Fertility preservation in men with cancer Tournaye, Herman, Prof; Dohle, Gert R, MD; Barratt, Christopher L R, Prof
The Lancet (British edition),
10/2014, Letnik:
384, Številka:
9950
Journal Article
Recenzirano
Summary During the past decade, advances in cancer treatment have increased survival rates of both boys and men. However, cancer treatment itself can compromise fertility, especially exposure to ...alkylating agents and whole body irradiation, which cause substantial germ cell loss. Children and adolescents with testicular cancer, leukaemia, and Ewing sarcomas are at the highest risk of developing permanent sterility from cancer treatment. Consequently, various strategies to preserve fertility are necessary. Sperm cryopreservation is an effective but underused method to safeguard spermatozoa. In the past few years, large advances have been made in prepubertal germ cell storage aimed at subsequent transplantation of testicular tissue and associated stem cells. Although still experimental, these approaches offer hope to many men in whom germ cell loss is associated with sterility. The derivation of male gametes from stem cells also holds much promise; however, data are only available in animals, and the use of this method in human beings is probably many years away.
Herein, we describe the consensus guideline methodology, summarize the evidence-based recommendations we provided to the World Health Organization (WHO) for their consideration in the development of ...global guidance and present a narrative review of the diagnosis of male infertility as related to the eight prioritized (problem or population (P), intervention (I), comparison (C) and outcome(s) (O) (PICO)) questions. Additionally, we discuss the challenges and research gaps identified during the synthesis of this evidence.
The aim of this paper is to present an evidence-based approach for the diagnosis of male infertility as related to the eight prioritized PICO questions.
Collating the evidence to support providing recommendations involved a collaborative process as developed by WHO, namely: identification of priority questions and critical outcomes; retrieval of up-to-date evidence and existing guidelines; assessment and synthesis of the evidence; and the formulation of draft recommendations to be used for reaching consensus with a wide range of global stakeholders. For each draft recommendation the quality of the supporting evidence was then graded and assessed for consideration during a WHO consensus.
Evidence was synthesized and recommendations were drafted to address the diagnosis of male infertility specifically encompassing the following: What is the prevalence of male infertility and what proportion of infertility is attributable to the male? Is it necessary for all infertile men to undergo a thorough evaluation? What is the clinical (ART/non ART) value of traditional semen parameters? What key male lifestyle factors impact on fertility (focusing on obesity, heat and tobacco smoking)? Do supplementary oral antioxidants or herbal therapies significantly influence fertility outcomes for infertile men? What are the evidence-based criteria for genetic screening of infertile men? How does a history of neoplasia and related treatments in the male impact on (his and his partner's) reproductive health and fertility options? And lastly, what is the impact of varicocele on male fertility and does correction of varicocele improve semen parameters and/or fertility?
This evidence synthesis analysis has been conducted in a manner to be considered for global applicability for the diagnosis of male infertility.
Urban groundwater management requires complex environmental models to represent interactions between hydrogeological processes and infrastructure systems. While the impacts of external uncertainties, ...such as climate and population growth, have been widely studied, there is limited understanding of how decision support is altered by endogenous uncertainties arising from model parameters and observations used for calibration. This study investigates (1) the importance of observation choice and parameter values on aquifer management objectives when controlling for model error and (2) how the relative performance of management alternatives varies when exposed to endogenous uncertainties, both individually and in combination. We use a spatially distributed groundwater model of the Valley of Mexico, where aquifer management alternatives include demand management, targeted infiltration, and wastewater reuse. The effects of uncertainty are evaluated using global sensitivity analysis, performance ranking of alternatives under a range of human–natural parameters, and identification of behavioral parameter sets filtered with an error metric calculated from varying subsets of observations. Results show that the parameters governing hydraulic conductivity and total water use in the basin have the greatest effect on management objectives. Error metrics (i.e., squared residuals of piezometric head) are not necessarily controlled by the same parameters as the head-based objectives needed for decision-making. Additionally, observational and parameter uncertainty each play a larger role in objective variation than the management alternatives themselves. Finally, coupled endogenous uncertainties have amplifying effects on decision-making, leading to larger variations in the ranking of management alternatives than each on their own. This study highlights how the uncertain parameters of a physically based model and their interactions with uncertain observations can affect water supply planning decisions in densely populated urban areas.
Sub-picosecond magnetisation manipulation via femtosecond optical pumping has attracted wide attention ever since its original discovery in 1996. However, the spatial evolution of the magnetisation ...is not yet well understood, in part due to the difficulty in experimentally probing such rapid dynamics. Here, we find evidence of a universal rapid magnetic order recovery in ferrimagnets with perpendicular magnetic anisotropy via nonlinear magnon processes. We identify magnon localisation and coalescence processes, whereby localised magnetic textures nucleate and subsequently interact and grow in accordance with a power law formalism. A hydrodynamic representation of the numerical simulations indicates that the appearance of noncollinear magnetisation via optical pumping establishes exchange-mediated spin currents with an equivalent 100% spin polarised charge current density of 10
A cm
. Such large spin currents precipitate rapid recovery of magnetic order after optical pumping. The magnon processes discussed here provide new insights for the stabilization of desired meta-stable states.
