An Embryonic Diapause-like Adaptation with Suppressed Myc Activity Enables Tumor Treatment Persistence

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Discovery of Novel Benzoxaborole-Based Potent Antitrypanosomal Agents

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Does the degree of intratumoural microvessel density and VEGF expression have prognostic significance in osteosarcoma?

The role of angiogenesis as a prognostic indicator in cancer has been extensively studied in recent times with several studies demonstrating a positive correlation for various malignant tumours. However, the role of angiogenesis in osteosarcoma remains a topic of debate. In this study, we aim to evaluate the significance of intratumoural microvessel density (MVD) and the degree of vascular epithelial growth factor (VEGF) expression as markers of angiogenesis and correlate this with disease outcome. Archival paraffin-embedded pre-treatment biopsy tissue of patients treated at St. Vincent's Hospital, Melbourne, with non-metastatic osteosarcoma at initial diagnosis was reviewed. Tissue was processed for immunofluorescent staining of the microvascular endothelial cells with antibodies directed against CD31 and CD34. The degree of angiogenesis was assessed, as determined by the microvessel density (MVD). Further histological examination was performed to assess the degree of VEGF expression. Histological observations were correlated with various clinicopathological factors and patient outcome in terms of recurrence, metastasis and death. Twenty-five cases were reviewed, 15 were male and 10 were female, and the median age was 26 years (range, 13-85). The mean follow-up was 21.5 months (range, 3-75 months). The median MVD was 43 microvessels/0.26 mm2 (range, 25-54) and 46 microvessels/0.26 mm2 (range, 30-58) for CD31 and CD34, respectively. Despite the moderate to high vascularity, there was no significant difference noted between the MVD and disease outcome factors for both CD31 and CD34. There was a trend towards a higher MVD in patients aged > 40 years compared to those < 40 years (p = 0.110 for CD31 and p = 0.097 for CD34). In terms of VEGF expression, 24 of 25 cases demonstrated either moderate or strong expression; however, no prognostic significance was determined. In this study, we were able to demonstrate that osteosarcoma is a relatively vascular tumour; however, the degree of MVD and VEGF expression does not provide prognostic information. It is likely that angiogenesis plays a key role in the pathogenesis of osteosarcoma and is, therefore, a potential target for novel anti-angiogenic therapies.     

Localization of Pigment Epithelium-Derived Factor in Growing Mouse Bone

Pigment epithelium-derived factor (PEDF) is a potent anti-angiogenic factor found in a wide range of fetal and adult tissues, where it is thought to play a role in the regulation of angiogenesis during development. The temporal expression of PEDF during endochondral bone formation has not previously been reported. In this study, we analysed the expression pattern of PEDF in growing mouse hindlimbs from newborn day one through to maturation at week 9, using immunohistochemistry and in situ hybridization. PEDF expression was demonstrated in chondrocytes within the resting, proliferative and upper hypertrophic zones of the epiphyseal growth plate. The pattern of expression was consistent throughout the developmental stages of the mouse. In addition, PEDF was expressed by osteoblasts lining the bone spicules in the ossification zone of metaphyseal bone, as well as by osteoblasts lining cortical periosteum. These novel results demonstrate that PEDF is developmentally expressed in both cartilage and bone cells during endochondral bone formation, and strongly suggest that it may play a regulatory role in the processes of chondrocyte and osteoblast differentiation, endochondral ossification, and bone remodelling during growth and development of long bones.     

Novel cruzain inhibitors for the treatment of Chagas' disease

The protozoan parasite Trypanosoma cruzi, the etiological agent of Chagas' disease, affects millions of individuals and continues to be an important global health concern. The poor efficacy and unfavorable side effects of current treatments necessitate novel therapeutics. Cruzain, the major cysteine protease of T. cruzi, is one potential novel target. Recent advances in a class of vinyl sulfone inhibitors are encouraging; however, as most potential therapeutics fail in clinical trials and both disease progression and resistance call for combination therapy with several drugs, the identification of additional classes of inhibitory molecules is essential. Using an exhaustive virtual-screening and experimental validation approach, we identify several additional small-molecule cruzain inhibitors. Further optimization of these chemical scaffolds could lead to the development of novel drugs useful in the treatment of Chagas' disease.     

Resistance of epiphyseal cartilage to invasion by osteosarcoma is likely to be due to expression of antiangiogenic factors.

OBJECTIVES: Epiphyseal cartilage is a barrier to osteosarcoma invasion, however the mechanisms behind this resistance remain unclear. The aim of this study was to examine the chronological and spatial patterns of osteosarcoma growth and invasion of local tissue structures including epiphyseal cartilage. METHODS: We used an in vivomouse model of osteosarcoma to histologically examine tumors at different stages of disease progression. We compared the pattern of osteosarcoma penetration of epiphyseal cartilage with the expression pattern of two potent mediators of angiogenesis; proangiogenic vascular endothelial growth factor (VEGF) and antiangiogenic pigment epithelium-derived factor (PEDF). RESULTS: Epiphyseal cartilage remained intact across its entire length in all sections examined, despite increasing tumor size as well as intra- and extraosseous destruction. In the most advanced cases, only the proangiogenic lowermost layers of the hypertrophic zone of the growth plate were eroded. This corresponded with the growth plate layers which highly expressed the angiogenic factor VEGF. In contrast, the resting, proliferative and upper hypertrophic layers were resistant to osteosarcoma invasion in all cases. This corresponded to the layers with the highest expression of the potent antiangiogenic factor PEDF. CONCLUSION: Epiphyseal cartilage is resistant to local invasion by osteosarcoma. The balance of angiogenesis, influenced by pro- and antiangiogenic factors, is likely to play an important role in this resistance.     

