designing a state feedback controller with observer to improve the performance of the insulin control for type ‘I’ diabetic patients. The dynamic model of glucose levels in diabetic patients is a nonlinear model. The system is a typical fourth-order single-input-single-output state space model. Using a linear time invariant controller based on an operating condition is a common method to simplify control design. On the other hand, adaptive control can potentially improve system performance. But it increases control complexity and may create further stability issues. This paper investigates patient models and presents a simplified control scheme using observer-based feedback controllers. By comparing different control schemes, it shows that a properly designed state feedback controller with observer can eliminate the adaptation strategy that the Proportional-Integral-Derivative (PID) controllers need to improve the control performance. Control strategies are simulated and their performance is evaluated in MATLAB and Simulink

Interaction between gemcitabine and topotecan in human non-small-cell lung cancer cells: effects on cell survival, cell cycle and pharmacogenetic profile

The pyrimidine analogue gemcitabine is an established effective agent in the treatment of non-small-cell lung cancer (NSCLC). The present study investigates whether gemcitabine would be synergistic with the topoisomerase I inhibitor topotecan against the NSCLC A549 and Calu-6 cells. Cells were treated with gemcitabine and topotecan for 1 h and the type of drug interaction was assessed using the combination index (CI). Cell cycle alterations were analysed by flow cytometry, while apoptosis was examined by the occurrence of DNA internucleosomal fragmentation, nuclear condensation and caspase-3 activation. Moreover, the possible involvement of the PI3K-Akt signalling pathway was investigated by the measurement of Akt phosphorylation. Finally, quantitative, real-time PCR (QRT-PCR) was used to study modulation of the gemcitabine-activating enzyme deoxycytidine kinase (dCK) and the cellular target enzyme ribonucleotide reductase (RR). In results, it was found that simultaneous and sequential topotecan → gemcitabine treatments were synergistic, while the reverse sequence was antagonistic in both cell lines. DNA fragmentation, nuclear condensation and enhanced caspase-3 activity demonstrated that the drug combination markedly increased apoptosis in comparison with either single agent, while cell cycle analysis showed that topotecan increased cells in S phase. Furthermore, topotecan treatment significantly decreased the amount of the activated form of Akt, and enhanced the expression of dCK (+155.0 and +115.3% in A549 and Calu-6 cells, respectively), potentially facilitating gemcitabine activity. In conclusion, these results indicate that the combination of gemcitabine and topotecan displays schedule-dependent activity in vitro against NSCLC cells. The gemcitabine → topotecan sequence is antagonistic while drug synergism is obtained with the simultaneous and the sequential topotecan → gemcitabine combinations, which are associated with induction of decreased Akt phosphorylation and increased dCK expression

The ABCDEF's of Matrix Models for Supersymmetric Chern-Simons Theories

We consider N = 3 supersymmetric Chern-Simons gauge theories with product unitary and orthosymplectic groups and bifundamental and fundamental fields. We study the partition functions on an S^3 by using the Kapustin-Willett-Yaakov matrix model. The saddlepoint equations in a large N limit lead to a constraint that the long range forces between the eigenvalues must cancel; the resulting quiver theories are of affine Dynkin type. We introduce a folding/unfolding trick which lets us, at the level of the large N matrix model, (i) map quivers with orthosymplectic groups to those with unitary groups, and (ii) obtain non-simply laced quivers from the corresponding simply laced quivers using a Z_2 outer automorphism. The brane configurations of the quivers are described in string theory and the folding/unfolding is interpreted as the addition/subtraction of orientifold and orbifold planes. We also relate the U(N) quiver theories to the affine ADE quiver matrix models with a Stieltjes-Wigert type potential, and derive the generalized Seiberg duality in 2 + 1 dimensions from Seiberg duality in 3 + 1 dimensions.Comment: 30 pages, 5 figure

Knee complaints vary with age and gender in the adult population. Population-based reference data for the Knee injury and Osteoarthritis Outcome Score (KOOS)

BACKGROUND: Self-reported knee complaints may vary with age and gender. Reference data from the adult population would help to better interpret the outcome of interventions due to knee complaints. The objectives of the present study were to describe the variation of self-reported knee pain, function and quality of life with age and gender in the adult population and to establish population-based reference data for the Knee injury and Osteoarthritis Outcome Score (KOOS). METHODS: Population-based cohort retrieved from the national population register. The knee-specific Knee injury and Osteoarthritis Outcome Score (KOOS) was mailed to 840 subjects aged 18–84 yrs. RESULTS: 68% response rate. Women in the age group 55–74 reported more knee-related complaints in all the KOOS subscales than age-matched men. The differences were significant for the subscales Pain (p = 0.027), Symptoms (p = 0.003) and ADL function (p = 0.046). In men, worse ADL and Sport and Recreation function was seen in the oldest age group 75–84 years compared to the younger age groups (p < 0.030). In women, worse Pain (p < 0.007), ADL (p < 0.030), Sport and Recreation (p < 0.001) and QOL (p < 0.002) were seen already in the age group 55–74 compared to the younger age groups. CONCLUSION: We found pain and other symptoms, physical function, and knee-related quality of life to vary with age and gender implying the use of age- and gender matched reference values for improved understanding of the outcome after interventions due to knee injury and knee OA