Urinary excretion profile of higenamine in females after oral administration of supplements - Doping scenario.

In 2017, higenamine was added to the World Antidoping Agency's (WADA) Prohibited list under group S3: beta-2 agonists and it is banned for athletes both in - and out of competition. Aim of this study was to characterize the urinary excretion profile of higenamine and its metabolite coclaurine after oral administration of multiple doses of higenamine capsules. For this purpose, an administration study including female basketball players was performed. For the detection of higenamine and cocalurine in the collected urine samples, a new, fast, and highly sensitive quantitative on-line SPE LC HRMS method was developed and validated. The method was applied for the quantification of higenamine and cocalurine in urine and their excretion pattern was defined. Results obtained show substantial inter-individual differences in the excretion profile of higenamine and coclaurine. For higenamine, half-lives were estimated to be between 4 and 27 h, and for coclaurine between 5 and 25 h. Furthermore, the data indicate that the elimination of coclaurine is rate-limited by its formation. Higenamine could be detected at a urine concentration above 10 ng/mL for at least 20 h after the last application for all study participants.

Flexible tape-drive target system for secondary high-intensity laser-driven sources.

We present the development of a flexible tape-drive target system to generate and control secondary high-intensity laser-plasma sources. Its adjustable design permits the generation of relativistic MeV particles and x rays at high-intensity (i.e., ≥1 × 1018 W cm-2) laser facilities, at high repetition rates (>1 Hz). The compact and robust structure shows good mechanical stability and a high target placement accuracy (<4 µm RMS). Its compact and flexible design allows for mounting in both the horizontal and vertical planes, which makes it practical for use in cluttered laser-plasma experimental setups. The design permits ∼170° of access on the laser-driver side and 120° of diagnostic access at the rear. A range of adapted apertures have been designed and tested to be easily implemented to the targetry system. The design and performance testing of the tape-drive system in the context of two experiments performed at the COMET laser facility at the Lawrence Livermore National Laboratory and at the Advanced Lasers and Extreme Photonics (ALEPH) facility at Colorado State University are discussed. Experimental data showing that the designed prototype is also able to both generate and focus high-intensity laser-driven protons at high repetition rates are also presented.

A flexible proton beam imaging energy spectrometer (PROBIES) for high repetition rate or single-shot high energy density (HED) experiments (invited).

The PROBIES diagnostic is a new, highly flexible, imaging and energy spectrometer designed for laser-accelerated protons. The diagnostic can detect low-mode spatial variations in the proton beam profile while resolving multiple energies on a single detector or more. When a radiochromic film stack is employed for "single-shot mode," the energy resolution of the stack can be greatly increased while reducing the need for large numbers of films; for example, a recently deployed version allowed for 180 unique energy measurements spanning ∼3 to 75 MeV with <0.4 MeV resolution using just 20 films vs 180 for a comparable traditional film and filter stack. When utilized with a scintillator, the diagnostic can be run in high-rep-rate (>Hz rate) mode to recover nine proton energy bins. We also demonstrate a deep learning-based method to analyze data from synthetic PROBIES images with greater than 95% accuracy on sub-millisecond timescales and retrained with experimental data to analyze real-world images on sub-millisecond time-scales with comparable accuracy.

Single-shot measurements of pulse-front tilt in intense ps laser pulses and its effect on accelerated electron and ion beam characteristics (invited).

We report recent single-shot spatiotemporal measurements of laser pulses, including pulse-front tilt (PFT) and spatial chirp, taken at the Compact Multipulse Terawatt laser at the Jupiter Laser Facility in Livermore, CA. STRIPED FISH, a device that measures the complete 3D electric field of fs to ps laser pulses on a single shot, was adapted to near infrared for these measurements. We present the design of the instrument used for these experiments, the on-shot measurements of systematic high-order PFT, and shot-to-shot variations in the measurements of spatiotemporal couplings. Finally, we simulate the effect of PFT in target normal sheath acceleration experiments. These simulations showed that pulse front tilt can steer hot electrons, shape the distribution of the accelerating sheath field, and increase the variability of cutoff energy in the resulting proton spectra. While these effects may be detrimental to experimental accuracy if the pulse front tilt is left unmeasured, hot electron steering shows promise for precision manipulation of the particle source for a range of applications, including irradiation of secondary targets for opacity measurements, radiography, or neutron generation.