Rationale
Nicotine cessation is associated with increased consumption of highly palatable foods and body weight gain in most smokers. Concerns about body weight gain are a major barrier to ...maintaining long-term smoking abstinence, and current treatments for nicotine use disorder (NUD) delay, but do not prevent, body weight gain during abstinence. Glucagon-like peptide-1 receptor (GLP-1R) agonists reduce food intake and are FDA-approved for treating obesity. However, the effects of GLP-1R agonist monotherapy on nicotine seeking and withdrawal-induced hyperphagia are unknown.
Objectives
We screened the efficacy of the long-lasting GLP-1R agonist liraglutide to reduce nicotine-mediated behaviors including voluntary nicotine taking, as well as nicotine seeking and hyperphagia during withdrawal.
Methods
Male and female rats self-administered intravenous nicotine (0.03 mg/kg/inf) for ~21 days. Daily liraglutide administration (25 μg/kg, i.p.) started on the last self-administration day and continued throughout the extinction and reinstatement phases of the experiment. Once nicotine taking was extinguished, the reinstatement of nicotine-seeking behavior was assessed after an acute priming injection of nicotine (0.2 mg/kg, s.c.) and re-exposure to conditioned light cues. Using a novel model of nicotine withdrawal-induced hyperphagia, intake of a high fat diet (HFD) was measured during home cage abstinence in male and female rats with a history of nicotine self-administration.
Results
Liraglutide attenuated nicotine self-administration and reinstatement in male and female rats. Repeated liraglutide attenuated withdrawal-induced hyperphagia and body weight gain in male and female rats at a dose that was not associated with malaise-like effects.
Conclusions
These findings support further studies investigating the translational potential of GLP-1R agonists to treat NUD.
Rats repeatedly exposed to restraint show a reduced hypothalamic–pituitary–adrenal axis response upon restraint re-exposure. This hypothalamic–pituitary–adrenal axis response habituation to restraint ...does not generalize to other novel stressors and is associated with a decrease in stress-induced c-fos expression in a number of stress-reactive brain regions. We examined whether habituation to repeated restraint is also associated with adaptation of immediate early gene expression in brain regions that process and relay primary sensory information. These brain regions may not be expected to show gene expression adaptation to repeated restraint because of their necessary role in experience discrimination. Rats were divided into a repeated restraint group (five 1-hour daily restraint sessions) and an unstressed group (restraint naïve). On the sixth day rats from each group were either killed with no additional stress experience or at 15, 30 or 60 min during restraint. Immediate early gene expression (corticotrophin-releasing hormone heteronuclear RNA, c-fos mRNA, zif268 mRNA) was determined by in situ hybridization. A reduction in stress-induced hypothalamic–pituitary–adrenal axis hormone secretion (plasma corticosterone and adrenocorticotropic hormone) and immediate early gene expression levels in the paraventricular nucleus of the hypothalamus, the lateral septum and the orbital cortex was observed in repeated restraint as compared with restraint naïve animals. This reduction was already evident at 15 min of restraint. Unexpectedly, we also found in repeated restraint rats a reduction in restraint-induced c-fos expression in primary sensory-processing brain areas (primary somatosensory cortex, and ventroposteriomedial and dorsolateral geniculate nuclei of thalamus). The overall levels of hippocampal mineralocorticoid receptor heteronuclear RNA or glucocorticoid receptor mRNA were not decreased by repeated restraint, as may occur in response to severe chronic stress. We propose that repeated restraint leads to a systems-level adaptation whereby re-exposure to restraint elicits a rapid inhibitory modulation of primary sensory processing (i.e. sensory gating), thereby producing a widespread attenuation of the neural response to restraint.
A catalogue of molecular aberrations that cause ovarian cancer is critical for developing and deploying therapies that will improve patients' lives. The Cancer Genome Atlas project has analysed ...messenger RNA expression, microRNA expression, promoter methylation and DNA copy number in 489 high-grade serous ovarian adenocarcinomas and the DNA sequences of exons from coding genes in 316 of these tumours. Here we report that high-grade serous ovarian cancer is characterized by TP53 mutations in almost all tumours (96%); low prevalence but statistically recurrent somatic mutations in nine further genes including NF1, BRCA1, BRCA2, RB1 and CDK12; 113 significant focal DNA copy number aberrations; and promoter methylation events involving 168 genes. Analyses delineated four ovarian cancer transcriptional subtypes, three microRNA subtypes, four promoter methylation subtypes and a transcriptional signature associated with survival duration, and shed new light on the impact that tumours with BRCA1/2 (BRCA1 or BRCA2) and CCNE1 aberrations have on survival. Pathway analyses suggested that homologous recombination is defective in about half of the tumours analysed, and that NOTCH and FOXM1 signalling are involved in serous ovarian cancer pathophysiology.
