Targeting quiescent leukemic stem cells using second generation autophagy inhibitors

In chronic myeloid leukemia (CML), tyrosine kinase inhibitor (TKI) treatment induces autophagy that promotes survival and TKI-resistance in leukemic stem cells (LSCs). In clinical studies hydroxychloroquine (HCQ), the only clinically approved autophagy inhibitor, does not consistently inhibit autophagy in cancer patients, so more potent autophagy inhibitors are needed. We generated a murine model of CML in which autophagic flux can be measured in bone marrow-located LSCs. In parallel, we use cell division tracing, phenotyping of primary CML cells, and a robust xenotransplantation model of human CML, to investigate the effect of Lys05, a highly potent lysosomotropic agent, and PIK-III, a selective inhibitor of VPS34, on the survival and function of LSCs. We demonstrate that long-term haematopoietic stem cells (LT-HSCs: Lin−Sca-1+c-kit+CD48−CD150+) isolated from leukemic mice have higher basal autophagy levels compared with non-leukemic LT-HSCs and more mature leukemic cells. Additionally, we present that while HCQ is ineffective, Lys05-mediated autophagy inhibition reduces LSCs quiescence and drives myeloid cell expansion. Furthermore, Lys05 and PIK-III reduced the number of primary CML LSCs and target xenografted LSCs when used in combination with TKI treatment, providing a strong rationale for clinical use of second generation autophagy inhibitors as a novel treatment for CML patients with LSC persistence

Quality of systematic reviews: an example of studies comparing artificial disc replacement with fusion in the cervical spine.

Cervical artificial disc replacement (C-ADR) is now an alternative to anterior cervical discectomy and fusion (ACDF). Many studies have evaluated the efficacy of C-ADR compared with ACDF. This led to a series of systematic reviews and meta-analyses to evaluate the evidence of the superiority of one intervention against the other. The aim of the study presented here was to evaluate the quality of these reviews and meta-analyses. Medline via Ovid, Embase, and Cochrane Library were searched using the keywords: (total disk replacement, prosthesis, implantation, discectomy, and arthroplasty) AND (cervical vertebrae, cervical spine, and spine) AND (systematic reviews, reviews, and meta-analysis). Screening and data extraction were conducted by two reviewers independently. Two reviewers then assessed the quality of the selected reviews and meta-analysis using 11-item AMSTAR score which is a validated measurement tool to assess the methodological quality of systematic reviews. Screening of full reports of 46 relevant abstracts resulted in the selection of 15 systematic reviews and/or meta-analyses as eligible for this study. The two reviewers' inter-rater agreement level was high as indicated by kappa of >0.72. The AMSTAR score of the reviews ranged from 3 to 11. Only one study (a Cochrane review) scored 100% (AMSTAR 11). Five studies scored below (AMSTAR 5) indicating low-quality reviews. The most significant drawbacks of reviews of a score below 5 were not using an extensive search strategy, failure to use the scientific quality of the included studies appropriately in formulating a conclusion, not assessing publication bias, and not reporting the excluded studies. With a significant exception of a Cochrane review, the methodological quality of systematic reviews evaluating the evidence of C-ADR versus ACDF has to be improved

The Incidence of Adjacent Segment Degeneration after Cervical Disc Arthroplasty (CDA): A Meta Analysis of Randomized Controlled Trials

Cervical disc arthroplasty is being used as an alternative degenerative disc disease treatment with fusion of the cervical spine in order to preserve motion. However, whether replacement arthoplasty in the spine achieves its primary patient centered objective of lowering the frequency of adjacent segment degeneration is not verified yet.We conducted a meta-analysis according to the guidelines of the Cochrane Collaboration using databases including PubMed, Cochrane Central Register of Controlled Trials and Embase. The inclusion criteria were: 1) Randomized, controlled study of degenerative disc disease of the cervical spine involving single segment or double segments using Cervical disc arthroplasty (CDA) with anterior cervical discectomy and fusion (ACDF) as controls; 2) A minimum of two-year follow-up using imaging and clinical analyses; 3) Definite diagnostic evidences for "adjacent segment degeneration" and "adjacent segment disease"; 4) At least a minimum of 30 patients per population. Two authors independently selected trials; assessed methodological quality, extracted data and the results were pooled.No study has specifically compared the results of adjacent segment degenerative; Two papers describing 140 patients with 162 symptomatic cervical segment disorders and compared the rate of postoperative adjacent segment disease development between CDA and ACDF treatments, three publications describing the rate of adjacent-segment surgery including 1273 patients with symptomatic cervical segments. The result of the meta-analysis indicates that there were fewer the rate of adjacent segment disease and the rate for adjacent-segment surgery comparing CDA with ACDF, but the difference was not statistically significant.Based on available evidence, it cannot be concluded, that CDA can significantly reduce the postoperative rate of the adjacent segment degenerative and adjacent segment disease. However, due to some limitations, the results of this meta-analysis should be cautiously accepted, and further studies are needed

Sequential surgical resection of hepatic and pulmonary metastases from colorectal cancer

