Waiting time models of cancer progression

Cancer progression is an evolutionary process that is driven by mutation and selection in a population of tumor cells. We discuss mathematical models of cancer progression, starting from traditional multistage theory. Each stage is associated with the occurrence of genetic alterations and their fixation in the population. We describe the accumulation of mutations using conjunctive Bayesian networks, an exponential family of waiting time models in which the occurrence of mutations is constrained to a partial temporal order. Two opposing limit cases arise if mutations either follow a linear order or occur independently. We derive exact analytical expressions for the waiting time until a specific number of mutations have accumulated in these limit cases as well as for the general conjunctive Bayesian network. Finally, we analyze a stochastic population genetics model that explicitly accounts for mutation and selection. In this model, waves of clonal expansions sweep through the population at equidistant intervals. We present an approximate analytical expression for the waiting time in this model and compare it to the results obtained for the conjunctive Bayesian networks

Fecundity compensation and tolerance to a sterilizing pathogen in <em>Daphnia</em>

Hosts are armed with several lines of defence in the battle against parasites: they may prevent the establishment of infection, reduce parasite growth once infected or persevere through mechanisms that reduce the damage caused by infection, called tolerance. Studies on tolerance in animals have focused on mortality, and sterility tolerance has not been investigated experimentally. Here, we tested for genetic variation in the multiple steps of defence when the invertebrate Daphnia magna is infected with the sterilizing bacterial pathogen Pasteuria ramosa: anti-infection resistance, anti-growth resistance and the ability to tolerate sterilization once infected. When exposed to nine doses of a genetically diverse pathogen inoculum, six host genotypes varied in their average susceptibility to infection and in their parasite loads once infected. How host fecundity changed with increasing parasite loads did not vary between genotypes, indicating that there was no genetic variation for this measure of fecundity tolerance. However, genotypes differed in their level of fecundity compensation under infection, and we discuss how, by increasing host fitness without targeting parasite densities, fecundity compensation is consistent with the functional definition of tolerance. Such infection-induced life-history shifts are not traditionally considered to be part of the immune response, but may crucially reduce harm (in terms of fitness loss) caused by disease, and are a distinct source of selection on pathogens

The role of Hall diffusion in the magnetically threaded thin accretion discs

We study role of the Hall diffusion in the magnetic star-disc interaction. In a simplified steady state configuration, the total torque is calculated in terms of the fastness parameter and a new term because of the Hall diffusion. We show the total torque reduces as the Hall term becomes more significant. Also, the critical fastness parameter (at which the total torque is zero) reduces because of the Hall diffusion.Comment: Accepted for publication in Astrophysics and Space Scienc

Circulating Tumor DNA Monitoring Reveals Molecular Progression before Radiologic Progression in a Real-life Cohort of Patients with Advanced Non-small Cell Lung Cancer

Purpose: The clinical potential of liquid biopsy in patients with advancedcancer is real-time monitoring for early detection of treatment failure.Our study aimed to investigate the clinical validity of circulating tumorDNA (ctDNA) treatment monitoring in a real-life cohort of patients withadvanced non–small cell lung cancer (NSCLC).Experimental Design: Patients with advanced or noncurative locallyadvanced NSCLC were prospectively included in an exploratory study(NCT03512847). Selected cancer-specific mutations were measured inplasma by standard or uniquely designed droplet digital PCR assays beforeevery treatment cycle during first-line treatment until progressive disease(PD). Correlation between an increase in ctDNA (= molecular progres-sion) and radiologic PD was investigated, defined as lead time, and thecorresponding numbers of likely futile treatment cycles were determined.Utility of ctDNA measurements in clarifying the results of nonconclusiveradiologic evaluation scans was evaluated.Results: Cancer-specific mutations and longitudinal plasma sampling werepresent in 132 of 150 patients. ctDNA was detectable in 88 (67%) of132 patients treated by respectively chemotherapy (n = 41), immunotherapy(n = 43), or combination treatment (n = 4). In 66 (90%) of 73 patients ex-periencing PD, a ctDNA increase was observed with a median lead time of1.5 months before radiologic PD. Overall, 119 (33%) of 365 treatment cy-cles were administered after molecular progression. In addition, ctDNAmeasurements could clarify the results in 38 (79%) of 48 nonconclusiveradiologic evaluations.Conclusions: ctDNA monitoring leads to earlier detection of treatmentfailure, and clarifies the majority of nonconclusive radiologic evaluations,giving the potential of sparing patients from likely futile treatments andneedless adverse events.Significance: Treatment monitoring by ctDNA has the clinical potentialto reveal PD before radiologic evaluation and consequently spare patientswith advanced cancer from likely ineffective, costly cancer treatments andadverse events