Ultra-compact x-ray spectrometer for high-repetition-rate laser-plasma experiments.

We present in this work the development of an ultra-compact, multi-channel x-ray spectrometer (UCXS). This diagnostic has been specially built and adapted to perform at high-repetition-rate (>1 Hz) for high-intensity, short-pulse laser plasma experiments. X-ray filters of varying materials and thicknesses are chosen to provide spectral resolution up to ΔE ≈ 1 keV over the x-ray energy range of 1-30 keV. These filters are distributed over a total of 25 channels, where each x-ray filter is coupled to a single scintillator. The UCXS is designed to detect and resolve a large variety of laser-driven x-ray sources such as low energy bremsstrahlung emission, fluorescence, and betatron radiation (up to 30 keV). Preliminary results from commissioning experiments at the ABL laser facility at Colorado State University are provided.

Applications of machine learning to a compact magnetic spectrometer for high repetition rate, laser-driven particle acceleration.

Accurately and rapidly diagnosing laser-plasma interactions is often difficult due to the time-intensive nature of the analysis and will only become more so with the rise of high repetition rate lasers and the desire to implement feedback on a commensurate timescale. Diagnostic analysis employing machine learning techniques can help address this problem while maintaining a high degree of accuracy. We report on the application of machine learning to the analysis of a scintillator-based electron spectrometer for experiments on high intensity, laser-plasma interactions at the Colorado State University Advanced Lasers and Extreme Photonics facility. Our approach utilizes a neural network trained on synthetic data and tested on experiments to extract the accelerated electron temperature. By leveraging transfer learning, we demonstrate an improvement in the neural network accuracy, decreasing the network error by 50%.

Dual-energy fast neutron imaging using tunable short-pulse laser-driven sources.

A novel dual-energy fast neutron imaging technique is presented using short-pulse laser-driven neutron sources to leverage their inherent adaptive spectral control to enable 3D volume segmentation and reconstruction. Laser-accelerated ion beams incident onto secondary targets create directional, broadband, MeV-class neutrons. Synthetic radiographs are produced of multi-material objects using ion and neutron spectra derived from analytic and numerical models. It is demonstrated that neutron images generated from small changes to the neutron spectra, controlled by altering the initial laser conditions, are sufficient to isolate materials with differing attenuation coefficients. This is first demonstrated using a simplistic combinatorial isolation method and then by employing more advanced reconstruction algorithms to reduce artifacts and generate a segmentation volume of the constituent materials.

Loss of p27 Associated with Risk for Endometrial Carcinoma Arising in the Setting of Obesity.

Endometrial carcinoma (EC) exhibits the strongest association with obesity of all cancers. Growth of these tumors is driven by PI3K/AKT activation, and opposed by tumor suppressors, including the tuberous sclerosis complex 2 (TSC-2) and p27, with inactivation of TSC2 and loss or cytoplasmic mislocalization of p27 both being linked to PI3K/AKT activation. However, little is known about the involvement of p27 in the development of EC arising in the setting of obesity, especially its role early in disease progression. Using a panel of EC cell lines, in vitro studies using PI3K inhibitors provided evidence that p27 rescue contributes to the efficacy of interventions that inhibit endometrial cell growth. In "at risk" obese patients, and in an animal model of obesity-associated EC (Tsc2-deficient Eker rats), p27 was moderately-to-severely reduced in both "normal" endometrial glands as well as in endometrial complex atypical hyperplasia (obese women), and endometrial hyperplasia (obese rats). In obese Eker rats, an energy balance intervention; caloric restriction from 2-4 months of age, reduced weight, increased adiponectin and lowered leptin to produce a favorable leptin:adiponectin ratio, and reduced circulating insulin levels. Caloric restriction also increased p27 levels, relocalized this tumor suppressor to the nucleus, and significantly decreased hyperplasia incidence. Thus, dietary and pharmacologic interventions that inhibit growth and decrease risk for development of endometrial lesions are associated with increased expression and nuclear (re)localization of p27. These data suggest that p27 levels and localization may be useful as a biomarker, and possible determinant, of risk for EC arising in the setting of obesity.