Breastfeeding practices and child growth outcomes in Haiti: an analysis of data from Demographic and Health Surveys

Haiti's national nutrition policy prioritises breastfeeding, but limited data are available to inform strategy. We examined national trends in early initiation of breastfeeding (ErIBF) and exclusive breastfeeding (EBF) over a 10‐year period using data from three Haitian Demographic and Health Surveys (1994–1995, 2000 and 2005–2006). We used multivariate regression methods to identify determinants of ErIBF and EBF in the 2005–2006 data set and to examine relationships to growth. There was no change in ErIBF across surveys [1994–1995: 36.6%, 95% confidence interval (CI) 29.9–43.9; 2000: 49.4%, 95% CI 44.1–54.8; 2005–2006: 43.8%, 95% CI 40.5–47.1]. EBF among 0–5‐month‐olds increased sharply (1994–18995: 1.1%, 95% CI 0.4–3.2; 2000: 22.4%, 95% CI 16.5–29.5; 2005–2006: 41.2%, 95% CI 35.4–47.2). The proportion of breastfeeding children 0–5 months who received soft, solid or semi‐solid foods decreased (1994–1995: 68.5%, 95% CI 57.3–77.9; 2000: 46.3%, 95% CI 39.3–53.4; 2005–2006: 30.9%, 95% CI 25.9–36.5). Child age at time of survey [odds ratio (OR) 1.73; P = 0.027], lower maternal education (OR = 2.14, P = 0.004) and residence in the Artibonite Department (OR 0.31; P = 0.001) were associated with ErIBF among children 0–23 months. Age group and department were significant predictors of EBF among children 0–5 months. ErIBF was associated with higher weight‐for‐age z‐scores [effect size (ES) 0.22; P = 0.033] and height‐for‐age z‐scores (ES 0.20; P = 0.044). There was no statistically significant relationship between EBF and growth. The 10‐year ErIBF and EBF trends in Haiti echo global and regional trends. ErIBF and EBF are related practices but with different determinants in the Haitian context. These differences have implications for intervention delivery.     

Natural product libraries to accelerate the high-throughput discovery of therapeutic leads

A high-throughput (HT) paradigm generating LC-MS-UV-ELSD-based natural product libraries to discover compounds with new bioactivities and or molecular structures is presented. To validate this methodology, an extract of the Indo-Pacific marine sponge Cacospongia mycofijiensis was evaluated using assays involving cytoskeletal profiling, tumor cell lines, and parasites. Twelve known compounds were identified including latrunculins (1-4, 10), fijianolides (5, 8, 9), mycothiazole (11), aignopsanes (6, 7), and sacrotride A (13). Compounds 1-5 and 8-11 exhibited bioactivity not previously reported against the parasite T. brucei, while 11 showed selectivity for lymphoma (U937) tumor cell lines. Four new compounds were also discovered including aignopsanoic acid B (13), apo-latrunculin T (14), 20-methoxy-fijianolide A (15), and aignopsane ketal (16). Compounds 13 and 16 represent important derivatives of the aignopsane class, 14 exhibited inhibition of T. brucei without disrupting microfilament assembly, and 15 demonstrated modest microtubule-stabilizing effects. The use of removable well plate libraries to avoid false positives from extracts enriched with only one or two major metabolites is also discussed. Overall, these results highlight the advantages of applying modern methods in natural products-based research to accelerate the HT discovery of therapeutic leads and/or new molecular structures using LC-MS-UV-ELSD-based libraries.     

Protecting and improving breastfeeding practices during a major emergency: lessons learnt from the baby tents in Haiti

Problem

The 2010 earthquake in Haiti displaced about 1.5 million people, many of them into camps for internally displaced persons. It was expected that disruption of breastfeeding practices would lead to increased infant morbidity, malnutrition and mortality.

Approach

Haiti’s health ministry and the United Nations Children’s Fund, in collaboration with local and international nongovernmental organizations, established baby tents in the areas affected by the earthquake. The tents provided a safe place for mothers to breastfeed and for non-breastfed infants to receive ready-to-use infant formula. Such a large and coordinated baby tent response in an emergency context had never been mounted before anywhere in the world.

Local setting

Baby tents were set up in five cities but mainly in Port-au-Prince, where the majority of Haiti’s 1555 camps for displaced persons had been established.

Relevant changes

Between February 2010 and June 2012, 193 baby tents were set up; 180 499 mother–infant pairs and 52 503 pregnant women were registered in the baby tent programme. Of infants younger than 6 months, 70% were reported to be exclusively breastfed and 10% of the “mixed feeders” moved to exclusive breastfeeding while enrolled. In 2010, 13.5% of registered infants could not be breastfed. These infants received ready-to-use infant formula.

Lessons learnt

Thanks to rapid programme scale-up, breastfeeding practices remained undisrupted. However, better evaluation methods and comprehensive guidance on the implementation and monitoring of baby tents are needed for future emergencies, along with a clear strategy for transitioning baby tent activities into facility and community programmes.