An autonomous mathematical model for the mammalian cell cycle.

A mathematical model for the mammalian cell cycle is developed as a system of 13 coupled nonlinear ordinary differential equations. The variables and interactions included in the model are based on detailed consideration of available experimental data. A novel feature of the model is inclusion of cycle tasks such as origin licensing and initiation, nuclear envelope breakdown and kinetochore attachment, and their interactions with controllers (molecular complexes involved in cycle control). Other key features are that the model is autonomous, except for a dependence on external growth factors; the variables are continuous in time, without instantaneous resets at phase boundaries; mechanisms to prevent rereplication are included; and cycle progression is independent of cell size. Eight variables represent cell cycle controllers: the Cyclin D1-Cdk4/6 complex, APCCdh1, SCFßTrCP, Cdc25A, MPF, NuMA, the securin-separase complex, and separase. Five variables represent task completion, with four for the status of origins and one for kinetochore attachment. The model predicts distinct behaviors corresponding to the main phases of the cell cycle, showing that the principal features of the mammalian cell cycle, including restriction point behavior, can be accounted for in a quantitative mechanistic way based on known interactions among cycle controllers and their coupling to tasks. The model is robust to parameter changes, in that cycling is maintained over at least a five-fold range of each parameter when varied individually. The model is suitable for exploring how extracellular factors affect cell cycle progression, including responses to metabolic conditions and to anti-cancer therapies.

Additive Damage Models for Cellular Pharmacodynamics of Radiation-Chemotherapy Combinations.

Many cancer patients receive combination treatments with radiation and chemotherapy. Available mathematical models for cellular pharmacodynamics have limited ability to represent observed in vitro responses to radiochemotherapy. Here, a family of additive damage models is proposed to describe cell kill resulting from radiochemotherapy with fixed schedule and variable doses. The pathways by which the agents produce cellular damage are assumed to converge in a single cell death process, so that survival depends on total damage, which can be represented as a sum of contributions from the various damage pathways. Heterogeneity in response across the cell population is ascribed to variations in the damage threshold for cell kill. The family of proposed models includes effects of one or two pathways of damage for each agent, saturation in drug responses, and cooperative or antagonistic interactions between agents. Models from this family with 4-7 unknown parameters are tested for their ability to fit 218 in vitro literature data sets for a range of drugs and cell lines. Overall, the additive damage models are found to outperform models based on the existing concept of independent cell kill, according to the corrected Akaike Information Criterion. The results are used to assess the importance of the various effects included in the models. These additive damage models have potential applications to the optimization of treatment and to the analysis and interpretation of in vitro screening data for new drug-radiation combinations.

Parental tobacco and alcohol use and risk of hepatoblastoma in offspring: a report from the children's oncology group.

BACKGROUND: Hepatoblastoma is a rare pediatric liver tumor that has significantly increased in incidence over the last several decades. The International Agency for Research on Cancer (IARC) recently classified hepatoblastoma as a tobacco-related cancer. Parental alcohol use has shown no association. We examined associations between parental tobacco and alcohol use around the time of pregnancy and hepatoblastoma in a large case-control study. METHODS: Maternal interviews were completed for 383 cases diagnosed in the United States during 2000-2008. Controls (n = 387) were identified through U.S. birth registries and frequency-matched to cases on birth weight, birth year, and region of residence. We used unconditional logistic regression to calculate ORs and 95% confidence intervals (CI) for associations between parental smoking and maternal drinking and offspring hepatoblastoma. RESULTS: We found no association between hepatoblastoma and maternal smoking at any time (OR, 1.0; 95% CI, 0.7-1.4), within the year before pregnancy (OR, 1.1; 95% CI, 0.8-1.6), early in pregnancy (OR, 1.0; 95% CI, 0.7-1.6), or throughout pregnancy (OR, 0.9; 95% CI, 0.5-1.6). We observed marginally positive associations between hepatoblastoma and paternal smoking in the year before pregnancy (OR, 1.4; 95% CI, 1.0-2.0) and during pregnancy (OR, 1.4; 95% CI, 0.9-2.0). Maternal alcohol use was not associated with hepatoblastoma. CONCLUSION: Our results do not provide evidence for an etiologic relationship between maternal smoking or drinking and hepatoblastoma, and only weak evidence for an association for paternal smoking in the year before pregnancy. IMPACT: Our study provides limited support for hepatoblastoma as a tobacco-related cancer; however, it remains wise to counsel prospective parents on the merits of smoking cessation.

