Predictive blood biomarkers of sheep pregnancy and litter size.

Early detection of sheep pregnancy and the prediction of how many lambs a pregnant ewe delivers affects sheep farmers in a number of ways, most notably with regard to feed management, lambing rate, and sheep/lamb health. The standard practice for direct detection of sheep pregnancy and litter size (PLS) is ultrasonography. However, this approach has a number of limitations. Indirect measurement of PLS using blood biomarkers could offer a simpler, faster and earlier route to PLS detection. Therefore, we undertook a large-scale metabolomics study to identify and validate predictive serum biomarkers of sheep PLS. We conducted a longitudinal experiment that analyzed 131 serum samples over five timepoints (from seven days pre-conception to 70 days post-conception) from six commercial flocks in Alberta and Ontario, Canada. Using LC-MS/MS and NMR, we identified and quantified 107 metabolites in each sample. We also identified three panels of serum metabolite biomarkers that can predict ewe PLS as early as 50 days after breeding. These biomarkers were then validated in separate flocks consisting of 243 animals yielding areas-under-the-receiver-operating-characteristic-curve (AU-ROC) of 0.81-0.93. The identified biomarkers could lead to the development of a simple, low-cost blood test to measure PLS at an early stage of pregnancy, which could help optimize reproductive management on sheep farms.

Candidate serum metabolite biomarkers of residual feed intake and carcass merit in sheep.

Mutton and lamb sales continue to grow globally at a rate of 5% per year. However, sheep farming struggles with low profit margins due to high feed costs and modest carcass yields. Selecting those sheep expected to convert feed efficiently and have high carcass merit, as early as possible in their life cycle, could significantly improve the profitability of sheep farming. Unfortunately, direct measurement of feed conversion efficiency (via residual feed intake [RFI]) and carcass merit is a labor-intensive and expensive procedure. Thus, indirect, marker-assisted evaluation of these traits has been explored as a means of reducing the cost of its direct measurement. One promising and potentially inexpensive route to discover biomarkers of RFI and/or carcass merit is metabolomics. Using quantitative metabolomics, we profiled the blood serum metabolome (i.e., the sum of all measurable metabolites) associated with sheep RFI and carcass merit and identified candidate biomarkers of these traits. The study included 165 crossbred ram-lambs that underwent direct measurement of feed consumption to determine their RFI classification (i.e., low vs. high) using the GrowSafe System over a period 40 d. Carcass merit was evaluated after slaughter using standardized methods. Prior to being sent to slaughter, one blood sample was drawn from each animal, and serum prepared and frozen at -80 °C to limit metabolite degradation. A subset of the serum samples was selected based on divergent RFI and carcass quality for further metabolomic analyses. The analyses were conducted using three analytical methods (nuclear magnetic resonance spectroscopy, liquid chromatography mass spectrometry, and inductively coupled mass spectrometry), which permitted the identification and quantification of 161 unique metabolites. Biomarker analyses identified three significant (P < 0.05) candidate biomarkers of sheep RFI (AUC = 0.80), seven candidate biomarkers of carcass yield grade (AUC = 0.77), and one candidate biomarker of carcass muscle-to-bone ratio (AUC = 0.74). The identified biomarkers appear to have roles in regulating energy metabolism and protein synthesis. These results suggest that serum metabolites could be used to categorize and predict sheep for their RFI and carcass merit. Further validation using a larger (3×) and more diverse cohort of sheep is required to confirm these findings.

Photovoice for healthy relationships: community-based participatory HIV prevention in a rural American Indian community.

This article provides an example of a culturally responsive, community-based project for addressing social determinants of health in rural American Indian (AI) communities through: 1) empowering youth and community voices to set directions for HIV, sexually transmitted infections, and unintended pregnancy prevention and education efforts; 2) using Photovoice to promote healthy relationships among AI youth; 3) using the socioecological model (Centers for Disease Control and Prevention, 2004; 2011) as a framework for organizing the creation and subsequent sharing of Photovoice messages from individual empowerment, to relationships, communities, institutions, and general society; and 4) framing analysis of Photovoice projects in alignment with Bell's (2010) model of storytelling for social justice that connects narrative and the arts in anti-racist teaching. A discussion on future steps and recommendations for future research is provided.

