Exploring structure/property relationships to health and environmental hazards of polymeric polyisocyanate prepolymer substances-3. Aquatic exposure and hazard of aliphatic diisocyanate-based prepolymers.

The water extractability and acute aquatic toxicity of seven aliphatic diisocyanate-based prepolymer substances were investigated to determine if lesser reactivity of the aliphatic isocyanate groups, as well as increased ionization potential of the expected (aliphatic amine-terminated) polymeric hydrolysis products, would influence their aquatic behavior compared to that of previously investigated aromatic diisocyanate-based prepolymers. At loading rates of 100 and 1,000 mg/L, only the substances having log Kow ≤9 exhibited more than 1% extractability in water, and a maximum of 66% water extractability was determined for a prepolymer having log Kow = 2.2. For the more hydrophobic prepolymer substances (log Kow values from 18-37), water extractability was negligible. High-resolution mass spectrometric analyses were performed on the water-accommodated fractions (WAF) of the prepolymers, which indicated the occurrence of primary aliphatic amine-terminated polymer species having backbones and functional group equivalent weights aligned to those of the parent prepolymers. Measurements of reduced surface tension and presence of suspended micelles in the WAFs further supported the occurrence of these surface-active cationic polymer species as hydrolysis products of the prepolymers. Despite these characteristics, the water-extractable hydrolysis products were practically non-toxic to Daphnia magna. All of the substances tested exhibited 48-h EL50 values of >1,000 mg/L, with one exception of EL50 = 157 mg/L. The results from this investigation support a grouping of the aliphatic diisocyanate-based prepolymers as a class of water-reactive polymer substances having predictable aquatic exposure and a uniformly low hazard potential, consistent with that previously demonstrated for the aromatic diisocyanate-based prepolymers.

Evaluating How a School-Based Skin Cancer Prevention Program Can Change Behavior Among North Carolina Highschoolers.

The incidence of skin cancer has risen steadily over recent decades. Childhood and adolescent sun exposure remains a critical risk factor in skin cancer development, making education of high schoolers imperative for promoting sun-safe behaviors. Medical students in North Carolina recognized this need and designed a skin cancer education program focused on portraying skin cancer in individuals with all Fitzpatrick skin phototypes. Eighty-seven students completed the pre-survey, and 84 completed the post-session survey. In the post-survey, 88% of students listed actionable behavioral changes they plan to make following the presentation. Following an educational session, students were able to demonstrate their new knowledge and provide meaningful behavioral changes. This program navigated challenges posed by COVID-19 and addressed the need for more inclusive skin cancer educational material.

Measuring and Improving Adherence to Crisaborole 2% Ointment in Patients With Atopic Dermatitis.

BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin condition with dry, scaly, and intensely itchy skin. Treatment failure is the result of poor adherence. OBJECTIVE: In this study, we assessed the impact of an internet-based survey on adherence to topical crisaborole 2% ointment in patients with mild AD. METHODS: Participants were randomized to the intervention or control group. The intervention group received weekly email surveys regarding adherence for 6 weeks, then monthly for 12 months. All participants came in for 5 visits over the year. RESULTS: Twenty-eight subjects were recruited for the study (n=19 adults, n=9 pediatrics). Adherence for adults that remained in study (n=6) was 60%. Adherence of the adult control and intervention groups were 49% and 45%, respectively (P>0.05). Adherence for pediatric participants that remained in study (n=2) was 6%. The adherence of the pediatric control and intervention groups were 27% and 29%, respectively (P>0.05). DISCUSSION: Medication adherence was low. The survey intervention did not improve adherence. However, more participants in the intervention group completed the study than in the control group of adults. Regular communication from the provider may help patients feel supported and continue treatment. CLINICALTRIALS: gov identifier: NCT03250663 J Drugs Dermatol. 2022;21(10):1043-1048. doi:10.36849/JDD.6280.

Exploring structure/property relationships to health and environmental hazards of polymeric polyisocyanate prepolymer substances-2. Dermal sensitization potential in the mouse local lymph node assay.

