Hematopoietic and epithelial cancer cells express CXCR4, a seven-transmembrane G-protein-coupled chemokine receptor. Stromal cells within the bone marrow microenvironment constitutively secrete ...stromal cell-derived factor-1 (SDF-1/CXCL12), the ligand for CXCR4. Activation of CXCR4 induces leukemia cell trafficking and homing to the marrow microenvironment, where CXCL12 retains leukemia cells in close contact with marrow stromal cells that provide growth and drug resistance signals. CXCR4 antagonists, such as Plerixafor (AMD3100) and T140 analogs, can disrupt adhesive tumor-stroma interactions and mobilize leukemia cells from their protective stromal microenvironment, making them more accessible to conventional drugs. Therefore, targeting the CXCR4-CXCL12 axis is a novel, attractive therapeutic approach that is explored in ongoing clinical trials in leukemia patients. Initially, CXCR4 antagonists were developed for the treatment of HIV, where CXCR4 functions as a co-receptor for virus entry into T cells. Subsequently, CXCR4 antagonists were noticed to induce leukocytosis, and are currently used clinically for mobilization of hematopoietic stem cells. However, because CXCR4 plays a key role in cross-talk between leukemia cells (and a variety of other tumor cells) and their microenvironment, cancer treatment may become the ultimate application of CXCR4 antagonists. Here, we summarize the development of CXCR4 antagonists and their preclinical and clinical activities, focusing on leukemia and other cancers.
The functional relevance of the B-cell receptor (BCR) and the evolution of protein kinases as therapeutic targets have recently shifted the paradigm for treatment of B-cell malignancies. Inhibition ...of p110δ with idelalisib has shown clinical activity in chronic lymphocytic leukemia (CLL). The dynamic interplay of isoforms p110δ and p110γ in leukocytes support the hypothesis that dual blockade may provide a therapeutic benefit. IPI-145, an oral inhibitor of p110δ and p110γ isoforms, sensitizes BCR-stimulated and/or stromal co-cultured primary CLL cells to apoptosis (median 20%, n=57; P<0.0001) including samples with poor prognostic markers, unmutated IgVH (n=28) and prior treatment (n=15; P<0.0001). IPI-145 potently inhibits the CD40L/IL-2/IL-10 induced proliferation of CLL cells with an IC50 in sub-nanomolar range. A corresponding dose-responsive inhibition of pAKT(Ser473) is observed with an IC50 of 0.36 nM. IPI-145 diminishes the BCR-induced chemokines CCL3 and CCL4 secretion to 17% and 37%, respectively. Pre-treatment with 1 μM IPI-145 inhibits the chemotaxis toward CXCL12; reduces pseudoemperipolesis to median 50%, inferring its ability to interfere with homing capabilities of CLL cells. BCR-activated signaling proteins AKT(Ser473), BAD(Ser112), ERK(Thr202/Tyr204) and S6(Ser235/236) are mitigated by IPI-145. Importantly, for clinical development in hematological malignancies, IPI-145 is selective to CLL B cells, sparing normal B- and T-lymphocytes.
This paper introduces the theme of the special issue ‘Agglomerations and the Rise of Urban Network Externalities’. Urban network externalities are defined as external economies from which firms and ...households can benefit by being located in agglomerations that are well embedded in networks that connect with other agglomerations. The contributions focus on the conceptualization of urban network externalities and their influence on urban performance. Finally, a research agenda is presented, that should focus on multiplexity and heterogeneity in networks and their impacts; interrelations between agglomerations and networks and their dynamic and place‐based nature; and, the policy implications of urban network externalities.