The effect of melatonin on the liver of rats exposed to microwave radiation.

OBJECTIVES: We aimed to clarify if melatonin treatment (2 mg/kg i.p.) may favorably impact the liver tissue in rats exposed to microwave radiation. The experiment was performed on 84 six-weeks-old Wistar male rats exposed for 4h a day, for 20, 40 and 60 days, respectively, to microwaves (900 MHz, 100-300 microT, 54-160 V/m). Rats were divided in to four groups: I (control) - rats treated with saline, II (Mel) - rats treated with melatonin, III (MWs) - microwave exposed rats, IV (MWs + Mel) - MWs exposed rats treated with melatonin. We evaluated oxidative stress parameters (malondialdehyde and carbonyl group content), catalase, xanthine oxidase, deoxyribonuclease I and II activity. BACKGROUND: Oxidative stress is the key mechanism of the microwave induced tissue injury. Melatonin, a lipophilic indoleamine primarily synthesized and released from the pineal gland is a powerful antioxidant. RESULTS: Exposure to microwaves caused an increase in malondialdehyde after 40 (p < 0.01), protein carbonyl content after 20 (p < 0.05), catalase (p < 0.05) and xantine oxidase activity (p < 0.05) after 40 days. Increase in deoxyribonuclease I activity was observed after 60 days (p < 0.05), while deoxyribonuclease II activity was unaffected. Melatonin treatment led to malondialdehyde decrease after 40 days (p< 0.05), but surprisingly had no effect on other analyzed parameters. CONCLUSION: Melatonin exerts certain antioxidant effects in the liver of rats exposed to microwaves, by diminishing the intensity of lipid peroxidation(Fig. 6, Ref. 32).

Effect of astaxanthin supplementation on muscle damage and oxidative stress markers in elite young soccer players.

AIM: The purpose of the current study was to examine the effect of Astaxanthin (Asx) supplementation on muscle enzymes as indirect markers of muscle damage, oxidative stress markers and antioxidant response in elite young soccer players. METHODS: Thirty-two male elite soccer players were randomly assigned in a double-blind fashion to Asx and placebo (P) group. After the 90 days of supplementation, the athletes performed a 2 hour acute exercise bout. Blood samples were obtained before and after 90 days of supplementation and after the exercise at the end of observational period for analysis of thiobarbituric acid-reacting substances (TBARS), advanced oxidation protein products (AOPP), superoxide anion (O2•¯), total antioxidative status (TAS), sulphydril groups (SH), superoxide-dismutase (SOD), serum creatine kinase (CK) and aspartate aminotransferase (AST). RESULTS: TBARS and AOPP levels did not change throughout the study. Regular training significantly increased O2•¯ levels (main training effect, P<0.01). O2•¯ concentrations increased after the soccer exercise (main exercise effect, P<0.01), but these changes reached statistical significance only in the P group (exercise x supplementation effect, P<0.05). TAS levels decreased significantly post- exercise only in P group (P<0.01). Both Asx and P groups experienced increase in total SH groups content (by 21% and 9%, respectively) and supplementation effect was marginally significant (P=0.08). Basal SOD activity significantly decreased both in P and in Asx group by the end of the study (main training effect, P<0.01). All participants showed a significant decrease in basal CK and AST activities after 90 days (main training effect, P<0.01 and P<0.001, respectively). CK and AST activities in serum significantly increased as result of soccer exercise (main exercise effect, P<0.001 and P<0.01, respectively). Postexercise CK and AST levels were significantly lower in Asx group compared to P group (P<0.05) CONCLUSION: The results of the present study suggest that soccer training and soccer exercise are associated with excessive production of free radicals and oxidative stress, which might diminish antioxidant system efficiency. Supplementation with Asx could prevent exercise induced free radical production and depletion of non-enzymatic antioxidant defense in young soccer players.

The effect of melatonin on body mass and behaviour of rats during an exposure to microwave radiation from mobile phone.