Feasibility of a randomized controlled trial to evaluate Text Reminders for Immunization Compliance in Kids (TRICKs).

OBJECTIVE: To pilot test the Text Reminders for Immunization Compliance in Kids (TRICKs) program to evaluate its feasibility and potential to increase immunization coverage. DESIGN: Randomized controlled trial (RCT). SETTING: Pediatric clinic. PARTICIPANTS: Parents of newborns being discharged from a local hospital who intended to seek child health care at the University-sponsored pediatric resident and faculty clinic. INTERVENTION: Text message immunization reminders prior to immunization due dates. MAIN OUTCOME MEASURES: Receipt and timeliness of immunizations at 2, 4 and 6 months of age. RESULTS: Participants (N=90) were English (83%) or Spanish (17%) speaking. The majority were female (83%), on public insurance (59%), and had adequate health literacy (96%). Parents were married or a member of an unmarried couple (62%). Over 66% had a high school diploma or less. Greater numbers of intervention children received immunizations and were "on time" using per protocol analysis; though not statistically significance. Limitations include sample size, problematic text messaging software, and loss of phone service at 7 months for 40% of intervention parents. However, post-intervention interviews (N=18) indicated strong support for TRICKs; 83% found the text message reminders very helpful and 17% somewhat helpful. DISCUSSION: Pilot testing allowed us to assess processes, including recruitment, retention, and software, which will increase the success of an RCT. Software with built-in backup systems is needed for follow-up when mobile service is interrupted. However, in spite of limitations, immunization rates were higher in the text message reminder group, though not statistically significant. Parent support and interest was high. A fully powered RCT is needed with follow-up over the full 4-3-1-3-3-1 series. Based on our results, for 80% power where we expected 90% compliance in the intervention group and 80% in the control group we need 219 per group, plus increases to address drop out and loss of follow-up.

Parent opinions about use of text messaging for immunization reminders.

BACKGROUND: Adherence to childhood immunization schedules is a function of various factors. Given the increased use of technology as a strategy to increase immunization coverage, it is important to investigate how parents perceive different forms of communication, including traditional means and text-message reminders. OBJECTIVE: To examine current forms of communication about immunization information, parents' satisfaction levels with these communication modes, perceived barriers and benefits to using text messaging, and the ideal content of text messages for immunization reminders. METHODS: Structured interviews were developed and approved by two Institutional Review Boards. A convenience sample of 50 parents was recruited from two local pediatric clinics. The study included a demographics questionnaire, the shortened form of the Test of Functional Health Literacy for Adults (S-TOFHLA), questions regarding benefits and barriers of text communication from immunization providers, and preferred content for immunization reminders. Content analyses were performed on responses to barriers, benefits, and preferred content (all Cohen's kappas > 0.70). RESULTS: Respondents were mostly female (45/50, 90%), white non-Hispanic (31/50, 62%), between 20-41 years (mean = 29, SD 5), with one or two children (range 1-9). Nearly all (48/50, 96%) had an S-TOFHLA score in the "adequate" range. All parents (50/50, 100%) engaged in face-to-face contact with their child's physician at appointments, 74% (37/50) had contact via telephone, and none of the parents (0/50, 0%) used email or text messages. Most parents were satisfied with the face-to-face (48/50, 96%) and telephone (28/50, 75%) communication. Forty-nine of the 50 participants (98%) were interested in receiving immunization reminders by text message, and all parents (50/50, 100%) were willing to receive general appointment reminders by text message. Parents made 200 comments regarding text-message reminders. Benefits accounted for 63.5% of comments (127/200). The remaining 37.5% (73/200) regarded barriers; however, no barriers could be identified by 26% of participants (13/50). Parents made 172 comments regarding preferred content of text-message immunization reminders. The most frequently discussed topics were date due (50/172, 29%), general reminder (26/172, 26%), and child's name (21/172, 12%). CONCLUSIONS: Most parents were satisfied with traditional communication; however, few had experienced any alternative forms of communication regarding immunizations. Benefits of receiving text messages for immunization reminders far outweighed the barriers identified by parents. Few barriers identified were text specific. Those that were, centered on cost if parents did not have unlimited texting plans.

