Radiobiological research over the past decades has provided evidence that cancer stem cell content and the intrinsic radiosensitivity of cancer stem cells varies between tumours, thereby affecting ...their radiocurability. Translation of this knowledge into predictive tests for the clinic has so far been hampered by the lack of methods to discriminate between stem cells and non-stem cells. New technologies allow isolation of cells expressing specific surface markers that are differentially expressed in tumour cell subpopulations that are enriched for cancer stem cells. Combining these techniques with functional radiobiological assays holds the potential to elucidate the role of cancer stem cells in radioresistance in individual tumours, and to use this knowledge for the development of predictive markers for optimization of radiotherapy.
The efficient market hypothesis is highly discussed in economic literature. In its strongest form, it states that there are no price trends. When weakening the non-trending assumption to arbitrary ...short, small, and fully unknown trends, we mathematically prove for a specific class of control-based trading strategies positive expected gains. These strategies are model free, i.e., a trader neither has to think about predictable patterns nor has to estimate market parameters such as the trend’s sign like momentum traders have to do. That means, since the trader does not have to know any trend, even trends too small to find are enough to beat the market. Adjustments for risk and comparisons with buy-and-hold strategies do not satisfactorily solve the problem. In detail, we generalize results from the literature on control-based trading strategies to market settings without specific model assumptions, but with time-varying parameters in discrete and continuous time. We give closed-form formulae for the expected gain as well as the gain’s variance and generalize control-based trading rules to a setting where older information counts less. In addition, we perform an exemplary backtesting study taking transaction costs and bid-ask spreads into account and still observe—on average—positive gains.
Technological advances and clinical research over the past few decades have given radiation oncologists the capability to personalize treatments for accurate delivery of radiation dose based on ...clinical parameters and anatomical information. Eradication of gross and microscopic tumours with preservation of health-related quality of life can be achieved in many patients. Two major strategies, acting synergistically, will enable further widening of the therapeutic window of radiation oncology in the era of precision medicine: technology-driven improvement of treatment conformity, including advanced image guidance and particle therapy, and novel biological concepts for personalized treatment, including biomarker-guided prescription, combined treatment modalities and adaptation of treatment during its course.
There has been a dramatic rise in the abuse of synthetic cathinones known as “bath salts,” including 3,4-methylenedioxypyrovalerone (MDPV), an analog linked to many adverse events. MDPV differs from ...other synthetic cathinones because it contains a pyrrolidine ring which gives the drug potent actions as an uptake blocker at dopamine and norepinephrine transporters. While MDPV is now illegal, a wave of “second generation” pyrrolidinophenones has appeared on the market, with α-pyrrolidinovalerophenone (α-PVP) being most popular. Here, we sought to compare the in vitro and in vivo pharmacological effects of MDPV and its congeners: α-PVP, α-pyrrolidinobutiophenone (α-PBP), and α-pyrrolidinopropiophenone (α-PPP). We examined effects of test drugs in transporter uptake and release assays using rat brain synaptosomes, then assessed behavioral stimulant effects in mice. We found that α-PVP is a potent uptake blocker at dopamine and norepinephrine transporters, similar to MDPV. α-PBP and α-PPP are also catecholamine transporter blockers but display reduced potency. All of the test drugs are locomotor stimulants, and the rank order of in vivo potency parallels dopamine transporter activity, with MDPV > α-PVP > α-PBP > α-PPP. Motor activation produced by all drugs is reversed by the dopamine receptor antagonist SCH23390. Furthermore, results of a functional observational battery show that all test drugs produce typical stimulant effects at lower doses and some drugs produce bizarre behaviors at higher doses. Taken together, our findings represent the first evidence that second generation analogs of MDPV are catecholamine-selective uptake blockers which may pose risk for addiction and adverse effects in human users.
This article is part of the Special Issue entitled ‘CNS Stimulants’.
•Bath salts are emerging drugs of abuse that contain legal and illegal cathinones.•Structurally related cathinones were assessed in neurochemical and behavioral assays.•α-PVP, α-PBP, and α-PPP are catecholamine transporter blockers and locomotor stimulants.•Typical stimulant effects occurred at low doses, and bizarre behaviors occurred at higher doses.•Analogs of MDPV may pose substantial risk for addiction and adverse effects in human users.