BACKGROUND: Microwave radiation (MW) produced by wireless telecommunications and a number of electrical devices used in household or in healthcare institutions may cause various disorders in human organism. On the other hand, melatonin is a potent antioxidant, immunostimulator and neuromodulator. The aim of this research was to determine body mass and behaviour changes in rats after a chronic microwave exposure, as well as to determine the effects of melatonin on body mass and behaviour in irradiated rats. METHODS: Wistar rats were divided into the four experimental groups: I group (control) - rats treated with 0,9 % saline, II group (Mel) - rats treated with melatonin (2 mg/kg), III group (MW) - rats exposed to MW radiation (4 h/day), IV group (MW+Mel) - rats, which were both exposed to MW radiation and received melatonin premedication (2 mg/kg). RESULTS: A significant body mass reduction was noted in animals exposed to MW radiation when compared to controls after 20, 40 and 60 days (p<0.001). Furthermore, body weight was significantly increased (p<0.05) in irradiated rats, which received melatonin pretreatment (MW+Mel) in comparison to irradiated group (MW) after 20 days. Microwave radiation exposed animals showed an anxiety related behaviour (agitation, irritability) after 10 days of exposure. After the radiation source removal, changes in behaviour were less noticeable. Melatonin administration to irradiated rats caused a decrease in the stress induced behaviour. CONCLUSION: Microwave radiation causes body mass decrease and anxiety related behaviour in rats, however melatonin causes a reverse of those effects on both body weight and behaviour of irradiated animals (Fig. 2, Ref. 32).

High clinical accuracy of asymmetric dimethylarginine and symmetric dimethylarginine in patients with ischemic heart disease.

Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA) were found in various clinical settings including coronary heart disease. To assess ADMA and SDMA diagnostic validity in patients with different stages of ischemic heart disease, we studied these markers in patients having stable angina pectoris (SAP), unstable angina (USAP), and acute myocardial infarction (AMI). The results were compared with the values of healthy individuals. Plasma ADMA and SDMA levels were measured by high-performance liquid chromatography. In all patient groups both markers were significantly elevated in comparison with control ones (p < 0.001). In SAP patients, the median ADMA value was 0.75 (0.31-2.73) µmol/L, and SDMA 1.11 (0.69-0.1.42) µmol/L, in USAP patients, the marker values were 0.94 (0.34-3.13) µmol/L and 1.23 (0.88-4.72) µmol/L, and in AMI patients, 0.98 (0.48-2.01) µmol/L and 1.26 (0.75-2.93) µmol/L, while in healthy subjects they were 0.31 (0.17-0.87) µmol/L and 0.29 (0.20-0.83) µmol/L, respectively. SDMA was found significantly different in SAP and AMI patients (p < 0.05). Diagnostic accuracy was determined by receiver operating characteristic (ROC) curve analysis. The highest area under the ROC (AUC) for ADMA was obtained in AMI patients (0.976), while for SDMA in USAP patients (1.000). There was no significant difference between the AUCs. The greatest sensitivity and specificity were found in the USAP group (95.65 and 96.30 % for ADMA, and 100 % for each characteristic of SDMA). Considering these results, SDMA showed better clinical accuracy in assessing ischemic disease, where it could be used as a valid marker and a therapeutic target.

Effect of nutritional status and sampling intensity on recovery after dorsal aorta cannulation in free-swimming Atlantic salmon (Salmo salar L.).

Recovery from implantation of a cannula in the dorsal aorta (DA) of Atlantic salmon (Salmo salar) was studied in relation to nutritional status and sampling intensity. The incentive for the study was the inconsistency between published reports and our own experience of recovery and longevity of fish exposed to this protocol. In two studies using starved fish, blood (0.3 ml) was sampled 0, 1 and 24 h after DA-cannulation, and thereafter at 48 and 72 h and thereafter once weekly for four weeks. In a third study using fed fish, four consecutive samples (0, 3, 6 and 12 h after a meal) were obtained twice a week over a four-week period. All fish displayed a sharp increase in pCO(2) and haematocrit (Hct) during surgery, followed by a marked raise in cortisol, glucose, sodium and potassium (1 h). pCO(2), pH and Hct approached baseline levels as early as the 1 h post-surgery sample, while this was not the case for cortisol and electrolytes before the 24 h post-surgery sample. Glucose did not display any significant changes post surgery. From then on, all variables displayed minor but non-significant (P > 0.05) changes indicating a steady state close to baseline values for unstressed fish. This pattern was independent of sampling procedure, i.e. repeated single or multiple samples and thus volume of blood removed. Nutritional status (fed vs. starved) did not affect post-surgical recovery pattern. Only K(+) and Hct displayed consistent and significant post-prandial patterns. We found marked differences between baseline level of cannulated fish and uncannulated control fish, in pH, K(+) and Hct indicating that cannulation may be the preferred method to obtain representative resting values in fish.

