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We propose a flexible model for a partially migrating species, which we demonstrate using yearly paths for golden eagles (Aquila chrysaetos). Our model relies on a smoothly time-varying potential surface defined by a number of attractors. We compare our proposed approach using varying coefficients to a latent-state model, which we define differently for migrating, dispersing, and local individuals. While latent-state models are more common in the existing animal movement literature, varying coefficient models have various benefits including the ability to fit a wide range of movement strategies without the need for major model adjustments. We compare simulations from the models for three individuals to illustrate the ability of our model to better describe movement behavior for specific movement strategies. We also demonstrate the flexibility of our model by fitting several individuals whose movement behavior is less stereotypical. [ABSTRACT FROM AUTHOR]

BACKGROUND Targeting the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway is of increasing interest as a therapeutic strategy in many tumors. The aim of this study was to identify molecular markers associated with mTOR inhibitor activity in women with metastatic endometrial cancer. METHODS Archival tumor samples were collected from 94 women with recurrent or metastatic endometrial cancer who participated in 3 National Cancer Insitute of Canada Clinical Trials Group phase 2 trials investigating single-agent mTOR inhibitors: IND160A and IND160B (temsirolimus) and IND192 (ridaforolimus). Analyses included mutational profiling using the OncoCarta Panel version 1.0 and immunohistochemical expression of the tumor suppressor gene PTEN (phosphatase and tensin homologue) and stathmin, a marker of PI3K activation. Associations between biomarker results and clinical outcomes were assessed. RESULTS Mutations were found in 32 of 73 analyzed tumors, PIK3CA (21 patients) was the most common mutated gene. Co-mutations were seen in 8 tumors, most frequently KRAS and PIK3CA (4 cases). PTEN loss was observed in 46 of 85 samples analyzed and increased stathmin expression was observed in 15 of 65 analyzed samples. No correlation was observed between biomarkers and response or progression. In patients taking concurrent metformin, there was a trend toward lower progression, of 11.8% versus 32.5% ( P = .14). CONCLUSIONS No predictive biomarker or combination of biomarkers for mTOR inhibitor activity were identified in this study. Restriction and enrichment of study entry, especially based on archival tumor tissue, should be undertaken with caution in trials using these agents. Cancer 2014;120:603-610. © 2013 American Cancer Society. [ABSTRACT FROM AUTHOR]

As the implementation of artificial intelligence and machine learning technologies progresses toward the clinic, the traditional roles of physicians will change. [ABSTRACT FROM AUTHOR]

Sorafenib is active in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The National Cancer Institute of Canada (NCIC) Clinical Trials Group initiated a phase I/II study of the combination of sorafenib with cytarabine in older patients with AML or high-risk MDS who were unsuitable for intensive chemotherapy. FLT3 mutational status was determined in all patients. Twenty-one patients were enrolled (four MDS, 17 AML) with a median age of 77 years. The recommended phase II dose (RP2D) was cytarabine 10 mg bid days 1-10 and sorafenib 600 mg/day days 2-28. Dose-limiting toxicities were fatigue, sepsis and skin rash. Of 15 evaluable patients treated at the RP2D, two patients responded. The overall response rate for eligible patients was 10%. FLT3 mutations were found in only three patients. We conclude that this combination of sorafenib and cytarabine has limited activity in this unselected cohort of elderly patients with AML/MDS in which FLT3 mutations seemed underrepresented. [ABSTRACT FROM AUTHOR]

Background: Somali Bantu refugees, with unique health information needs, created challenges for health and social service providers. Objectives: A service innovation was developed (i) to raise awareness, especially among local health and social service providers, about the Bantu refugees' presence in the community, their culture, and their information needs and (ii) to deliver needed health information, emphasizing child health, to the Bantu mothers in their homes. Methods: The project consisted of: (i) a community conference targeting local health and social service providers, describing the refugees' presence in the community, their culture, and information needs. (ii) Focus groups conducted with members of the Bantu population elicited additional information needs. (iii) Curriculum was developed based on identified needs, and (iv) the curriculum was delivered to the refugees in their homes. A clinical informationist and MP3 technology enhanced the project. Findings: Conference attendees' evaluation responses indicated improved understanding of Bantu culture. Focus groups' identification of health information needs provided a framework for the health education curriculum. A project website made educational materials available to other healthcare providers. Conclusions: The project raised awareness of the Bantus' presence, culture, and information needs. Identification of other unmet needs demonstrated that additional support for refugees is required. [ABSTRACT FROM AUTHOR]