The sensitization potencies of twenty custom-designed monomer-depleted polymeric polyisocyanate prepolymer substances and their associated toluene diisocyanate (TDI), methylene diphenyl diisocyanate (MDI), hexamethylene diisocyanate (HDI), and isophorone diisocyanate (IPDI) monomer precursors were investigated by means of the mouse Local Lymph Node Assay (LLNA). These polymeric prepolymers were designed to represent the structural features and physical-chemical properties exhibited by a broad range of commercial polymeric polyisocyanate prepolymers that are produced from the reaction of aromatic and aliphatic diisocyanate monomers with aliphatic polyether and polyester polyols. The normalization of LLNA responses to the applied (15-45-135 mM) concentrations showed that the skin sensitization potency of polymeric polyisocyanate prepolymers is at least 300 times less than that of the diisocyanate monomers from which they are derived. The sensitization potency of the prepolymers was shown to be mainly governed by their hydrophobicity (as expressed by the calculated octanol-water partition coefficient, log Kow) and surfactant properties. Neither hydrophilic (log Kow <0) nor very hydrophobic (log Kow >25) prepolymers stimulated lymphocyte proliferation beyond that of the dosing vehicle control. The findings of this investigation challenge the generally held assumption that all isocyanate (-N=C=O) bearing substances are potential skin (and respiratory) sensitizers. Further, these findings can guide the future development of isocyanate chemistries and associated polyurethane applications toward reduced exposure and health hazard potentials.

Gaining Insights about Forest Health Prescriptions from Loggers and Foresters: Understudied Voices in the Human Dimensions of Forest Health.

Maintaining healthy forests requires multiple individuals, including foresters who develop timber sale silvicultural prescriptions and loggers who implement those prescriptions, resulting in the transplantation of forest health science into workable management plans. However, data on the experiences, attitudes, and opinions of these two groups are often missing when developing or refining forest health treatment strategies. To explore the role that these groups play in sustaining forest health, we examined timber sale administrators' and loggers' perspectives on treatment approaches for eastern spruce dwarf mistletoe (Arceuthobium pusillum) (ESDM), a parasitic plant native to Minnesota that increases mortality and reduces growth rate and regeneration success of black spruce (Picea mariana). While ESDM has been managed for decades in black spruce stands in Minnesota, little is known about the effectiveness of the management approaches. Data were gathered through interviews and focus groups with loggers, as well as an online survey and focus groups with foresters who administer timber sales. Study participants identified a range of field-based barriers, knowledge gaps, and uncertainties that hamper the ability to effectively implement ESDM treatment strategies as designed, including financial, administrative, informational, policy-related, and environmental factors. These factors have a significant bearing on the ability to effectively implement ESDM treatment approaches; yet may be factors that were not known or considered when developing treatment strategies. This case study underscores the value of nurturing a science-management partnership to ensure that a broad set of voices are considered when developing or revising forest health treatment strategies.

Adherence to levetiracetam for management of epilepsy: Assessment with electronic monitors.

INTRODUCTION: Anti-seizure medications are used to manage epilepsy and require long-term adherence to maintain therapeutic drug levels. We assessed adherence to levetiracetam and the use of a digital intervention to improve adherence in patients with epilepsy. METHODS: 30 participants with epilepsy were randomized 1:1 either to a digital email adherence intervention or control group. All patients were provided levetiracetam equipped with electronic monitoring caps to assess patient adherence to medication. Patients were followed for 6 months, with return visits at 1 month, 3 months, and 6 months. RESULTS: Subjects randomized to the control arm (n = 15) took 66% of the prescribed doses compared to the intervention group, who took 65% of prescribed doses (n = 15). Nine participants did not complete the study. Of the twenty-one participants that completed the study, the overall rate of adherence was 72% of prescribed doses taken. Two subjects in the control group and three subjects in the intervention group were adherent every month of the study-taking at least 80% of prescribed doses. Those randomized to the control group took the correct number of doses 44% of days in the study, and those in the intervention group took the correct number of doses 37% of days. DISCUSSION: Poor adherence to levetiracetam is common. An internet-based email survey intervention did not improve adherence to levetiracetam in epilepsy patients. Further advances in adherence are needed to help patients receive the maximum benefit of their medical treatments.