Current approach to epithelial ovarian cancer based on the concept of cancer stem cells.

Epithelial ovarian cancer (EOC) is the most common ovarian malignancy. EOCs comprise a diverse group of neoplasms, exhibiting a wide range of morphological characteristics, genetic alterations, and biological behaviors. Currently, there is no effective screening for early detection of EOCs and more than two-thirds of EOC patients are diagnosed with advanced stage disease. The major limiting factors in the treatment of EOC patients are recurrence and chemoresistance. Recent studies suggest that EOCs, like other solid tumors, contain distinct populations of cells that are responsible for tumor initiation, maintenance and growth. These cells, termed cancer stem cells (CSCs), display some of the features of normal stem cells and are thought to evade current chemotherapeutic strategies for the treatment of EOCs. Distinguishing CSC-associated antigen profiles may elucidate novel, more sensitive biomarkers for early detection of EOCs and provide molecular targets for the development of new treatment modalities. This review summarizes the current approaches to EOCs based on the concept of CSCs and evaluates their clinical relevance.

Late recurrence of malignant melanoma mimicking ovarian malignancy.

BACKGROUND: Malignant melanoma (MM) is an extremely malignant tumor with an unpredictable profile of spread and variable periods of remission. CASE: We describe an unusual case of malignant melanoma metastatic to the omentum occurring seven years after diagnosis and treatment of cutaneous malignant melanoma in the patient's arm. She received surgery and chemoimmunotherapy. To date, nine months after detection of malignant melanoma metastatic to the omentum, the patient is alive with no clinical and radiological metastatic disease. CONCLUSIONS: The diagnosis of omentum malignant melanoma in a living patient is uncommon, thus very few individuals and referral centers can build up an adequate experience of handling this disease. Optimal management has been a challenge and a subject of debate and has not yet been established.

Polypoid or non-polypoid? A novel dichotomous approach to uterine carcinosarcoma.

OBJECTIVE: To examine the impact of the polypoid morphology of uterine carcinosarcoma on clinical outcome, as well as its relationship to well-established prognostic factors. METHODS: In a retrospective study of fifty eight patients with uterine carcinosarcoma treated with hysterectomy, we correlated the polypoid status of tumors with stage, lymphatic vascular invasion, myometrial invasion, size, carcinoma to sarcoma ratio, type of carcinomatous and sarcomatous components, disease free survival and overall survival. RESULTS: By multivariate analysis, the polypoid status had no impact on disease free survival (p=0.8958), but approached significance as a positive predictor for overall survival (p=0.0569); patients in the polypoid group lived on average 14.9 months longer than those with non-polypoid tumors. Polypoid neoplasms had a smaller average size and grew to a smaller maximum size than the non-polypoid tumors. While non-polypoid tumors were either carcinoma or sarcoma predominant, polypoid tumors were mostly sarcoma predominant (p=0.0348). Polypoid carcinosarcomas also demonstrated an appreciably lesser extent of myometrial invasion (p=0.0019), a markedly lower rate of lymphatic vascular invasion (p=0.0002), and tended to present as early stage tumors (p=0.0265). Carcinomatous component in polypoid tumors tended to have pure or nearly pure (>or=90%) endometrioid histology (p=0.1608). There was no relationship between polypoid status and type of sarcomatous component (p=0.5299). CONCLUSIONS: Polypoid carcinosarcomas differ from their non-polypoid counterparts in key histological parameters such as the carcinoma to sarcoma ratio, myometrial and lymphatic vascular invasion, stage and type of carcinomatous component. Patients with polypoid tumors may have a better survival outcome than those with non-polypoid tumors.

Molecular pathogenesis of borderline and invasive ovarian tumors.