To determine whether a standardized clinical application of dual-energy computed tomography (DECT) for proton treatment planning based on pseudomonoenergetic CT scans (MonoCTs) is feasible and ...increases the precision of proton therapy in comparison with single-energy CT (SECT).
To define an optimized DECT protocol, CT scan settings were analyzed experimentally concerning beam hardening, image quality, and influence on the heuristic conversion of CT numbers into stopping-power ratios (SPRs) and were compared with SECT scans with identical CT dose. Differences in range prediction and dose distribution between SECT and MonoCT were quantified for phantoms and a patient.
Dose distributions planned on SECT and MonoCT datasets revealed mean range deviations of 0.3 mm, γ passing rates (1%, 1 mm) greater than 99.9%, and no clinically relevant changes in dose-volume histograms. However, image noise and CT-related uncertainties could be reduced by MonoCT compared with SECT, which resulted in a slightly decreased dependence of SPR prediction on beam hardening. Consequently, DECT was clinically implemented at the University Proton Therapy Dresden in 2015. Until October 2016, 150 patients were treated based on MonoCTs, and more than 950 DECT scans of 351 patients were acquired during radiation therapy.
A standardized clinical use of MonoCT for treatment planning is feasible, leads to improved image quality and SPR prediction, extends diagnostic variety, and enables a stepwise clinical implementation of DECT toward a physics-based, patient-specific, nonheuristic SPR determination. Further reductions of CT-related uncertainties, as expected from such SPR approaches, can be evaluated on the resulting DECT patient database.
Radiotheranostics: a roadmap for future development Herrmann, Ken; Schwaiger, Markus; Lewis, Jason S ...
Lancet oncology/Lancet. Oncology,
March 2020, 2020-03-00, 20200301, Letnik:
21, Številka:
3
Journal Article
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Radiotheranostics, injectable radiopharmaceuticals with antitumour effects, have seen rapid development over the past decade. Although some formulations are already approved for human use, more ...radiopharmaceuticals will enter clinical practice in the next 5 years, potentially introducing new therapeutic choices for patients. Despite these advances, several challenges remain, including logistics, supply chain, regulatory issues, and education and training. By highlighting active developments in the field, this Review aims to alert practitioners to the value of radiotheranostics and to outline a roadmap for future development. Multidisciplinary approaches in clinical trial design and therapeutic administration will become essential to the continued progress of this evolving therapeutic approach.
Psychoactive “bath salts”: Not so soothing Baumann, Michael H.; Partilla, John S.; Lehner, Kurt R.
European journal of pharmacology,
01/2013, Letnik:
698, Številka:
1-3
Journal Article
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Recently there has been a dramatic rise in the abuse of so-called “bath salts” products that are purchased as legal alternatives to illicit drugs like cocaine and 3,4-methylenedioxymethamphetamine ...(MDMA). Baths salts contain one or more synthetic derivatives of the naturally-occurring stimulant cathinone. Low doses of bath salts produce euphoria and increase alertness, but high doses or chronic use can cause serious adverse effects such as hallucinations, delirium, hyperthermia and tachycardia. Owing to the risks posed by bath salts, the governments of many countries have made certain cathinones illegal, namely: 4-methylmethcathinone (mephedrone), 3,4-methylenedioxymethcathinone (methylone) and 3,4-methylenedioxypyrovalerone (MDPV). Similar to other psychomotor stimulants, synthetic cathinones target plasma membrane transporters for dopamine (i.e., DAT), norepinephrine (i.e., NET) and serotonin (i.e, SERT). Mephedrone and methylone act as non-selective transporter substrates, thereby stimulating non-exocytotic release of dopamine, norepinephrine and serotonin. By contrast, MDPV acts as a potent blocker at DAT and NET, with little effect at SERT. Administration of mephedrone or methylone to rats increases extracellular concentrations of dopamine and serotonin in the brain, analogous to the effects of MDMA. Not surprisingly, synthetic cathinones elicit locomotor activation in rodents. Stimulation of dopamine transmission by synthetic cathinones predicts a high potential for addiction and may underlie clinical adverse effects. As popular synthetic cathinones are rendered illegal, new replacement cathinones are appearing in the marketplace. More research on the pharmacology and toxicology of abused cathinones is needed to inform public health policy and develop strategies for treating medical consequence of bath salts abuse.
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