# The Author(s) 2010. This article is published with open access at Springerlink.com Background Resection of isolated hepatic or pulmonary metastases from colorectal cancer is widely accepted and associated with a 5-year survival rate of 25–40%. The value of aggressive surgical management in patients with both hepatic and pulmonary metastases still remains a controversial area. Materials and methods A retrospective review of 1,497 patients with colorectal carcinoma (CRC) was analysed. Of 73 patients identified with resection of CRC and, at some point in time, both liver and lung metastases, 17 patients underwent metastasectomy (resection group). The remaining 56 patients comprised the non-resection group. Primary tumour, hepatic and pulmonary metastases of all patients were surgically treated in our department of surgery, and the results are that of a single institution. Results The resection group had a 3-year survival of 77%, a 5-year survival of 55 % and a 10-year survival of 18%; median survival was 98 months. The longest overall survival was 136 months; six patients are still alive. In the resection group, overall survival was significantly higher than in the non-resection group (p<0.01). Independent from the chronology of metastasectomy, 5-year survival was 55 % with respect to the primary resection, 28 % with respect to the first metastasectomy and 14 % with respect t

Identification of Degraded Land in the Canary Islands; Tests and Reviews

Degraded Land is an area that either by natural causes (fires, floods, storms or volcanic eruptions) or more by direct or indirect causes of human action, has been altered or modified from its natural state. Restoration is an activity that initiates or accelerates the recovery of an ecosystem. It can be defined as the set of actions taken in order to reverse or reduce the damage caused in the territory. In the case of the Canary Islands there is a high possibility for the territory to suffer processes that degrade the environment, given that the islands are very fragile ecosystems. Added to this they are territories isolated from the continent, which complicates the process of restoring them. In this paper, the different types of common degraded areas in the Canary Islands are identified, as well as the proposed solutions for remediation, such as afforestation of agricultural land or landfill closure and restoration

Vertical Coordination Through Renegotiation

This paper analyzes the strategic use of bilateral supply contracts in sequential negotiations between one manufacturer and two differentiated retailers. Allowing for general contracts and retail bargaining power, I show that the first contracting parties have incentives to manipulate their contract to shift rent from the second contracting retailer and these incentives distort the industry profit away from the fully integrated monopoly outcome. To avoid such distortion, the first contracting parties may prefer to sign a contract which has no commitment power and can be renegotiated from scratch should the manufacturer fail in its subsequent negotiation with the second retailer. Renegotiation from scratch induces the first contracting parties to implement the monopoly prices and might enable them to capture the maximized industry profit. A slotting fee, an up-front fee paid by the manufacturer to the first retailer, and a menu of tariff-quantity pairs are sufficient contracts to implement the monopoly outcome. These results do not depend on the type of retail competition, the level of differentiation between the retailers, the order of sequential negotiations, the level of asymmetry between the retailers in terms of their bargaining power vis-à-vis the manufacturer or their profitability in exclusive dealing

Why there and then, not here and now? Ecological offsetting in California and England, and the sharpening contradictions of neoliberal natures

Failure has become an increasingly important theme of debate in the literature on neoliberal natures. In this article we take up this topic with respect to ecological offsetting, often regarded as an exemplar of market-oriented conservation. Comparing the case of species banking which emerged in California in the 1990s with frustrated efforts to implement a biodiversity offsetting programme in England beginning in 2010, we develop a novel analytical framework for explaining why this kind of environmental market-making may or may not be successful in different contexts. Drawing on work in geography on the neoliberalisation of nature and insights from economic sociology, we characterise ecological offsetting as ‘command-and-commodify’ regulation: a peculiar form of hybrid ecological regulation which depends on an institutional mix of ‘authoritative’ and ‘economic’ power to function. In California, these kinds of environmental markets initially emerged at a moment of compromise, contingent on an embrace of ‘market’ solutions to environmental problems on the one hand, and a somewhat paradoxical expansion of authoritative power to ecologically regulate land development, on the other. In England, by contrast, deep fiscal austerity and deregulatory zeal, combined with resistance from nearly every quarter, initially undermined the possibility of balancing economic and authoritative power, which we argue is necessary for the construction of viable ecological offsetting. Reflecting on themes in the wider literature, we conclude by questioning whether the English experience is indicative of sharpening tensions between economy and ecology in the late neoliberal era

ICAR: endoscopic skull‐base surgery

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The Effects of MiFID II on Sell-Side Analysts, Buy-Side Analysts, and Firms

This paper provides early but broad empirical evidence on a major new investor protection regulation in Europe, MiFID II, which requires investment firms to unbundle investment research from other costs they charge to clients. We predict that the price separation resulting from unbundling and a hard-dollar system leads to a shrinking of the market for sell-side investment research, manifested in lower quantity of sell-side coverage that is of higher quality than before the regulation. We test our predictions in difference-in-differences matched-sample research designs with firm fixed effects. We find a decrease in the number of sell-side analysts covering European firms after MiFID II implementation, particularly for firms that are less important to the sell-side. However, research quality improves; specifically, individual analyst forecasts are more accurate and stock recommendations garner greater market reactions. In addition, sell-side analysts seem to cater more to the buy-side after MiFID II by providing industry recommendations along with stock recommendations. Importantly, we predict and find evidence that buy-side investment firms turn to more in-house research after MiFID II implementation. Equally interesting, buy-side analysts increase their participation and engagement in earnings conference calls compared to the control group. Finally, we find some evidence that stock-market liquidity decreases post-MiFID II. Our findings have implications beyond Europe, as investors are currently pressuring the U.S. Securities and Exchange Commission to adopt a similar regulation