要約
本論文では、「集積化と都市ネットワーク外部性の出現」という特別な問題をテーマとする。都市ネットワーク外部性とは、企業または家計が、他の集積地と集積をつなぐネットワークに十分組み込まれた集積地に立地することにより、便益を享受できる外部経済と定義される。本論文では、都市ネットワーク外部性の概念化とその都市パフォーマンスに対する影響に注目する。最後に、ネットワークの多重性と多様性およびその影響、集積とネットワークおよびそのダイナミックで地域固有的な特徴との相互関係、都市ネットワーク外部性の政策的インプリケーションに焦点を当てるべきとする研究課題を提示する。
Resumen
Este artículo presenta el tema de la edición especial ‘Aglomeraciones y la aparición de las externalidades de red urbanas’. Las externalidades de red urbanas se definen como las economías externas de las que se pueden beneficiar las empresas y los hogares situados en aglomeraciones que están bien arraigadas en redes que conectan con otras aglomeraciones. Las contribuciones se centran en la conceptualización de las externalidades de red urbana y su influencia en el desempeño urbano. Por último, se presenta un programa de investigación, que debería centrarse en: la multiplicidad y heterogeneidad de las redes y sus impactos; las interrelaciones entre las aglomeraciones y las redes, y su naturaleza dinámica y basada en la localización; y las implicaciones políticas de las externalidades de red urbanas.
The current dynamics in the Western European urban system are in marked contrast with the bourgeoning literature stressing the importance of agglomeration for economic growth. This paper explores ...whether this is due to the rise of ‘city network economies’, leading to processes of borrowed size as well as the rise of agglomeration shadows in networks of cities. The spread of metropolitan functions over Western European cities is analysed. It is found that network connectivity positively enhances the presence of metropolitan functions, but local size remains the most significant determinant for most types of functions. The importance of size and network connectivity differs across metropolitan functions and across cities.
要約
西欧の都市システムの現在の動向は、経済成長に対する集積の重要性を強調する研究論文が増大していることと著しく対照的である。本論文は、これが都市経済ネットワークの出現によるものかどうかを検討し、これが借りものの規模のプロセスで都市ネットワークに集積の影が拡大していることを示す。西欧の都市の大都市としての機能拡大を分析する。ネットワークの連結性は大都市機能が存在していることをプラスに強調するが、地域の規模がほとんどのタイプの機能の最も大きな決定要因であることが分かる。規模とネットワークの連結性の重要性は、大都市の機能および都市によって異なる。
Resumen
Las dinámicas actuales en el sistema urbano de Europa occidental aparecen en marcado contraste con la literatura emergente que hace hincapié en la importancia de la aglomeración en el crecimiento económico. Este artículo examina si esto se debe al aumento de las ‘economías de redes de ciudades’, que dan lugar a procesos de tamaño prestado, así como al aumento de las manchas de aglomeración en redes de ciudades. Se analiza la propagación de las funciones metropolitanas en las ciudades de Europa occidental. Se ha encontrado que la conectividad de las redes mejora de manera positiva la presencia de las funciones metropolitanas, pero el tamaño local sigue siendo el factor determinante más significativo para la mayoría de tipos de funciones. La importancia del tamaño y la conectividad de la red varían entre las funciones metropolitanas y entre ciudades.
Recent concepts such as ‘megaregions' and ‘polycentric urban regions' emphasize that external economies are not confined to a single urban core, but are shared among a collection of nearby and linked ...cities. However, empirical analyses of agglomeration and agglomeration externalities have so far neglected the multicentric spatial organization of agglomeration and the possibility of the ‘sharing’ or ‘borrowing’ of size between cities. The authors take up this empirical challenge by analyzing how different spatial structures, in particular the monocentricity–polycentricity dimension, affect the economic performance of US metropolitan areas. Ordinary least squares and two-stage least-squares models explaining labor productivity show that spatial structure matters: polycentricity is associated with higher labor productivity. This appears to justify suggestions that, compared with more monocentric metropolitan areas, agglomeration diseconomies remain relatively limited in the more polycentric metropolitan areas, whereas agglomeration externalities are to some extent shared among the cities in such an area. However, it was also found that a network of geographically proximate smaller cities cannot substitute for the urbanization externalities of a single large city.
By conducting a meta-analysis of the empirical literature on the net employment effects of renewable energy, we explore the extent to which the reported net employment effects are driven by the ...applied methodology. We find that the reported conclusions on net employment effects are to a large extent driven by the methodology that is applied, where computable general equilibrium (CGE) and I/O methods that include induced effects and studies that consider only the near future in their study period (up to 2020) are generally less optimistic about net employment creation in the wake of the energy transition. In addition, we found that policy reports have a greater tendency to report a positive net employment effect than academic studies.