Factors Influencing Family Forest Owners' Interest in Community-led Collective Invasive Plant Management.

Effective invasive plant management requires collective action. However, little is known about what motivates individuals to work collectively. We conducted a mail survey of 2,600 randomly selected family forest owners in Indiana, USA to examine factors associated with community-led collective action. Specifically, we examined the role of perceived self-efficacy, perceived collective efficacy, concerns about invasive plants, and social norms associated with invasive plant management in shaping family forest owners' self-reported likelihood to work with their neighbors to remove invasive plants. We found that past experience talking to others or working with neighbors to remove invasive plants were important predictors of landowners' intention to work collectively, as were perceived self-efficacy in their own ability to manage invasive plants, perceived need for collective action, social norms, and concerns about invasive plants on neighboring or nearby properties. However, most socio-demographic characteristics (e.g., age, gender, education level, income) and land ownership characteristics (e.g., residence status, having a written forest management plan) were not statisically significant predictors of family forest owners' likelihood to work with their neighbors. Our findings suggest that building individual sense of competence, facilitating neighbor interactions, and strengthening shared concerns may facilitate community-led collective action to manage invasive plants.

Understanding invasive plant management on family forestlands: An application of protection motivation theory.

Invasive forest plants are a growing concern because of their perceived and actual negative ecological, economic, and social impacts. To effectively manage invasive plants in forest ecosystems, it is paramount to understand the management decisions made by family forest owners (FFOs), who collectively own 36% of forestlands in the United States. We contribute to the growing literature on invasive plant management and the factors that influence FFOs' likelihood to manage invasive plants on their property by incorporating protection motivation theory (PMT; Rogers 1975). Protection Motivation Theory argues that the degree to which individuals protect themselves from a perceived threat varies as a function of the perceived severity of the threat, their vulnerability to the threat, their perceptions of self-efficacy to effectively mitigate the threat, and the degree to which they believe they have access to the resources needed to effectively respond to the threat. We surveyed a random sample of 2,600 FFOs in Indiana about their knowledge, perceptions, experience, and plans regarding invasive plants on their wooded lands. Consistent with PMT, we constructed a hierarchical binary logistic model and found that FFOs reported greater intentions to manage invasive plants when they perceived the problem to be more severe and also when they felt a stronger sense of self-efficacy to address the problem. Although perceived vulnerability was not significant in our final model, our results also show that FFOs who had previous invasive plant management experience, had a Bachelor's degree or higher level of education, owned woodlands for recreational purposes, and were more subject to normative social influence also tended to report greater intentions to manage invasive plants. Together, these results suggest that components of PMT (perceived severity and self-efficacy) may be used to inform potential strategies, programs, and outreach for engaging family forest owners in invasive plant management.

Maple Syrup Producers of the Lake States, USA: Attitudes Towards and Adaptation to Social, Ecological, and Climate Conditions.

Maple syrup is an important non-timber forest product derived from the sap of the sugar maple (Acer saccharum Marshall). However, maple syrup producers are facing a diversity of challenges, including: potential range shifts in the maple resource; increasing variability in the timing, duration and yield of sap flow and syrup operations; invasive species, pests and diseases; and intergenerational land and business transfer challenges. Members of Maple Syrup Producer Associations in Minnesota, Wisconsin, and Michigan were surveyed to learn about their operations, adaptation strategies, concerns, and information needs. While many respondents indicated they have undertaken or plan to undertake adaptation activities, only 11% had done so out of specific concern over changing climate conditions. Climate-motivated activities included: being prepared to tap earlier and utilizing newer technology such as vacuum tubing or reverse osmosis to enhance sap collection and processing efficiency. Respondents were generally unlikely to consider planting climate-resilient maple cultivars or tapping trees other than sugar maple. They expressed the greatest concerns over tree health and forest pests, as well as their physical ability and family member interest to continue their operations. Boil season variability and weather issues were viewed with less concern. Respondents were generally optimistic that they can adapt to future conditions, likely in large measure through the adoption of new technologies, and they expect their syrup production levels to slightly increase in the future. If future climate scenarios play out, however, additional planning and adaptation strategies may be called for, particularly as they relate to forest health and productivity issues.