A phase II study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in relapsed small cell lung cancer.

INTRODUCTION: We previously reported data on the safety, tolerability, and recommended phase II dose of obatoclax mesylate in conjunction with topotecan in patients with advanced solid tumor malignancies. Preliminary efficacy data suggested activity in patients with recurrent small cell lung cancer (SCLC). Based on these data, we performed a phase II study of obatoclax mesylate plus topotecan in patients with relapsed SCLC to assess efficacy. METHODS: This was an open-label, single-arm, phase II extension of obatoclax mesylate plus topotecan in patients with relapsed SCLC. Obatoclax mesylate was given intravenously (IV) at a dose of 14mg/m(2) on days 1 and 3 with IV topotecan at 1.25mg/m(2) on days 1-5 of an every 3-week cycle. The primary end-point of this study was overall response rate. RESULTS: Nine patients with recurrent SCLC were enrolled into the first stage of the study. Patients received a median of 2 cycles of treatment. All patients were evaluable for the primary end-point of overall response. There were no partial or complete responses. Five patients (56%) had stable disease. The remaining four patients (44%) developed progressive disease. The most common grade 3 or 4 adverse events included thrombocytopenia (22%), anemia (11%), neutropenia (11%), and ataxia (11%). CONCLUSION: Obatoclax mesylate added to topotecan does not exceed the historic response rate seen with topotecan alone in patients with relapsed SCLC following the first-line platinum-based therapy.

A phase I study of obatoclax mesylate, a Bcl-2 antagonist, plus topotecan in solid tumor malignancies.

PURPOSE: To establish the safety, maximum tolerated dose (MTD), recommended phase II dose, and preliminary antitumor activity of obatoclax mesylate (GX15-070MS), a Bcl-2 antagonist, in combination with topotecan in patients with solid tumor malignancies. PATIENTS AND METHODS: Patients with solid tumor malignancies for whom topotecan was an appropriate treatment were administered obatoclax mesylate and topotecan on a 3-week cycle in a pre-defined, standard 3 + 3 dose escalation scheme. The starting dose for obatoclax mesylate was 14 mg/m(2) by 3-h intravenous (IV) infusion. Topotecan 1.25 mg/m(2) was given concurrently as an IV infusion on days 1-5 of each cycle. RESULTS: Fourteen patients received 40 cycles of obatoclax mesylate at the following doses: 14 mg/m(2) on day 1, 14 mg/m(2) on days 1 and 3, and 20 mg/m(2) on day 1. The most common toxicities related to obatoclax were neurologic, including ataxia, mood alterations, somnolence, and cognitive dysfunction. The majority of these were grades 1 and 2 (88%). Two of five patients experienced dose-limiting grade 3 neurologic toxicity at a dose of 20 mg/m(2); no patients experienced grade 4 neurologic toxicities, and no other patients experienced grade 3 neurologic toxicity. Of the patients who experienced grade 3 neurologic events, one later developed febrile neutropenia, which was also a dose-limiting toxicity (DLT). After an additional three patients were treated without DLT at the previously tolerated dose of 14 mg/m(2) on day 1, the level was escalated to 14 mg/m(2) on days 1 and 3. Three patients were treated at this dose and, with none experiencing a DLT, 14 mg/m(2) on days 1 and 3 was defined as the recommended phase II dose. Two patients with small-cell lung cancer (SCLC) achieved partial responses and four patients had stable disease. Median time to progression (TTP) was 12 weeks. CONCLUSION: Obatoclax mesylate administered at 14 mg/m(2) IV on days 1 and 3 is safe and well tolerated when given in combination with topotecan 1.25 mg/m(2) IV on days 1-5 of an every 3-week cycle. A phase II trial to assess the efficacy of this combination for patients with relapsed SCLC is currently accruing patients.