•The reported size on net employment effects of renewable energy depend on the methodology that is applied.•The direct and indirect employment effects are generally positive, the induced effects can be either positive or negative.•Policymakers have to be cautious when drawing conclusions regarding net employment creation based on a single study.•Results may be sensitive to model specification, and studies may not consider all potential effects of a transition.
In this study, we examine the relationship between neighborhood-based social capital and residents' life satisfaction by considering resident heterogeneity. Using a database of the city of Rotterdam, ...The Netherlands, we find a small but significant positive association between neighborhood-based social capital and individual life satisfaction. However, we also find considerable differences among residents because neighborhood-based social capital is important mainly for people who are more likely to spend considerable time in the neighborhood or who are more neighborhood dependent (i.e. less-educated people, people who live on welfare, people with poor health, retired people, and those who are divorced or widowed). Our results confirm the importance of neighborhood-based social capital for residents' life satisfaction in terms of both actual social contacts with neighbors and the perceived social cohesion within a neighborhood. At the same time, the importance of neighborhood-based social capital varies among different groups of residents. These findings have important implications for policy-makers.
The majority of patients with locally recurrent rectal cancer (LRRC) present with extensive metastatic disease or an unresectable recurrence, and will be treated palliatively. Only a minority of ...patients will be eligible for potential cure by surgical treatment. The aim of this study is to evaluate the long-term outcome of surgical treatment and non-surgical treatment of patients with LRRC.
All patients with LRRC referred to our tertiary institute between 2000 and 2015 were retrospectively analysed. Patients were discussed in a multidisciplinary tumour board (MDT) and eventually received curative surgical or non-surgical treatment. Overall survival (OS) was compared by resection margin status and non-surgical treatment.
A total of 447 patients were discussed in our MDT of which 193 patients underwent surgical treatment and 254 patients received non-surgical treatment. Surgically treated patients were significantly younger, received less neoadjuvant therapy for the primary tumour, had less metastasis at diagnosis and more central recurrences. The 5-year OS was 51% for R0-resections and 34% for R1-resections. Although numbers with R2-resections were too small to implicate prognostic significance, there was no difference in 5-year OS between R2-resections and non-surgical treatment (10% vs. 4%, p = 0.282). In a subgroup analysis the OS of R2-patients was even poorer compared to optimal palliative treated patients with combined chemotherapy and radiotherapy (22 vs 29 months, p = 0.413).
R2-resections do not result in a survival benefit compared to non-surgical treatment in this non-randomized series. Patients with a high chance on a R2-resection could be offered non-surgical treatment, without local resection.
Background
Despite improvements in the multimodality treatment for patients with locally recurrent rectal cancer (LRRC), oncological outcomes remain poor. This study evaluated the effect of induction ...chemotherapy and subsequent chemo(re)irradiation on the pathologic response and the rate of resections with clear margins (R0 resection) in relation to long-term oncological outcomes.
Methods
All consecutive patients with LRRC treated in the Catharina Hospital Eindhoven who underwent a resection after treatment with induction chemotherapy and subsequent chemo(re)irradiation between January 2010 and December 2018 were retrospectively reviewed. Induction chemotherapy consisted of CAPOX/FOLFOX. Endpoints were pathologic response, resection margin and overall survival (OS), disease free survival (DFS), local recurrence free survival (LRFS), and metastasis free survival (MFS).
Results
A pathologic complete response was observed in 22 patients (17%), a “good” response (Mandard 2–3) in 74 patients (56%), and a “poor” response (Mandard 4–5) in 36 patients (27%). An R0 resection was obtained in 83 patients (63%). The degree of pathologic response was linearly correlated with the R0 resection rate (
p
= 0.026). In patients without synchronous metastases, pathologic response was an independent predictor for LRFS, MFS, and DFS (
p
= 0.004,
p
= 0.003, and
p
= 0.024, respectively), whereas R0 resection was an independent predictor for LRFS and OS (
p
= 0.020 and
p
= 0.028, respectively).
Conclusions
Induction chemotherapy in addition to neoadjuvant chemo(re)irradiation is a promising treatment strategy for patients with LRRC with high pathologic response rates that translate into improved oncological outcomes, especially when an R0 resection has been achieved.
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