Using human factors techniques to design text message reminders for childhood immunization.

This study engaged parents to develop concise, informative, and comprehensible text messages for an immunization reminder system using Human Factors techniques. Fifty parents completed a structured interview including demographics, technology questions, willingness to receive texts from their child's doctor, and health literacy. Each participant was assigned to one user-centered design test: card sort, needs analysis, or comprehension. The majority of respondents were female (90%), White non-Hispanic (62%), and averaged 29 years (SD = 5). Nearly all (96%) had "adequate" health literacy. The card sort, an activity in which end users organize information into categories, identified six pieces of critical information. These were compiled into eight example texts, which were ranked in the needs assessment. The top two were assessed for comprehension, with 100% of participants able to understand the content and describe intention to act. Using user-centered design methods, the authors developed concise, informative text messages that parents indicated would prompt them to schedule their child's immunization appointment.

Physician impressions of using text message technology to increase vaccination compliance.

INTRODUCTION: Immunization schedules are complicated and difficult for parents to remember. Parents are willing to receive text message reminders. However, it is unknown whether physicians are willing to implement such a system. The purpose of this study was to evaluate the feasibility of a text messaging reminder system from the physician's perspective. MATERIALS AND METHODS: Surveys were distributed in the winter of 2009-2010 by e-mail, facsimile, and telephone interview to 149 family physicians and pediatricians who provide immunizations in Sedgwick County, Kansas. RESULTS: A 69% response rate was achieved. Nearly all (92%) respondents reported that they currently communicate information about immunization schedules to parents using traditional methods such as verbal reminders or appointment cards; however, none (0%) currently use text or email to generate reminders to parents. Even when asked to assume they had all of the necessary resources, almost one-third (31%) reported that they were "very unwilling" or "unwilling" to use a general text-messaging program, 43% were "neutral" or "undecided," and only 27% were "willing" or "very willing." Physician willingness to use a text-messaging program was not related to their reported gender (χ²(2)=0.224, p=0.894), specialization (χ² (2)=4.363, p=0.113), years in practice (F(2, 91)=0.435, p=0.149), or comfort level with technology (χ²(4)=1.861, p=0.761). CONCLUSIONS: There is a hesitancy to implement a text message reminder system for childhood vaccine schedules. This may be due to the lack of empirical evidence supporting the use of this technology for health reminders or the lack of willingness to implement another system. Further investigation is needed to determine why few physicians are willing to implement text messaging for immunization reminders.

Dynamic interactions between orexin and dynorphin may delay onset of functional orexin effects: a modeling study.

Orexin (also known as hypocretin) neurons play a key role in regulating sleep-wake behavior, but the links between orexin neuron electrophysiology and function have not been explored. Orexin neurons are wake-active, and spiking activity in orexin neurons may anticipate transitions to wakefulness by several seconds. However, it is suggested that while the orexin system is necessary to maintain sustained wake bouts, orexin has little effect on brief wake bouts. In vitro experiments investigating the actions of orexin and dynorphin, a colocalized neuropeptide, on orexin neurons indicate that the dynamics of desensitization to dynorphin may represent a mechanism for modulating local network activity and resolving the apparent discrepancy between the onset of firing in orexin neurons and the onset of functional orexin effects. To investigate the role of dynorphin on orexin neuron activity, a Hodgkin-Huxley-type model orexin neuron was developed in which baseline electrophysiology, orexin/dynorphin action, and dynorphin desensitization were closely tied to experimental data. In this model framework, model orexin neuron responses to orexin/dynorphin action were calibrated by simulating the physiologic effects of static orexin and dynorphin bath application on orexin neurons. Then behavior in a small network of model orexin neurons was simulated with pure orexin, pure dynorphin, or combined orexin and dynorphin coupling based on the mechanisms established in the static case. It was found that the dynamics of desensitization to dynorphin can mediate a clear shift from a network in which firing is suppressed by dynorphin-mediated inhibition to a network of neurons with high firing rates sustained by orexin-mediated excitation. The findings suggest that dynamic interactions between orexin and dynorphin at transitions from sleep to wake may delay onset of functional orexin effects.