Preliminary investigation of cognitive function in aged multiple sclerosis patients: Challenges in detecting comorbid Alzheimer's disease.

BACKGROUND: Cognitive impairment can be seen in patients of all ages with multiple sclerosis (MS). However, there is limited research on neurocognitive disorder in older adults with MS and how to detect Alzheimer's disease (AD) or its prodromal stage, amnestic mild cognitive impairment (aMCI). Thus, the MS clinician is challenged to discriminate between signs of MS-related cognitive decline versus a secondary neurodegenerative process. OBJECTIVE: Compare cognition in older MS patients to patients with AD and aMCI. METHODS: We evaluated cognitively impaired and unimpaired MS patients, AD patients, aMCI patients, and healthy controls (HCs), all elderly (n = 20 per group). AD and aMCI diagnoses were derived by consensus conference independent of the MS research project. Neuropsychological measures assessed domains commonly affected in AD, including verbal memory and expressive language. RESULTS: Cognitively impaired and unimpaired MS groups did not differ on any measures sensitive to AD. Unimpaired MS patients were comparable to HCs. Impaired MS patients showed decreased semantic fluency, similar to aMCI patients. Lastly, while both AD and aMCI groups had deficient memory retention, there was no evidence of a retention deficit in either MS group. CONCLUSION: Our findings suggest that the cognitive profiles of MS and AD are distinct. In contrast to AD, MS is not associated with impairment of memory consolidation. However, there may be overlap between cognitive deficits related to MS and aMCI. Thus, evidence of poor memory retention, in an older MS patient may merit comprehensive dementia evaluation. The study is preliminary and includes no AD biomarkers (e.g., amyloid imaging) to confirm or rule out AD pathology.

Visitor Preferences for Visual Changes in Bark Beetle-Impacted Forest Recreation Settings in the United States and Germany.

Extensive outbreaks of tree-killing insects are increasing across forests in Europe and North America due to climate change and other factors. Yet, little recent research examines visitor response to visual changes in conifer forest recreation settings resulting from forest insect infestations, how visitors weigh trade-offs between physical and social forest environment factors, or how visitor preferences might differ by nationality. This study explored forest visitor preferences with a discrete choice experiment that photographically simulated conifer forest stands with varying levels of bark beetle outbreaks, forest and visitor management practices, and visitor use levels and compositions. On-site surveys were conducted with visitors to State Forest State Park in Colorado (n = 200), Lake Bemidji State Park in Minnesota (n = 228), and Harz National Park in Germany (n = 208). Results revealed that the condition of the immediate forest surrounding was the most important variable influencing visitors' landscape preferences. Visitors preferred healthy mature forest stands and disliked forests with substantial dead wood. The number of visitors was the most important social factor influencing visitor landscape preferences. Differences in the influence of physical and social factors on visual preferences existed between study sites. Findings suggest that both visual forest conditions and visitor use management are important concerns in addressing landscape preferences for beetle-impacted forest recreation areas.

Quantitative analysis of unconjugated and total bisphenol A in human urine using solid-phase extraction and UPLC-MS/MS: method implementation, method qualification and troubleshooting.

The aim of the presented investigation was to document challenges encountered during implementation and qualification of a method for bisphenol A (BPA) analysis and to develop and discuss precautions taken to avoid and to monitor contamination with BPA during sample handling and analysis. Previously developed and published HPLC-MS/MS methods for the determination of unconjugated BPA (Markham et al. Journal of Analytical Toxicology, 34 (2010) 293-303) [17] and total BPA (Markham et al. Journal of Analytical Toxicology, 38 (2014) 194-203) [20] in human urine were combined and transferred into another laboratory. The initial method for unconjugated BPA was developed and evaluated in two independent laboratories simultaneously. The second method for total BPA was developed and evaluated in one of these laboratories to conserve resources. Accurate analysis of BPA at sub-ppb levels is a challenging task as BPA is a widely used material and is ubiquitous in the environment at trace concentrations. Propensity for contamination of biological samples with BPA is reported in the literature during sample collection, storage, and/or analysis. Contamination by trace levels of BPA is so pervasive that even with extraordinary care, it is difficult to completely exclude the introduction of BPA into biological samples and, consequently, contamination might have an impact on BPA biomonitoring data. The applied UPLC-MS/MS method was calibrated from 0.05 to 25ng/ml. The limit of quantification was 0.1ng/ml for unconjugated BPA and 0.2ng/ml for total BPA, respectively, in human urine. Finally, the method was applied to urine samples derived from 20 volunteers. Overall, BPA can be analyzed in human urine with acceptable recovery and repeatability if sufficient measures are taken to avoid contamination throughout the procedure from sample collection until UPLC-MS/MS analysis.

