Angiopoietins Modulate Survival, Migration, and the Components of the Ang-Tie2 Pathway of Chronic Lymphocytic Leukaemia (CLL) Cells In Vitro

In actuality, chronic lymphocytic leukaemia (CLL) remains an incurable haematopoietic malignancy of high prevalence amongst elderly populations in the West. Malignant CLL cells characteristically accumulate in the peripheral blood, bone marrow, lymph nodes, and spleen of CLL patients. There is evidence that CLL cells express Ang2 and Tie1, two central components of the Ang-Tie2 pro-angiogenic pathway. Central to blood vessel development and maintenance, at present it remains unclear how the Ang-Tie2 pathway modulates CLL pathophysiology. Here we evaluate the status of the Ang-Tie2 pathway in CLL cells and assess Ang1 levels in plasma/cell medium from CLL samples. To understand how angiopoietins in the microenvironment regulate the components of Ang-Tie2 pathway, survival, migration, and metabolic fitness of CLL cells, we exposed CLL cells to recombinant angiopoietins. CLL plasma and CLL cells in culture present significant lower levels of Ang1. CLL cells simultaneously express Ang1, Ang2, and Tie1 mRNA, but lack that of Tie2 and its regulator, VE-PTP. Exposure to Ang1 confers survival advantage in the long-term, whereas Ang2 and trebananib, an angiopoietin blocker, proved detrimental. Angiopoietins differentially modulate expression of Ang1, Ang2, and Tie1 transcripts. Ang2, but not Ang1, induces the concomitant and transient expression of Tie2 and VE-PTP mRNA. Both angiopoietins, particularly Ang2, increase CLL-Tie1 expression and Ang1 clearly induces chemotaxis and transendothelial-like migration of CLL cells. Besides, changes in caspase and ATP content corroborate the sensitivity of CLL cells to angiopoietin exposure. Altogether, this work shows that angiopoietins regulate the fate of CLL cells in a Tie2-independent manner and highlights the potential of the Ang-Tie2 pathway as a therapeutic target in CLL research

Trichostatin A effectively induces apoptosis in chronic lymphocytic leukemia cells via inhibition of Wnt signaling and histone deacetylation

Background T he ontogenetic Wnt pathway shows almost no activity in adult tissues. In contrast, chronic lymphocytic leukemia (CLL) cells show constitutionally active Wnt signaling, which is associated with upregulated levels of pathway members such as Wnt3 and lymphoid enhancer-binding factor-1. Functionally, this results in increased resistance to apoptosis. We therefore assumed that targeting members of the pathway could reveal new therapeutic options for the treatment of CLL. Methods Screening a Wnt compound library with 75 Wnt modulators via AT P assay revealed Trichostatin A as an outstanding substance with strong viability decreasing effects on CLL cells and little effect on healthy peripheral blood mononuclear cells (PBMCs). Further survival analysis was performed via fluorescence-activated cell sorting analysis. Results A maximum effect was achieved after 48 h with a wide therapeutic window in contrast to PBMCs (CLL cells: 0.253 mu M, PBMCs: 145.22 mu M). Trichostatin A induced caspases and acted via a dual mechanism to reveal histone and non-histone targets. Histone targets were displayed in deacetylation inhibition at DNA level, and non-histone targeting was demonstrated by elevated levels of Dickkopf-related protein 1 mRNA. Primary cells of patients with critical mutations such as TP53 or those who had already undergone extensive previous treatment responded well to the treatment. Moreover, the approved histone deacetylase (HDAC) inhibitor suberoylanilidehydroxamic acid (SAHA) was not as effective as Trichostatin A (Trichostatin A: 0.253 mu M, SAHA: 7.88 mu M). Combining Trichostatin A with established CLL drugs fludarabine or bendamustine showed an additive effect in vitro. Conclusion Taken together, Trichostatin A appears to act via a dual anti-HDAC/Wnt mechanism with a high selectivity and efficacy in CLL and therefore warrants further investigation

The Impact of Agricultural Irrigation on Landslide Triggering: A Review from Chinese, English, and Spanish Literature

Landslides are considered a natural process, with hundreds of events occurring every year in many regions of the world. However, human activities can significantly affect how stable a slope or cliff is, increasing the chances of slope collapses. Moreover, agricultural irrigation has potential to saturate subsurface materials well below ground level and is known to be an important factor that can trigger landslides in many countries. A macroregional literature review of irrigation-induced landslides was developed in this investigation, considering what has been published in Chinese, English, and Spanish. A total of 115 peer-reviewed papers, books and book chapters, graduate and undergraduate theses, and government reports were found, including 82 case studies (23 in Chinese, 26 in English, and 33 in Spanish). Results from this analysis indicate that studies focusing on this important topic have increased exponentially since the 1960s, with most irrigation-induced landslides occurring in dry climates (precipitation less than 600 mm/year), with rainfall concentrated during summer months. The majority of studies have been done in the loess region of China (Asian region), followed by Peru (Latin American region), though cases were found from other macroregions (African, Indian, Russian, Angloamerican, and Indonesian). Based on this global review, new agricultural irrigation projects located in collapsible areas must include a landslide risk analysis. Cultivated areas can follow a series of measures to minimize the chances of triggering a landslide, which would put human lives, ecosystems, food production, and infrastructure at risk