Observation of Apparently Zero-Conductance States in Corbino Samples

Using Corbino samples we have observed oscillatory conductance in a high-mobility two-dimensional electron system subjected to crossed microwave and magnetic fields. On the strongest of the oscillation minima the conductance is found to be vanishingly small, possibly indicating an insulating state associated with these minima.Comment: 4 pages, 3 figures, RevTex

Nonlinear effects in microwave photoconductivity of two-dimensional electron systems

We present a model for microwave photoconductivity of two-dimensional electron systems in a magnetic field which describes the effects of strong microwave and steady-state electric fields. Using this model, we derive an analytical formula for the photoconductivity associated with photon- and multi-photon-assisted impurity scattering as a function of the frequency and power of microwave radiation. According to the developed model, the microwave conductivity is an oscillatory function of the frequency of microwave radiation and the cyclotron frequency which turns zero at the cyclotron resonance and its harmonics. It exhibits maxima and minima (with absolute negative conductivity) at the microwave frequencies somewhat different from the resonant frequencies. The calculated power dependence of the amplitude of the microwave photoconductivity oscillations exhibits pronounced sublinear behavior similar to a logarithmic function. The height of the microwave photoconductivity maxima and the depth of its minima are nonmonotonic functions of the electric field. It is pointed to the possibility of a strong widening of the maxima and minima due to a strong sensitivity of their parameters on the electric field and the presence of strong long-range electric-field fluctuations. The obtained dependences are consistent with the results of the experimental observations.Comment: 9 pages, 6 figures Labeling of the curves in Fig.3 correcte

High intratumoral dihydrotestosterone is associated with antiandrogen resistance in VCaP prostate cancer xenografts in castrated mice

Antiandrogen treatment resistance is a major clinical concern in castration-resistant prostate cancer (CRPC) treatment. Using xenografts of VCaP cells we showed that growth of antiandrogen resistant CRPC tumors were characterized by a higher intratumor dihydrotestosterone (DHT) concentration than that of treatment responsive tumors. Furthermore, the slow tumor growth after adrenalectomy was associated with a low intratumor DHT concentration. Reactivation of androgen signaling in enzalutamide-resistant tumors was further shown by the expression of several androgen-dependent genes. The data indicate that intratumor DHT concentration and expression of several androgen-dependent genes in CRPC lesions is an indication of enzalutamide treatment resistance and an indication of the need for further androgen blockade. The presence of an androgen synthesis, independent of CYP17A1 activity, has been shown to exist in prostate cancer cells, and thus, novel androgen synthesis inhibitors are needed for the treatment of enzalutamide-resistant CRPC tumors that do not respond to abiraterone.Peer reviewe

Contrasting Cases: The Lotka-Volterra Model Times Three

How do philosophers of science make use of historical case studies? Are their accounts of historical cases purpose-built and lacking in evidential strength as a result of putting forth and discussing philosophical positions? We will study these questions through the examination of three different philosophical case studies. All of them focus on modeling and on Vito Volterra, contrasting his work to that of other theoreticians. We argue that the worries concerning the evidential role of historical case studies in philosophy are partially unfounded, and the evidential and hermeneutical roles of case studies need not be played against each other. In philosophy of science, case studies are often tied to conceptual and theoretical analysis and development, rendering their evidential and theoretic/hermeneutic roles intertwined. Moreover, the problems of resituating or generalizing local knowledge are not specific to philosophy of science but commonplace in many scientific practices—which show similarities to the actual use of historical case studies by philosophers of science

Adrenals Contribute to Growth of Castration-Resistant VCaP Prostate Cancer Xenografts

The role of adrenal androgens as drivers for castration-resistant prostate cancer (CRPC) growth in humans is generally accepted; however, the value of preclinical mouse models of CRPC is debatable, because mouse adrenals do not produce steroids activating the androgen receptor. In this study, we confirmed the expression of enzymes essential for de novo synthesis of androgens in mouse adrenals, with high intratissue concentration of progesterone (P-4) and moderate levels of androgens, such as androstenedione, testosterone, and dihydrotestosterone, in the adrenal glands of both intact and orchectomized (ORX) mice. ORX alone had no effect on serum P-4 concentration, whereas orchectomized and adrenalectomized (ORX + ADX) resulted in a significant decrease in serum P-4 and in a further reduction in the Low levels of serum androgens (androstenedione, testosterone, and dihydrotestosterone), measured by mass spectrometry. In line with this, the serum prostate-specific antigen and growth of VCaP xenografts in mice after ORX + ADX were markedly reduced compared with ORX alone, and the growth difference was not abolished by a glucocorticoid treatment. Moreover, ORX + ADX altered the androgen-dependent gene expression in the tumors, similar to that recently shown for the enzalutamide treatment. These data indicate that in contrast to the current view, and similar to humans, mouse adrenals synthesize significant amounts of steroids that contribute to the androgen receptor dependent growth of CRPC.Peer reviewe

