Effect of anti-inflammatory agents on transforming growth factor beta over-expressing mouse brains: a model revised.

BACKGROUND: The over-expression of transforming growth factor beta-1(TGF-beta1) has been reported to cause hydrocephalus, glia activation, and vascular amyloidbeta (Abeta) deposition in mouse brains. Since these phenomena partially mimic the cerebral amyloid angiopathy (CAA) concomitant to Alzheimer's disease, the findings in TGF-beta1 over-expressing mice prompted the hypothesis that CAA could be caused or enhanced by the abnormal production of TGF-beta1. This idea was in accordance with the view that chronic inflammation contributes to Alzheimer's disease, and drew attention to the therapeutic potential of anti-inflammatory drugs for the treatment of Abeta-elicited CAA. We thus studied the effect of anti-inflammatory drug administration in TGF-beta1-induced pathology. METHODS: Two-month-old TGF-beta1 mice and littermate controls were orally administered pioglitazone, a peroxisome proliferator-activated receptor-gamma agonist, or ibuprofen, a non steroidal anti-inflammatory agent, for two months. Glia activation was assessed by immunohistochemistry and western blot analysis; Abeta precursor protein (APP) by western blot analysis; Abeta deposition by immunohistochemistry, thioflavin-S staining and ELISA; and hydrocephalus by measurements of ventricle size on autoradiographies of brain sections. Results are expressed as means +/- SD. Data comparisons were carried with the Student's T test when two groups were compared, or ANOVA analysis when more than three groups were analyzed. RESULTS: Animals displayed glia activation, hydrocephalus and a robust thioflavin-S-positive vascular deposition. Unexpectedly, these deposits contained no Abeta or serum amyloid P component, a common constituent of amyloid deposits. The thioflavin-S-positive material thus remains to be identified. Pioglitazone decreased glia activation and basal levels of Abeta42- with no change in APP contents - while it increased hydrocephalus, and had no effect on the thioflavin-S deposits. Ibuprofen mimicked the reduction of glia activation caused by pioglitazone and the lack of effect on the thioflavin-S-labeled deposits. CONCLUSIONS: i) TGF-beta1 over-expressing mice may not be an appropriate model of Abeta-elicited CAA; and ii) pioglitazone has paradoxical effects on TGF-beta1-induced pathology suggesting that anti-inflammatory therapy may reduce the damage resulting from active glia, but not from vascular alterations or hydrocephalus. Identification of the thioflavin-S-positive material will facilitate the full appraisal of the clinical implication of the effects of anti-inflammatory drugs, and provide a more thorough understanding of TGF-beta1 actions in brain

The Role of Meson Retardation in the NN Interaction above Pion Threshold

A model is developed for the hadronic interaction in the two-nucleon system above pion threshold which is based on meson, nucleon and $\Delta$ degrees of freedom and which includes full meson retardation in the exchange operators. For technical reasons, the model allows maximal one meson to be present explicitly. Thus the Hilbert space contains besides $NN$ and $N\Delta$ also configurations consisting of two nucleons and one meson. For this reason, only two- and three-body unitarity is obeyed, and the model is suited for reactions in the two nucleon sector only, where one pion is produced or absorbed. Starting from a realistic pure nucleonic retarded potential, which had to be renormalized because of the additional $\pi$ and $\Delta$ degrees of freedom, a reasonable fit to experimental $NN$-scattering data could be achieved.Comment: 30 pages revtex including 17 figures, outline of model and discussion shortened, typos correcte

Reversal of end-stage renal disease after aortic dissection using renal artery stent: a case report