Extensive metabolism and route-dependent pharmacokinetics of bisphenol A (BPA) in neonatal mice following oral or subcutaneous administration.

Orally administered bisphenol A (BPA) undergoes efficient first-pass metabolism to produce the inactive conjugates BPA-glucuronide (BPA-G) and BPA-sulfate (BPA-S). This study was conducted to evaluate the pharmacokinetics of BPA, BPA-G and BPA-S in neonatal mice following the administration of a single oral or subcutaneous (SC) dose. This study consisted of 3 phases: (1) mass-balance phase in which effective dose delivery procedures for oral or SC administration of (3)H-BPA to postnatal day three (PND3) mice were developed; (2) pharmacokinetic phase during which systemic exposure to total (3)H-BPA-derived radioactivity in female PND3 mice was established; and (3) metabolite profiling phase in which 50 female PND3 pups received either a single oral or SC dose of (3)H-BPA. Blood was collected from 5 pups/route/time-point at various times post-dosing, the blood plasma samples were pooled by group, and time-point and samples were profiled by HPLC with fraction collection. Fractions were analyzed for total radioactivity and data used to reconstruct radiochromatograms and to integrate individual peaks. The identity of the BPA, BPA-G, and BPA-S peaks was confirmed using authentic standards and LC-MS/MS analysis. The result of this study revealed that female PND3 mice have the capacity to metabolize BPA to BPA-G, BPA-S and other metabolites after both routes of administration. Systemic exposure to free BPA is route-dependent as the plasma concentrations were lower following oral administration compared to SC injection.

Family forest landowners' interest in forest carbon offset programs: focus group findings from the lake States, USA.

In 2012, focus groups were organized with individuals owning 20+ acres in the Lake States region of the United States (Michigan, Minnesota, and Wisconsin) to discuss various issues related to forest carbon offsetting. Focus group participants consisted of landowners who had responded to an earlier mail-back survey (2010) on forest carbon offsets. Two focus groups were held per state with an average of eight participants each (49 total). While landowner participant types varied, overall convergence was reached on several key issues. In general, discussion results found that the current payment amounts offered for carbon credits are not likely, on their own, to encourage participation in carbon markets. Landowners are most interested in other benefits they can attain through carbon management (e.g., improved stand species mix, wildlife, and trails). Interestingly, landowner perceptions about the condition of their own forest land were most indicative of prospective interest in carbon management. Landowners who felt that their forest was currently in poor condition, or did not meet their forest ownership objectives, were most interested in participating. While the initial survey sought landowner opinions about carbon markets, a majority of focus group participants expressed interest in general carbon management as a means to achieve reduced property taxes.

The Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS-P): description and validation in a psychiatric sample and healthy controls.