The study was conducted to evaluate a regional, prospective database of information on mothers of low birth weight (LBW) infants. The database informs on unidentified or under-reported modifiable risk factors from which evidence-based, targeted community intervention strategies could be designed to lower the rate of low birth weight in the region. The LBW Registry is based on informed consent, a semi-structured face-to-face (FTF) interview with the mother of the newborn LBW infant, medical record review, and birth certificate worksheet data collection. Descriptive statistics were used to summarize data from the registry. High rates of modifiable risk factors among mothers of low birth weight infants (October 2007-October 2008) include smoking (44%), alcohol consumption (16%), and drug abuse (14%). Preconception vitamin use was low (34%). The reported use of fertility drugs in FTF interviews was notably higher than information reported on the birth certificate worksheets by the same set of interviewed mothers (5.4 vs. 1.5%), as was alcohol use during pregnancy (16 vs. 1.3%). More than half (52%) of the mothers of low birth weight infants reported a vaginal or urinary tract infection during pregnancy. Additionally there were higher than average rates of unmarried mothers (62%), unintended pregnancies (67%), and Medicaid beneficiaries (57%). Mothers repeatedly expressed excessive demands in their lives, straining their coping abilities and resources. The LBW Registry provides expanded local data on potentially modifiable risk factors to aid in designing targeted prevention and intervention strategies. [ABSTRACT FROM AUTHOR]

We undertook a phase I/II study of the EGFR/erbB2 inhibitor lapatinib in patients with recurrent glioblastoma multiforme (GBM) to determine response rate, pharmacokinetics (PK) and recommended dose in patients taking enzyme-inducing anti-epileptic drugs (EIAEDs) and to explore relationships of molecular genetics to outcome. Recurrent GBM patients taking EIAEDs were enrolled on the phase I portion (starting dose of lapatinib 1,000 mg po bid). In the absence of dose-limiting toxicity (DLT), escalation continued in cohorts of three patients. Patients not on EIAEDs enrolled in the phase II arm (lapatinib 750 mg bid po). Immunohistochemical and quantitative RT PCR studies were performed on tumor to determine PTEN and EGFRvIII status, respectively. Lapatinib PK was analyzed using HPLC with tandem mass spectrometry. Phase II: Of 17 patients, 4 had stable disease and 13 progressed. Accrual ceased because of no responses. Phase I: Four patients received 1,000 mg bid and three, 1,500 mg bid. No DLT occurred, but escalation stopped because of lack of phase II efficacy. Lapatinib apparent oral clearance in patients taking EIAEDs was 106.9 L h−1 m−2 in comparison to 12.1 L h−1 m−2 in those not on EIAEDs. In 16 phase II patients, PTEN loss was seen in 6 and EGFRvIII expression in 4. No correlation was seen with outcome and molecular results. Lapatinib apparent oral clearance increased by approximately tenfold when given with EIAEDs. In this small sample, EGFRvIII expression and PTEN loss did not predict a favorable subtype. Overall, lapatinib did not show significant activity in GBM patients. [ABSTRACT FROM AUTHOR]

Despite both the increase in basic biologic knowledge and the fact that many new agents have reached various stages of development during the last 10 years, the number of new treatments that have been approved for patients has not increased as expected. We propose the multi-arm, multi-stage trial design as a way to evaluate treatments faster and more efficiently than current standard trial designs. By using intermediate outcomes and testing a number of new agents (and combinations) simultaneously, the new design requires fewer patients. Three trials using this methodology are presented. [ABSTRACT FROM AUTHOR]

Background: Clusterin is a cytoprotective chaperone protein that promotes cell survival and confers broad-spectrum treatment resistance. OGX-011 is a 2′-methoxyethyl modified phosphorothioate antisense oligonucleotide that is complementary to clusterin mRNA and has been reported to inhibit clusterin expression and enhance drug efficacy in xenograft models. The primary objective of this clinical study was to determine a biologically effective dose of OGX-011 that would inhibit clusterin expression in human cancer. Methods: Subjects (n = 25) with localized prostate cancer with high-risk features who were candidates for prostatectomy were treated with OGX-011 by 2-hour intravenous infusion on days 1, 3, and 5 and then weekly from days 8–29 combined with androgen blockade starting on day 1; prostatectomy was performed on days 30–36. Six different doses were tested, from 40 to 640 mg. OGX-011 plasma and prostate tissue concentrations were measured by an enzyme-linked immunosorbent assay method, and the pharmacokinetics of OGX-011 were determined from these data. Prostate cancer tissue, lymph nodes, and serial samples of peripheral blood mononuclear cells were assessed for clusterin expression using quantitative real-time polymerase chain reaction and immunohistochemistry. All statistical tests were two-sided. Results: Only grade 1 and 2 toxicities were observed. The plasma half-life of OGX-011 was approximately 2–3 hours, and the area under the concentration versus time curve and CMAX (peak plasma concentration) increased proportionally with dose (Ptrend«.001). OGX-011 in prostate tissue increased with dose (Ptrend«.001). Dose-dependent decreases in prostate cancer and lymph node clusterin expression were observed by polymerase chain reaction of greater than 90% (Ptrend = .008 and Ptrend«.001, respectively) and by immunohistochemistry (Ptrend«.001 and Ptrend = .01, respectively). Conclusions: OGX-011 is well tolerated and reduces clusterin expression in primary prostate tumors. The optimal biologic dose for OGX-011 at the schedule used is 640 mg. [ABSTRACT FROM AUTHOR]