BACKGROUND: Medical management is the conventional treatment for Stanford Type B aortic dissections as surgery is associated with significant morbidity and mortality. The advent of endovascular interventional techniques has revived interest in treating end-organ complications of Type B aortic dissection. We describe a patient who benefited from endovascular repair of renal artery stenosis caused by a dissection flap, which resulted in reversal of his end-stage renal disease (ESRD). CASE PRESENTATION: A 69 y/o male with a Type B aortic dissection diagnosed two months earlier was found to have a serum creatinine of 15.2 mg/dL (1343.7 μmol/L) on routine visit to his primary care physician. An MRA demonstrated a rightward spiraling aortic dissection flap involving the origins of the celiac artery, superior mesenteric artery, and both renal arteries. The right renal artery arose from the false lumen with lack of blood flow to the right kidney. The left renal artery arose from the true lumen, but an intimal dissection flap appeared to be causing an intermittent stenosis of the left renal artery with compromised blood flow to the left kidney. Endovascular reconstruction with of the left renal artery with stent placement was performed. Hemodialysis was successfully discontinued six weeks after stent placement. CONCLUSION: Percutaneous intervention provides a promising alternative for patients with Type B aortic dissections when medical treatment will not improve the likelihood of meaningful recovery and surgery entails too great a risk. Nephrologists should therefore be aggressive in the workup of ischemic renal failure associated with aortic dissection as percutaneous intervention may reverse the effects of renal failure in this population

MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, and CIMP-status

The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene is an important predictive biomarker for benefit from alkylating agent therapy in glioblastoma. Recent studies in anaplastic glioma suggest a prognostic value for MGMT methylation. Investigation of pathogenetic and epigenetic features of this intriguingly distinct behavior requires accurate MGMT classification to assess high throughput molecular databases. Promoter methylation-mediated gene silencing is strongly dependent on the location of the methylated CpGs, complicating classification. Using the HumanMethylation450 (HM-450K) BeadChip interrogating 176 CpGs annotated for the MGMT gene, with 14 located in the promoter, two distinct regions in the CpG island of the promoter were identified with high importance for gene silencing and outcome prediction. A logistic regression model (MGMT-STP27) comprising probes cg1243587 and cg12981137 provided good classification properties and prognostic value (kappa=0.85; log-rank p<0.001) using a training-set of 63 glioblastomas from homogenously treated patients, for whom MGMT methylation was previously shown to be predictive for outcome based on classification by methylation-specific PCR. MGMT-STP27 was successfully validated in an independent cohort of chemo-radiotherapy-treated glioblastoma patients (n=50; kappa=0.88; outcome, log-rank p<0.001). Lower prevalence of MGMT methylation among CpG island methylator phenotype (CIMP) positive tumors was found in glioblastomas from The Cancer Genome Atlas than in low grade and anaplastic glioma cohorts, while in CIMP-negative gliomas MGMT was classified as methylated in approximately 50% regardless of tumor grade. The proposed MGMT-STP27 prediction model allows mining of datasets derived on the HM-450K or HM-27K BeadChip to explore effects of distinct epigenetic context of MGMT methylation suspected to modulate treatment resistance in different tumor type

From Effective Lagrangians, to Chiral Bags, to Skyrmions with the Large-N_c Renormalization Group

We explicitly relate effective meson-baryon Lagrangian models, chiral bags, and Skyrmions in the following way. First, effective Lagrangians are constructed in a manner consistent with an underlying large-N_c QCD. An infinite set of graphs dress the bare Yukawa couplings at *leading* order in 1/N_c, and are summed using semiclassical techniques. What emerges is a picture of the large-N_c baryon reminiscent of the chiral bag: hedgehog pions for r > 1/\Lambda patched onto bare nucleon degrees of freedom for r < 1/\Lambda, where the ``bag radius'' 1/\Lambda is the UV cutoff on the graphs. Next, a novel renormalization group (RG) is derived, in which the bare Yukawa couplings, baryon masses and hyperfine baryon mass splittings run with \Lambda. Finally, this RG flow is shown to act as a *filter* on the renormalized Lagrangian parameters: when they are fine-tuned to obey Skyrme-model relations the continuum limit \Lambda --> \infty exists and is, in fact, a Skyrme model; otherwise there is no continuum limit.Comment: Figures included (separate file). This ``replaced'' version corrects the discussion of backwards-in-time baryon

Defining the role of real-world data in cancer clinical research: The position of the European Organisation for Research and Treatment of Cancer