OBJECTIVE: The aim of the present study was to investigate the psychometric properties of the Bipolar Prodrome Symptom Interview and Scale-Prospective (BPSS-P), the first specific interview for emerging bipolar disorder (BD) symptoms. METHODS: A total of 205 youth aged 12-23 years and/or their caregivers underwent BPSS-P interviews: 129 patients with mood spectrum disorders [depression spectrum disorder (n = 77), mood disorder not otherwise specified (NOS) (n = 27), BD-NOS (n = 14), bipolar I disorder (BD-I)/bipolar II disorder (BD-II)/cyclothymia (n = 11), 34 with non-mood spectrum disorders, and 42 healthy controls (HCs)]. We used Cronbach's α to assess internal consistency; intra-class correlation (ICC) for inter-rater reliability; Spearman's rho for convergent validity with the Young Mania Rating Scale (YMRS), General Behavior Inventory-10-item Mania Form (GBI-M-10), and Cyclothymic-Hypersensitive Temperament (CHT) scale; and analysis of variance for discriminatory power between diagnostic groups. RESULTS: Internal consistency was good to very good for the BPSS-P Mania (Cronbach's α = 0.87), Depression (Cronbach's α = 0.89), and General Symptom indices (Cronbach's α = 0.74). Inter-rater reliability was high for the BPSS-P Total score (ICC = 0.939), and BPSS-P Mania (ICC = 0.934), Depression (ICC = 0.985), and General (ICC = 0.981) indices. Convergent validity was large (ρ ≥ 0.50) between the BPSS-P Mania Index and YMRS, GBI-M-10, and CHT; BPSS-P Depression Index and Montgomery-Åsberg Depression Rating Scale (MADRS) and CHT; and BPSS-P General Index and GBI-M-10 and CHT. Expectedly, convergent validity was small (ρ = 0.10 to < 0.30) between the BPSS-P Mania Index and MADRS, and BPSS-P Depression Index and YMRS. Furthermore, the BPSS-P and its subscales discriminated each patient group from HCs and from non-mood spectrum patients (except for the BPSS-P General Index). Moreover, the BPSS-P Total score discriminated BD-I/BD-II/cyclothymia from depression spectrum patients, and the BPSS-Mania Index differentiated all three bipolar spectrum groups from depression spectrum patients. CONCLUSIONS: The BPSS-P has good to excellent psychometric properties. Its use across multiple settings and predictive validity requires further investigation.

Development of a method for the determination of total bisphenol a at trace levels in human blood and urine and elucidation of factors influencing method accuracy and sensitivity.

This publication describes a method for the determination of total bisphenol A (BPA and conjugated BPA) following enzyme hydrolysis and is intended as a companion to our previously developed analytical method for the determination of free BPA (the aglycone) in human blood and urine using high-performance liquid chromatography-tandem mass spectrometry ( 1). That free BPA method provided a means to account for and/or eliminate background contamination and demonstrated accuracy and reproducibility in both matrices fortified with BPA or a surrogate analyte ((13)C BPA) at a low method quantitation limit (MQL) of 0.1-0.2 ng/mL. In contrast to the free BPA method results and based on stringent accuracy, precision and confirmation criteria set for the MQLs of the method developed for total BPA, the MQL achieved in blood was 1.020-2.550 and 0.510-1.020 ng/mL in urine. These data showed higher MQLs than the desired MQLs of 0.5 ng/mL (blood) and 0.2 ng/mL (urine) with increased variability between analyses which demonstrates the importance of generating method validation data with each analysis. In contrast, the MQL achieved for (13)C BPA-G (monoglucuronide as a surrogate analyte in blood was 0.2-0.5 and 0.2 ng/mL in urine illustrating that the method is capable of meeting lower MQL requirements if the contribution from exogenous BPA can be well controlled. This method for the determination total BPA in human blood and urine is intended to be used in conjunction with the free BPA method ( 1) to obtain accurate and complete BPA biomonitoring data to support human exposure assessments.

Medical adherence to acne therapy: a systematic review.

BACKGROUND: Poor adherence of acne patients to treatment may equate to poor clinical efficacy, increased healthcare costs, and unnecessary treatments. Authors have investigated risk factors for poor medical adherence and how to improve this difficult problem in the context of acne. OBJECTIVE: This systematic review aims to describe what methods have been used to measure adherence, what is known about acne patients' adherence to treatment, and the factors affecting adherence. METHODS: A MEDLINE search was performed for randomized controlled trials published between 1978 and June 2013, focusing on patient adherence to prescribed acne medications. A test for equality of proportions was performed on studies of similar design to collectively analyze adherence to oral versus topical medication. The self-reported adherence data collected from these clinical trials were then compared with adherence data from a pharmacy database study. RESULTS: Studies varied in modalities of data collection, but the majority utilized subjective methods. Topical therapies were more often studied than oral. The overall oral adherence rate, as calculated by a test of equality of proportions, was 76.3%, while the overall topical adherence rate was 75.8% (p=0.927). The occurrence of side effects and young age were cited as the top reasons for poor adherence, followed by forgetfulness. LIMITATIONS: The MEDLINE search resulted in a limited sample of adherence studies. In addition, there is currently no standardized or fully validated method of measurement, allowing for variability in what was considered 'adherent'. Lastly, data collected via subjective methods cannot guarantee reliable results. CONCLUSIONS: Overall, the values reflected a population adherent to both topical and oral medications, with no significant difference in adherence between the two. However, the methodologies used by many of the studies were weak, and the findings are not consistent with results of more objective measures of adherence. The leading factors that contribute to poor adherence may be reduced with enhanced patient consultation, reminder systems, and education.