Parkinson disease (PD) is a progressive neurodegenerative disorder affecting motor and cognitive functions. Prior studies showed that patients with PD and diabetes (DM) demonstrate worse clinical ...outcomes compared to nondiabetic subjects with PD. Our study aimed at defining the relationship between DM, gray matter volume, and cognition in patients with PD.
This study included 36 subjects with PD (12 with DM, 24 without DM, mean age = 66). Subjects underwent high-resolution T1-weighted brain magnetic resonance imaging, (11)Cdihydrotetrabenazine positron emission tomography imaging to quantify nigrostriatal dopaminergic denervation, clinical, and cognitive assessments. Magnetic resonance images were postprocessed to determine total and lobar cortical gray matter volumes. Cognitive testing scores were converted to z-scores for specific cognitive domains and a composite global cognitive z-score based on normative data computed. Analysis of covariance, accounting for effects of age, gender, intracranial volume, and striatal (11)Cdihydrotetrabenazine binding, was used to test the relationship between DM and gray matter volumes.
Impact of DM on total gray matter volume was significant (P = 0.02). Post hoc analyses of lobar cortical gray matter volumes revealed that DM was more selectively associated with lower gray matter volumes in the frontal regions (P = 0.01). Cognitive post hoc analyses showed that interaction of total gray matter volume and DM status was significantly associated with composite (P = 0.007), executive (P = 0.02), and visuospatial domain cognitive z-scores (P = 0.005). These associations were also significant for the frontal cortical gray matter.
DM may exacerbate brain atrophy and cognitive functions in PD with greater vulnerability in the frontal lobes. Given the high prevalence of DM in the elderly, delineating its effects on patient outcomes in the PD population is of importance.
The AquaVIT-1 intercomparison of atmospheric water vapor measurement techniques was conducted at the aerosol and cloud simulation chamber AIDA (Aerosol Interaction and Dynamics in the Atmosphere) at ...the Karlsruhe Institute of Technology, Germany, in October 2007. The overall objective was to intercompare state-of-the-art and prototype atmospheric hygrometers with each other and with independent humidity standards under controlled conditions. This activity was conducted as a blind intercomparison with coordination by selected referees. The effort was motivated by persistent discrepancies found in atmospheric measurements involving multiple instruments operating on research aircraft and balloon platforms, particularly in the upper troposphere and lower stratosphere, where water vapor reaches its lowest atmospheric values (less than 10 ppm). With the AIDA chamber volume of 84 m3, multiple instruments analyzed air with a common water vapor mixing ratio, by extracting air into instrument flow systems, by locating instruments inside the chamber, or by sampling the chamber volume optically. The intercomparison was successfully conducted over 10 days during which pressure, temperature, and mixing ratio were systematically varied (50 to 500 hPa, 185 to 243 K, and 0.3 to 152 ppm). In the absence of an accepted reference instrument, the absolute accuracy of the instruments was not established. To evaluate the intercomparison, the reference value was taken to be the ensemble mean of a core subset of the measurements. For these core instruments, the agreement between 10 and 150 ppm of water vapor is considered good with variation about the reference value of about ±10% (±1σ). In the region of most interest between 1 and 10 ppm, the core subset agreement is fair with variation about the reference value of ±20% (±1σ). The upper limit of precision was also derived for each instrument from the reported data. The implication for atmospheric measurements is that the substantially larger differences observed during in-flight intercomparisons stem from other factors associated with the moving platforms or the non-laboratory environment. The success of AquaVIT-1 provides a template for future intercomparison efforts with water vapor or other species that are focused on improving the analytical quality of atmospheric measurements on moving platforms.
Ulotaront (SEP-363856) is a trace-amine associated receptor 1 (TAAR1) agonist with 5-HT1A receptor agonist activity in Phase 3 clinical development, with FDA Breakthrough Therapy Designation, for the ...treatment of schizophrenia. TAAR1 is a G-protein-coupled receptor (GPCR) that is expressed in cortical, limbic, and midbrain monoaminergic regions. It is activated by endogenous trace amines, and is believed to play an important role in modulating dopaminergic, serotonergic, and glutamatergic circuitry. TAAR1 agonism data are reported herein for ulotaront and its analogues in comparison to endogenous TAAR1 agonists. In addition, a human TAAR1 homology model was built around ulotaront to identify key interactions and attempt to better understand the scaffold-specific TAAR1 agonism structure–activity relationships.
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