Ovarian cancer still ranks first as the leading cause of death among gynecological malignancies. Malignant transformation of normal ovarian epithelial cells is caused by genetic alterations that disrupt regulation of proliferation, programmed cell death, and senescence. The vast majority of ovarian tumors arise due to accumulation of genetic damage, but the specific genetic pathways for the development of epithelial ovarian tumors, borderline and malignant, are largely unknown. Our results show that in progressive stages of carcinoma, the oxidative stress can contribute to the uncontrolled tumor expansion. Circulating levels of antioxidants may be important to consider when evaluating a woman's risk of cancer, even among women who are at higher predicted risk. The purpose of this article was to review the current approaches to molecular pathogenesis of borderline and invasive epithelial ovarian tumors.

Risk factors and adjuvant chemotherapy in the treatment of endometrial cancer.

Endometrial carcinoma is the most common and potentially curable gynecologic malignant neoplasm. The staging of endometrial cancer, according to the International Federation of Gynecology and Obstetrics (FIGO), is surgical. Recent studies suggest a therapeutic benefit associated with extensive retroperitoneal lymph node evaluation to determine the disease extent and thereby more effectively direct potentially life-saving adjuvant therapy. Due to the increasing number of endometrial cancer patients who undergo surgical staging, some independent prognostic factors have been identified in early stages (stage I-II), including lymph-vascular space involvement, histologic grade 3, aggressive histologic subtypes (uterine papillary serous carcinoma, clear cell carcinoma), depth of myometrial invasion, cervical invasion and the age of patients. Adjuvant radiation therapy, known to offer survival benefit in advanced-stage disease, may also offer survival benefit in intermediate-risk surgical stage I, but this is followed by a significant risk of serious complications. Based on randomized clinical trials, this review identified that only a limited body of evidence is available which can help clinicians make decisions about adjuvant chemotherapy of patients with high-risk stage I and II, as well as stage IIIA endometrial cancer. Further investigations are required to define the subgroup of patients who benefit from postoperative adjuvant chemotherapy. In addition, the optimal regimen remains to be defined as all of them (doxorubicin/cisplatin--AP, cyclophosphamide/ doxorubicin/cisplatin--CAP, paclitaxel/carboplatin--TC, paclitaxel/doxorubicin/cisplatin--TAP) cause significant toxicity. Thereby, combination of carboplatin plus paclitaxel represents an efficacious, low-toxicity regimen for managing intermediate-risk surgical stage I, as well as advanced or recurrent endometrial cancer.

Generation of narrowband antisymmetric lamb waves using a formed laser source in the ablative regime.

A formed laser source, using a four-element lenticular array, is used in the ablative regime to generate select, narrowband, acoustic plate waves. The arrangement of the array produces acoustical signals that have frequencies compatible with the response of the broadband capacitive air-coupled transducer used in this study. A simplified concept is presented to explain the effect of a line array source on the frequency content of acoustic waves. The analytical model for a point pulse surface displacement is derived from the point load solution to Lamb's problem. The point pulse displacement elements of a line array source are summed mathematically, taking into account all applicable propagation modes and dispersion of plate waves. The model considers only the out-of-plane displacement of the antisymmetric plate modes to represent the detection capability of the broadband receiver. The distribution function of the laser beam energy profile is modified to depict the actual energy distribution that illuminates the surface of the plate. Filtering functions are made compatible with the sensitivity of the broadband receiver so as to retain only the detected frequencies in the model. The theoretical model showed good agreement with experimental results.

Sensitivity of point- and line-source laser-generated acoustic wave to surface flaws.

Laser generation and air-coupled detection were combined as a hybrid ultrasonic technique for the inspection of surface flaws in rail. Narrowband acoustic signals were generated using a formed laser source by focusing the laser light to a point and to a line on the surface of the rail. The pulse energy, and therefore the intensity of the laser source, varied such that the generated signal transitioned from the weak thermoelastic to the strong ablative regime. The detection of flaws using laser-generated surface acoustic wave, to the presence of surface flaws, was compared between both point and line laser sources operating under different pulse energy levels. The line source was found to be more sensitive to the presence of surface flaws than a point source. The sensitivity of the laser-generated acoustic signal appeared to be independent of the severity of the flaw and, within the ablative regime, independent of the laser-pulse energy. Theoretical analysis is provided to explain the underlying cause that influences the interaction of a formed laser-generated surface acoustic wave to surface flaws and how this sensitivity may vary between the thermoelastic and ablative regimes.