Ibrutinib inhibits SDF1/CXCR4 mediated migration in AML

Pharmacological targeting of BTK using ibrutinib has recently shown encouraging clinical activity in a range of lymphoid malignancies. Recently we reported that ibrutinib inhibits human acute myeloid leukemia (AML) blast proliferation and leukemic cell adhesion to the surrounding bone marrow stroma cells. Here we report that in human AML ibrutinib, in addition, functions to inhibit SDF1/CXCR4-mediated AML migration at concentrations achievable in vivo. It has previously been shown that SDF1/CXCR4-induced migration is dependent on activation of downstream BTK in chronic lymphocytic leukaemia (CLL) and multiple myeloma. Here we show that SDF-1 induces BTK phosphorylation and downstream MAPK signalling in primary AML blast. Furthermore, we show that ibrutinib can inhibit SDF1-induced AKT and MAPK activation. These results reported here provide a molecular mechanistic rationale for clinically evaluating BTK inhibition in AML patients and suggests that in some AML patients the blasts count may initially rise in response to ibrutinib therapy, analgous to similar clinical observations in CLL

Ammonium salicylate: a synchrotron study

The structure of the title salt, NH4 +·C7H5O3 −, is stabilized by substantial hydrogen bonding between ammonium cations and salicylate anions that links the components into a two-dimensional array

HIV-1 exploits importin 7 to maximize nuclear import of its DNA genome

<p>Abstract</p> <p>Background</p> <p>Nuclear import of the HIV-1 reverse transcription complex (RTC) is critical for infection of non dividing cells, and importin 7 (imp7) has been implicated in this process. To further characterize the function of imp7 in HIV-1 replication we generated cell lines stably depleted for imp7 and used them in conjunction with infection, cellular fractionation and pull-down assays.</p> <p>Results</p> <p>Imp7 depletion impaired HIV-1 infection but did not significantly affect HIV-2, simian immunodeficiency virus (SIVmac), or equine infectious anemia virus (EIAV). The lentiviral dependence on imp7 closely correlated with binding of the respective integrase proteins to imp7. HIV-1 RTC associated with nuclei of infected cells with remarkable speed and knock down of imp7 reduced HIV-1 DNA nuclear accumulation, delaying infection. Using an HIV-1 mutant deficient for reverse transcription, we found that viral RNA accumulated within nuclei of infected cells, indicating that reverse transcription is not absolutely required for nuclear import. Depletion of imp7 impacted on HIV-1 DNA but not RNA nuclear import and also inhibited DNA transfection efficiency.</p> <p>Conclusion</p> <p>Although imp7 may not be essential for HIV-1 infection, our results suggest that imp7 facilitates nuclear trafficking of DNA and that HIV-1 exploits imp7 to maximize nuclear import of its DNA genome. Lentiviruses other than HIV-1 may have evolved to use alternative nuclear import receptors to the same end.</p

Some problems in the study of the chronology of the ancient nomadic cultures in Eurasia (9th - 3rd centuries BC)

This research is focused on the chronological investigations of ancient nomads belonging to the Scythian cultures which occupied the steppe and forest-steppe zones of Eurasia during the 9th-3rd centuries BC. The 14C dates for the pre-scythian and early scythian time in both Europe and Asia are presented and compared to their chronological position based on archaeological evidence. The first 14C dates have been produced for the Scythian time monuments located in the Lower Volga River basin, Urals and Transurals regions. Their chronological positions are compared with the position of the monuments of Southern Siberia and Central Asia. It was shown that the nomadic cultures belonging to the Scythian culture began to exist over the wide territory of Eurasia from the 9th-8th centuries cal BC and there are some monuments which may be synchronous to the Arzhan royal barrow (the oldest monument known). A list of new 14C dates and a map of the monuments are presented

A chronology of the Scythian antiquities of Eurasia based on new archaeological and C-14 data

The paper is compares the chronology of the monuments of the Scythian epoch located in the east and west of the Eurasian steppe zone on the basis of both archaeological and radiocarbon data. The lists of C-14 dates for the monuments located in different parts of Eurasia are presented according to the periods of their existence. Generally, the C-14 dates are confirmed the archaeological point of view and allow us to compare the chronological position of the European and Asian Scythian monuments on the united C-14 time scale

Identification of Bruton's tyrosine kinase as a therapeutic target in acute myeloid leukemia

Bruton's tyrosine kinase (BTK) is a cytoplasmic protein found in all hematopoietic cell lineages except for T cells. BTK mediates signalling downstream of a number of receptors. Pharmacological targeting of BTK using ibrutinib (previously PCI-32765) has recently shown encouraging clinical activity in a range of lymphoid malignancies. This study reports for the first time that ibrutinib inhibits blast proliferation from human acute myeloid leukaemia (AML) and that treatment with ibrutinib significantly augmented cytotoxic activities of standard AML chemotherapy cytarabine or daunorubicin. Here we describe that BTK is constitutively phosphorylated in the majority of AML samples tested, with BTK phosphorylation correlating highly with the cell's cytotoxic sensitivity towards ibrutinib. BTK targeted RNAi knock-down reduced colony forming capacity of primary AML blasts and proliferation of AML cell lines. We showed ibrutinib binds at nanomolar range to BTK. Furthermore, we also showed ibrutinib's anti-proliferative effects in AML are mediated via an inhibitory effect on downstream nuclear factor-κB (NF-κB) survival pathways. Moreover, ibrutinib inhibited AML cell adhesion to bone marrow stroma. Furthermore, these effects of ibrutinib in AML were seen at comparable concentrations efficacious in chronic lymphocytic leukemia (CLL). These results provide a biologic rationale for clinical evaluation of BTK inhibition in AML patients

A tree-ring and C-14 chronology of the key Sayan-Altai monuments

We present a radiocarbon chronology of key Sayan-Altai monuments from the Scythian period, based on a statistical analysis of dates produced in the 1980s and now supplemented with new dates. These new C-14 dates were produced for samples from the Tuekta-1 barrows (burial mounds) and were measured both in St. Petersburg and Groningen. These tree-ring samples were fitted to the calibration curve. Chronologies were established for the Arzhan, Tuekta-1 and Pazyryk-5 barrows. The time of the construction of the Arzhan and Pazyryk-5 barrows is the 9th and late 5th-4th centuries BC, respectively, and agrees with archaeology. According to new data obtained, the time of the Tuekta-1 barrow construction is some years older than has been accepted thus far by archaeologists.</p