The emergence of the precision medicine paradigm in oncology has led to increasing interest in the integration of real-world data (RWD) into cancer clinical research. As sources of real-world evidence (RWE), such data could potentially help address the uncertainties that surround the adoption of novel anticancer therapies into the clinic following their investigation in clinical trials. At present, RWE-generating studies which investigate antitumour interventions seem to primarily focus on collecting and analysing observational RWD, typically forgoing the use of randomisation despite its methodological benefits. This is appropriate in situations where randomised controlled trials (RCTs) are not feasible and non-randomised RWD analyses can offer valuable insights. Nevertheless, depending on how they are designed, RCTs have the potential to produce strong and actionable RWE themselves. The choice of which methodology to employ for RWD studies should be guided by the nature of the research question they are intended to answer. Here, we attempt to define some of the questions that do not necessarily require the conduct of RCTs. Moreover, we outline the strategy of the European Organisation for Research and Treatment of Cancer (EORTC) to contribute to the generation of robust and high-quality RWE by prioritising the execution of pragmatic trials and studies set up according to the trials-within-cohorts approach. If treatment allocation cannot be left up to random chance due to practical or ethical concerns, the EORTC will consider undertaking observational RWD research based on the target trial principle. New EORTC-sponsored RCTs may also feature concurrent prospective cohorts composed of off-trial patients

Defining the role of real-world data in cancer clinical research:The position of the European Organisation for Research and Treatment of Cancer

The emergence of the precision medicine paradigm in oncology has led to increasing interest in the integration of real-world data (RWD) into cancer clinical research. As sources of real-world evidence (RWE), such data could potentially help address the uncertainties that surround the adoption of novel anticancer therapies into the clinic following their investigation in clinical trials. At present, RWE-generating studies which investigate antitumour interventions seem to primarily focus on collecting and analysing observational RWD, typically forgoing the use of randomisation despite its methodological benefits. This is appropriate in situations where randomised controlled trials (RCTs) are not feasible and non-randomised RWD analyses can offer valuable insights. Nevertheless, depending on how they are designed, RCTs have the potential to produce strong and actionable RWE themselves. The choice of which methodology to employ for RWD studies should be guided by the nature of the research question they are intended to answer. Here, we attempt to define some of the questions that do not necessarily require the conduct of RCTs. Moreover, we outline the strategy of the European Organisation for Research and Treatment of Cancer (EORTC) to contribute to the generation of robust and high-quality RWE by prioritising the execution of pragmatic trials and studies set up according to the trials-within-cohorts approach. If treatment allocation cannot be left up to random chance due to practical or ethical concerns, the EORTC will consider undertaking observational RWD research based on the target trial principle. New EORTC-sponsored RCTs may also feature concurrent prospective cohorts composed of off-trial patients

Pion-Nucleon Scattering in a Large-N Sigma Model

We review the large-N_c approach to meson-baryon scattering, including recent interesting developments. We then study pion-nucleon scattering in a particular variant of the linear sigma-model, in which the couplings of the sigma and pi mesons to the nucleon are echoed by couplings to the entire tower of I=J baryons (including the Delta) as dictated by large-N_c group theory. We sum the complete set of multi-loop meson-exchange \pi N --> \pi N and \pi N --> \sigma N Feynman diagrams, to leading order in 1/N_c. The key idea, reviewed in detail, is that large-N_c allows the approximation of LOOP graphs by TREE graphs, so long as the loops contain at least one baryon leg; trees, in turn, can be summed by solving classical equations of motion. We exhibit the resulting partial-wave S-matrix and the rich nucleon and Delta resonance spectrum of this simple model, comparing not only to experiment but also to pion-nucleon scattering in the Skyrme model. The moral is that much of the detailed structure of the meson-baryon S-matrix which hitherto has been uncovered only with skyrmion methods, can also be described by models with explicit baryon fields, thanks to the 1/N_c expansion.Comment: This LaTeX file inputs the ReVTeX macropackage; figures accompany i