Supplemental chromium and revaccination effects on performance and health of newly weaned calves

Two trials were conducted to evaluate the effects of chromium (Cr) supplementation (4 mg/hd/day in a yeast form) or no supplementation, with or without revaccination with a modified live viral vaccine at 9 days postweaning o n performance, health, and ability to withstand an IBR challenge infection. In Trial 1, Cr supplementation had no effect on performance of newly weaned calves in a 28-day receiving study, but reduced the incidence of respiratory disease by 37%. Revaccinati on depressed dry matter intake and had no effect on animal health. In trial 2, blood plasma levels of cortisol and ACTH (stress hormones ) were measured at 6 and 26 days postweaning. Cortisol levels were unaffected by treatment or by time after weaning. Plasma ACTH conc e ntrations were lower at 26 vs 6 days postweaning, and were reduced at 26 days by revaccination. Despite some slight differences in rectal temperature, treatment did not appear to affect the animals\u27 ability to withstand a live IBR challenge. We concluded that supplemental Cr was beneficial in reducing the incidence of bovine respiratory disease, although mediation of stress hormones was not involved. Revaccination of newly weaned calves with a modified live viral vaccine showed no performance or health benefit

The antiferromagnetic phi4 Model, II. The one-loop renormalization

It is shown that the four dimensional antiferromagnetic lattice phi4 model has the usual non-asymptotically free scaling law in the UV regime around the chiral symmetrical critical point. The theory describes a scalar and a pseudoscalar particle. A continuum effective theory is derived for low energies. A possibility of constructing a model with a single chiral boson is mentioned.Comment: To appear in Phys. Rev.

Continuous admission to primary school and mental health problems

Background: Younger children in a school class have higher rates of mental health problems if admission to primary school occurs once a year. This study examines whether this relative age effect also occurs if children are admitted to school continuously throughout the year. Methods: We assessed mental health problems based on parent-reports (using the Child Behavior Checklist, CBCL) and on professional assessments, among two Dutch national samples of in total 12,221 children aged 5-15 years (response rate: 86.9%). Results: At ages 5-6, we found a higher occurrence of mental health problems in relatively young children, both for mean CBCL scores (p = 0.017) and for problems assessed by child health professionals (p < 0.0001). At ages 7-15, differences by relative age did not reach statistical significance. Conclusion: Continuous admission to primary school does not prevent mental health problems among young children, but may do so at older ages. Its potential for the prevention of mental problems deserves further study

Adolescents' use of care for behavioral and emotional problems: Types, trends, and determinants

Objective: While adolescents use various types of care for behavioral and emotional problems, evidence on age trends and determinants per type is scarce. We aimed to assess use of care by adolescents because of behavioral and emotional problems, overall and by type, and its determinants, for ages 10-19 years. Methods: We obtained longitudinal data on 2,230 adolescents during ages 10-19 from four measurements regarding use of general care and specialized care (youth social care and mental healthcare) in the preceding 6 months, the Child Behavior Checklist (CBCL) and Youth Self-Report, and child and family characteristics. We analyzed data by multilevel logistic regression. Results: Overall rates of use increased from 20.1% at age 10/11 to 32.2% at age 19: general care was used most. At age 10/11 use was higher among boys, at age 19 among girls. Use of general care increased for both genders, whereas use of specialized care increased among girls but decreased among boys. This differential change was associated with CBCL externalizing and internalizing problems, school problems, family socioeconomic status, and parental divorce. Preceding CBCL problems predicted more use: most for mental health care and least for general care. Moreover, general care was used more frequently by low and medium socioeconomic status families, with odds ratios (95%-confidence intervals): 1.52 (1.23;1.88) and 1.40 (1.17;1.67); youth social care in case of parental divorce, 2.07 (1.36;3.17); and of special education, 2.66 (1.78;3.95); and mental healthcare in case of special education, 2.66 (1.60;4.51). Discussion: Adolescents with behavioral and emotional problems use general care most frequently. Overall use increases with age. Determinants of use vary per type