Shifts in the vascular endothelial growth factor isoforms result in transcriptome changes correlated with early neural stem cell proliferation and differentiation in mouse forebrain.

Regulation of neural stem cell (NSC) fate decisions is critical during the transition from a multicellular mammalian forebrain neuroepithelium to the multilayered neocortex. Forebrain development requires coordinated vascular investment alongside NSC differentiation. Vascular endothelial growth factor A (Vegf) has proven to be a pleiotrophic gene whose multiple protein isoforms regulate a broad range of effects in neurovascular systems. To test the hypothesis that the Vegf isoforms (120, 164, and 188) are required for normal forebrain development, we analyzed the forebrain transcriptome of mice expressing specific Vegf isoforms, Vegf120, VegfF188, or a combination of Vegf120/188. Transcriptome analysis identified differentially expressed genes in embryonic day (E) 9.5 forebrain, a time point preceding dramatic neuroepithelial expansion and vascular investment in the telencephalon. Meta-analysis identified gene pathways linked to chromosome-level modifications, cell fate regulation, and neurogenesis that were altered in Vegf isoform mice. Based on these gene network shifts, we predicted that NSC populations would be affected in later stages of forebrain development. In the E11.5 telencephalon, we quantified mitotic cells [Phospho-Histone H3 (pHH3)-positive] and intermediate progenitor cells (Tbr2/Eomes-positive), observing quantitative and qualitative shifts in these populations. We observed qualitative shifts in cortical layering at P0, particularly with Ctip2-positive cells in layer V. The results identify a suite of genes and functional gene networks that can be used to further dissect the role of Vegf in regulating NSC differentiation and downstream consequences for NSC fate decisions.

A novel monoclonal antibody to secreted frizzled-related protein 2 inhibits tumor growth.

Secreted frizzled-related protein 2 (SFRP2) is overexpressed in human angiosarcoma and breast cancer and stimulates angiogenesis via activation of the calcineurin/NFATc3 pathway. There are conflicting reports in the literature as to whether SFRP2 is an antagonist or agonist of ß-catenin. The aims of these studies were to assess the effects of SFRP2 antagonism on tumor growth and Wnt-signaling and to evaluate whether SFRP2 is a viable therapeutic target. The antiangiogenic and antitumor properties of SFRP2 monoclonal antibody (mAb) were assessed using in vitro proliferation, migration, tube formation assays, and in vivo angiosarcoma and triple-negative breast cancer models. Wnt-signaling was assessed in endothelial and tumor cells treated with SFRP2 mAb using Western blotting. Pharmacokinetic and biodistribution data were generated in tumor-bearing and nontumor-bearing mice. SFRP2 mAb was shown to induce antitumor and antiangiogenic effects in vitro and inhibit activation of ß-catenin and nuclear factor of activated T-cells c3 (NFATc3) in endothelial and tumor cells. Treatment of SVR angiosarcoma allografts in nude mice with the SFRP2 mAb decreased tumor volume by 58% compared with control (P = 0.004). Treatment of MDA-MB-231 breast carcinoma xenografts with SFRP2 mAb decreased tumor volume by 52% (P = 0.03) compared with control, whereas bevacizumab did not significantly reduce tumor volume. Pharmacokinetic studies show the antibody is long circulating in the blood and preferentially accumulates in SFRP2-positive tumors. In conclusion, antagonizing SFRP2 inhibits activation of ß-catenin and NFATc3 in endothelial and tumor cells and is a novel therapeutic approach for inhibiting angiosarcoma and triple-negative breast cancer.