Adjuvant chemotherapy for resected early-stage non-small cell lung cancer

BACKGROUND: To evaluate the effects of administering chemotherapy following surgery, or following surgery plus radiotherapy (known as adjuvant chemotherapy) in patients with early stage non-small cell lung cancer (NSCLC),we performed two systematic reviews and meta-analyses of all randomised controlled trials using individual participant data. Results were first published in The Lancet in 2010. OBJECTIVES: To compare, in terms of overall survival, time to locoregional recurrence, time to distant recurrence and recurrence-free survival:A. Surgery versus surgery plus adjuvant chemotherapyB. Surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapyin patients with histologically diagnosed early stage NSCLC.(2)To investigate whether or not predefined patient subgroups benefit more or less from cisplatin-based chemotherapy in terms of survival. SEARCH METHODS: We supplemented MEDLINE and CANCERLIT searches (1995 to December 2013) with information from trial registers, handsearching relevant meeting proceedings and by discussion with trialists and organisations. SELECTION CRITERIA: We included trials of a) surgery versus surgery plus adjuvant chemotherapy; and b) surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapy, provided that they randomised NSCLC patients using a method which precluded prior knowledge of treatment assignment. DATA COLLECTION AND ANALYSIS: We carried out a quantitative meta-analysis using updated information from individual participants from all randomised trials. Data from all patients were sought from those responsible for the trial. We obtained updated individual participant data (IPD) on survival, and date of last follow-up, as well as details of treatment allocated, date of randomisation, age, sex, histological cell type, stage, and performance status. To avoid potential bias, we requested information for all randomised patients, including those excluded from the investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of survival. For trials using cisplatin-based regimens, we carried out subgroup analyses by age, sex, histological cell type, tumour stage, and performance status. MAIN RESULTS: We identified 35 trials evaluating surgery plus adjuvant chemotherapy versus surgery alone. IPD were available for 26 of these trials and our analyses are based on 8447 participants (3323 deaths) in 34 trial comparisons. There was clear evidence of a benefit of adding chemotherapy after surgery (hazard ratio (HR)= 0.86, 95% confidence interval (CI)= 0.81 to 0.92, p< 0.0001), with an absolute increase in survival of 4% at five years.We identified 15 trials evaluating surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy alone. IPD were available for 12 of these trials and our analyses are based on 2660 participants (1909 deaths) in 13 trial comparisons. There was also evidence of a benefit of adding chemotherapy to surgery plus radiotherapy (HR= 0.88, 95% CI= 0.81 to 0.97, p= 0.009). This represents an absolute improvement in survival of 4% at five years.For both meta-analyses, we found similar benefits for recurrence outcomes and there was little variation in effect according to the type of chemotherapy, other trial characteristics or patient subgroup.We did not undertake analysis of the effects of adjuvant chemotherapy on quality of life and adverse events. Quality of life information was not routinely collected during the trials, but where toxicity was assessed and mentioned in the publications, it was thought to be manageable. We considered the risk of bias in the included trials to be low. AUTHORS' CONCLUSIONS: Results from 47 trial comparisons and 11,107 patients demonstrate the clear benefit of adjuvant chemotherapy for these patients, irrespective of whether chemotherapy was given in addition to surgery or surgery plus radiotherapy. This is the most up-to-date and complete systematic review and individual participant data (IPD) meta-analysis that has been carried out

Lysophosphatidic acid and sphingosine-1-phosphate promote morphogenesis and block invasion of prostate cancer cells in three-dimensional organotypic models

Normal prostate and some malignant prostate cancer (PrCa) cell lines undergo acinar differentiation and form spheroids in three-dimensional (3-D) organotypic culture. Acini formed by PC-3 and PC-3M, less pronounced also in other PrCa cell lines, spontaneously undergo an invasive switch, leading to the disintegration of epithelial structures and the basal lamina, and formation of invadopodia. This demonstrates the highly dynamic nature of epithelial plasticity, balancing epithelial-to-mesenchymal transition against metastable acinar differentiation. This study assessed the role of lipid metabolites on epithelial maturation. PC-3 cells completely failed to form acinar structures in delipidated serum. Adding back lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) rescued acinar morphogenesis and repressed invasion effectively. Blocking LPA receptor 1 (LPAR1) functions by siRNA (small interference RNA) or the specific LPAR1 inhibitor Ki16425 promoted invasion, while silencing of other G-protein-coupled receptors responsive to LPA or S1P mainly caused growth arrest or had no effects. The G-proteins Gα12/13 and Gαi were identified as key mediators of LPA signalling via stimulation of RhoA and Rho kinases ROCK1 and 2, activating Rac1, while inhibition of adenylate cyclase and accumulation of cAMP may be secondary. Interfering with these pathways specifically impeded epithelial polarization in transformed cells. In contrast, blocking the same pathways in non-transformed, normal cells promoted differentiation. We conclude that LPA and LPAR1 effectively promote epithelial maturation and block invasion of PrCa cells in 3-D culture. The analysis of clinical transcriptome data confirmed reduced expression of LPAR1 in a subset of PrCa's. Our study demonstrates a metastasis-suppressor function for LPAR1 and Gα12/13 signalling, regulating cell motility and invasion versus epithelial maturation

The interpretations and uses of fitness landscapes in the social sciences

__Abstract__ This working paper precedes our full article entitled “The evolution of Wright’s (1932) adaptive field to contemporary interpretations and uses of fitness landscapes in the social sciences” as published in the journal Biology & Philosophy (http://link.springer.com/article/10.1007/s10539-014-9450-2). The working paper features an extended literature overview of the ways in which fitness landscapes have been interpreted and used in the social sciences, for which there was not enough space in the full article. The article features an in-depth philosophical discussion about the added value of the various ways in which fitness landscapes are used in the social sciences. This discussion is absent in the current working paper. Th

Postulated Vasoactive Neuropeptide Autoimmunity in Fatigue-Related Conditions: A Brief Review and Hypothesis

Disorders such as chronic fatigue syndrome (CFS) and gulf war syndrome (GWS) are characterised by prolonged fatigue and a range of debilitating symptoms of pain, intellectual and emotional impairment, chemical sensitivities and immunological dysfunction. Sudden infant death syndrome (SIDS) surprisingly may have certain features in common with these conditions. Post-infection sequelae may be possible contributing factors although ongoing infection is unproven. Immunological aberration may prove to be associated with certain vasoactive neuropeptides (VN) in the context of molecular mimicry, inappropriate immunological memory and autoimmunity