Investigation of quasi-periodic variations in hard X-rays of solar flares. II. Further investigation of oscillating magnetic traps

In our recent paper (Solar Physics 261, 233) we investigated quasi-periodic oscillations of hard X-rays during impulsive phase of solar flares. We have come to conclusion that they are caused by magnetosonic oscillations of magnetic traps within the volume of hard-X-ray (HXR) loop-top sources. In the present paper we investigate four flares which show clear quasi-periodic sequences of HXR pulses. We also describe our phenomenological model of oscillating magnetic traps to show that it can explain observed properties of HXR oscillations. Main results are the following: 1. We have found that low-amplitude quasi-periodic oscillations occur before impulsive phase of some flares. 2. We have found that quasi-period of the oscillations can change in some flares. We interpret this as being due to changes of the length of oscillating magnetic traps. 3. During impulsive phase a significant part of the energy of accelerated (non-thermal) electrons is deposited within the HXR loop-top source. 4. Our analysis suggests that quick development of impulsive phase is due to feedback between pulses of the pressure of accelerated electrons and the amplitude of magnetic-trap oscillation. 5. We have also determined electron number density and magnetic filed strength for HXR loop-top sources of several flares. The values fall within the limits of $N \approx (2 -15) \times 10^{10}$ cm$^{-3}$, $B \approx (45 - 130)$ gauss.Comment: 18 pages, 14 figures, submitted to Solar Physic

Adrenocorticotropic hormone elicits gonadotropin secretion in premenopausal women

STUDY QUESTION Does adrenocorticotropic hormone (ACTH) induce gonadotropin release in premenopausal women? SUMMARY ANSWER Administration of ACTH stimulates gonadotropin release, most likely by stimulation of the production of cortisol, in premenopausal women. WHAT IS KNOWN ALREADY In animal models, acute activation of the hypothalamic-pituitary-adrenal (HPA) axis has been shown to induce gonadotropin release in the presence of sufficiently high estrogen levels. However, it is unknown whether the HPA axis has a similar influence on gonadotropin release in humans. STUDY DESIGN, SIZE, DURATION This study had a mixed factorial design. A total of 60 healthy female participants participated in the experimental study. PARTICIPANTS/MATERIALS, SETTING, METHODS The study sample comprised three distinct hormonal-based populations according to their levels of progesterone (PROG) and estradiol (E2): (i) low-PROG-low-E2, (ii) low-PROG-high-E2 and (iii) high-PROG-high-E2 women. A low dose (1 μg) of ACTH was administered to all study participants. Serum steroid and gonadotropin concentrations were measured prior to, and at 30 and 90 minutes after, intravenous ACTH administration. MAIN RESULTS AND THE ROLE OF CHANCE Mean serum cortisol levels increased significantly following ACTH administration in all groups (P < 0.001). Similarly, the serum levels of 17-OH-PROG, androstenedione, dehydroepiandrosterone and testosterone increased significantly in all groups (P < 0.01). The low-PROG-high-E2 and high-PROG-high-E2 groups exhibited a significant increase in LH and FSH levels (P < 0.001), whereas the low-PROG-low-E2 group demonstrated blunted LH and FSH responses to ACTH administration (P < 0.05). LIMITATIONS, REASONS FOR CAUTION Testing was performed during the lut