IInteractions between laminins and integrin receptors hold neural stem cells in place at the ventricular surface of embryonic brain. Transient disruption leads to abnormal stem cell divisions and permanent cortical malformation.

The identification of markers for the isolation of human neural stem cells (hNSCs) is essential for studies of their biology and therapeutic applications. This study investigated expression of the integrin receptor family by hNSCs as potential markers. Selection of ␣6 hi or ␤1 hi cells by fluorescence-activated cell sorting led to an enrichment of human neural precursors, as shown by both neurosphere forming assays and increased expression of prominin-1, sox2, sox3, nestin, bmi1, and musashi1 in the ␤1 hi population. Cells expressing high levels of ␤1 integrin also expressed prominin-1 (CD133), a marker previously used to isolate hNSCs, and selection using integrin ␤1 hi cells or prominin-1 hi cells was found to be equally effective at enriching for hNSCs from neurospheres. Therefore, integrin subunits ␣6 and ␤1 are highly expressed by human neural precursors and represent convenient markers for their prospective isolation.

Objective Glioblastomas (GBMs) are lethal cancers that display cellular hierarchies parallel to normal brain. At the apex are GBM stem cells (GSCs), which are relatively resistant to conventional therapy. An important driver of malignancy and self-renewal in GSCs are interactions with the adjacent perivascular niche. Extracellular matrix (ECM) cues instruct neural stem/progenitor cell-niche interactions and the objective of our study was to elucidate its composition and contribution to GSC maintenance in the perivascular niche. Methods We interrogated human tumor tissue for immunofluorescence analysis and derived GSC from tumor tissues for functional studies. Bioinformatics analyses were conducted by mining publicly available databases. Results We find that laminin ECM proteins are localized to the perivascular GBM niche and inform negative patient prognosis. To identify the source of laminins, we characterized cellular elements within the niche and found that laminin α chains were expressed by non-stem tumor cells and tumor associated endothelial cells (ECs). RNA interference targeting laminin α2 inhibited GSC growth and self-renewal. In co-culture studies of GSCs and ECs, laminin α2 knockdown in ECs resulted in decreased tumor growth. Interpretation Our studies highlight the contribution of non-stem tumor cell-derived laminin juxtracrine signaling. As laminin α2 has recently been identified as a molecular marker of aggressive ependymoma, we propose that the brain vascular ECM promotes tumor malignancy through maintenance of the GSC compartment providing not only a molecular fingerprint but also a possible therapeutic target.

Background: Human neural stem cells (hNSC) have the potential to provide novel cell-based therapies for neurodegenerative conditions such as multiple sclerosis and Parkinson's disease. In order to realise this goal, protocols need to be developed that allow for large quantities of hNSC to be cultured efficiently. As such, it is important to identify factors which enhance the growth of hNSC. In vivo, stem cells reside in distinct microenvironments or niches that are responsible for the maintenance of stem cell populations. A common feature of niches is the presence of the extracellular matrix molecule, laminin. Therefore, this study investigated the effect of exogenous laminin on hNSC growth.

The introduction of new contraceptive technologies has great potential for expanding contraceptive choice, but in practice, benefits have not always materialized as new methods have been added to public-sector programs. In response to lessons from the past, the UNDP/UNFPA/WHO/World Bank Special Programme of Research, Development, and Research Training in Human Reproduction (HRP) has taken major steps to develop a new approach and to support governments interested in its implementation. After reviewing previous experience with contraceptive introduction, the article outlines the strategic approach and discusses lessons from eight countries. This new approach shifts attention from promotion of a particular technology to an emphasis on the method mix, the capacity to provide services with quality of care, reproductive choice, and users' perspectives and needs. It also suggests that technology choice should be undertaken through a participatory process that begins with an assessment of the need for contraceptive introduction and is followed by research and policy and program development. Initial results from Bolivia, Brazil, Burkina Faso, Chile, Myanmar, South Africa, Vietnam, and Zambia confirm the value of the new approach.

Purpose: Patients with recurrent high-grade gliomas (HGG) are usually managed with alkylating chemotherapy AE bevacizumab. However, prognosis remains very poor. Preclinically, we showed that HGGs are a target for arginine depletion with pegargiminase (ADI-PEG20) due to epimutations of argininosuccinate synthetase (ASS1) and/or argininosuccinate lyase (ASL). Moreover, ADI-PEG20 disrupts pyrimidine pools in ASS1-deficient HGGs, thereby impacting sensitivity to the antifolate, pemetrexed. Patients and Methods: We expanded a phase I trial of ADI-PEG20 with pemetrexed and cisplatin (ADIPEMCIS) to patients with ASS1-deficient recurrent HGGs (NCT02029690). Patients were enrolled (01/16-06/17) to receive weekly ADI-PEG20 36 mg/m 2 intramuscularly plus pemetrexed 500 mg/m 2 and cisplatin 75 mg/m 2 intravenously once every 3 weeks for up to 6 cycles. Patients with disease control were allowed ADI-PEG20 maintenance. The primary end-points were safety, tolerability, and preliminary estimates of efficacy. Results: Ten ASS1-deficient heavily pretreated patients were treated with ADIPEMCIS therapy. Treatment was well tolerated with the majority of adverse events being Common Terminology Criteria for Adverse Events v4.03 grade 1-2. The best overall response was stable disease in 8 patients (80%). Plasma arginine was suppressed significantly below baseline with a reciprocal increase in citrulline during the sampling period. The anti-ADI-PEG20 antibody titer rose during the first 4 weeks of treatment before reaching a plateau. Median progression-free survival (PFS) was 5.2 months (95% confidence interval (CI), 2.5-20.8) and overall survival was 6.3 months (95% CI, 1.8-9.7). Conclusions: In this recurrent HGG study, ADIPEMCIS was well tolerated and compares favorably to historical controls.

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