ALBERT

Description: The double pulsar system PSR J0737-3039A/B is unique in that both neutron stars are detectable as radio pulsars. They are also known to have much higher mean orbital velocities and accelerations than those of other binary pulsars. The system is therefore a good candidate for testing Einstein's theory of general relativity and alternative theories of gravity in the strong-field regime. We report on precision timing observations taken over the 2.5 years since its discovery and present four independent strong-field tests of general relativity. These tests use the theory-independent mass ratio of the two stars. By measuring relativistic corrections to the Keplerian description of the orbital motion, we find that the "post-Keplerian" parameter s agrees with the value predicted by general relativity within an uncertainty of 0.05%, the most precise test yet obtained. We also show that the transverse velocity of the system's center of mass is extremely small. Combined with the system's location near the Sun, this result suggests that future tests of gravitational theories with the double pulsar will supersede the best current solar system tests. It also implies that the second-born pulsar may not have formed through the core collapse of a helium star, as is usually assumed.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kramer, M -- Stairs, I H -- Manchester, R N -- McLaughlin, M A -- Lyne, A G -- Ferdman, R D -- Burgay, M -- Lorimer, D R -- Possenti, A -- D'Amico, N -- Sarkissian, J M -- Hobbs, G B -- Reynolds, J E -- Freire, P C C -- Camilo, F -- New York, N.Y. -- Science. 2006 Oct 6;314(5796):97-102. Epub 2006 Sep 14.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉University of Manchester, Jodrell Bank Observatory, Macclesfield SK11 9DL, UK. mkramer@jb.man.ac.uk〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16973838" target="_blank"〉PubMed〈/a〉

Description: PSR B1931+24 (J1933+2421) behaves as an ordinary isolated radio pulsar during active phases that are 5 to 10 days long. However, when the radio emission ceases, it switches off in less than 10 seconds and remains undetectable for the next 25 to 35 days, then switches on again. This pattern repeats quasi-periodically. The origin of this behavior is unclear. Even more remarkably, the pulsar rotation slows down 50% faster when it is on than when it is off. This indicates a massive increase in magnetospheric currents when the pulsar switches on, proving that pulsar wind plays a substantial role in pulsar spin-down. This allows us, for the first time, to estimate the magnetospheric currents in a pulsar magnetosphere during the occurrence of radio emission.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kramer, M -- Lyne, A G -- O'Brien, J T -- Jordan, C A -- Lorimer, D R -- New York, N.Y. -- Science. 2006 Apr 28;312(5773):549-51. Epub 2006 Feb 23.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Jodrell Bank Observatory, University of Manchester, Macclesfield, SK11 9DL, UK.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/16497886" target="_blank"〉PubMed〈/a〉

Description: Background: PBI-1402 is a novel orally active low molecular weight synthetic compound with erythropoiesis stimulating activity. Furthermore, a clinical phase I study showed that PBI-1402 induced a significant increase (100%, p 〈 0.0001, compared to placebo) of relative and absolute reticulocyte count in healthy volunteers after 21 days of oral treatment and was devoid of significant side effects. Outcomes: The objectives of this clinical phase Ib/II trial were to study the safety and tolerability of PBI-1402 and to assess its biological efficacy on hemoglobin (Hb) level and red blood cell (RBC) count in patients with Chemotherapy-Induced Anemia (CIA). Methods: An open label phase Ib/II trial, monitored by a US CRO (Pharm-Olam International), was conducted in patients developing anemia after chemotherapy treatment. Three cohorts of 6 CIA patients received 8 weeks of treatment with PBI-1402 once a day, at different doses, and were monitored every two weeks for safety, tolerability, Hb level, RBC count and blood chemistry. Patients remained on their chemotherapy during PBI-1402 treatment. Results: To date, 12 CIA patients have completed their PBI-1402 treatment. 83% of patients demonstrated a significant increase in RBC (p = 0.015) and 66% in Hb (p = 0.038). Among the responders, the mean Hb increase was 1.1 g/dL (p = 0.0007) from a baseline Hb value of 9.8 g/dL. No patient required a blood transfusion and only one patient had an Hb content below 9 g/dL (8.9 g/dL). PBI-1402 was well tolerated and no significant side effects were observed. Conclusion: PBI-1402, via a mechanism of action distinct from erythropoietin, induced sufficient erythropoiesis to raise the RBC level and Hb in CIA patients. In addition, PBI-1402 is safe and well tolerated. PBI-1402 offers the potential for a novel therapy of the anemia of CIA.

Description: The goal of this study was to determine the potential of PBI-1402, a compound that was shown to provide radio- and chemoprotection, to ameliorate the myeloablative therapy induced cytopenia and/or accelerate blood cell recovery of myeloablated hosts following autologous bone marrow transplantation in mouse model. Mice were exposed to irradiation and transplanted the following day with 5×105 bone marrow cells from syngeneic donors. Following transplantation, mice were divided into two groups that received two different doses of PBI-1402 orally and a control group that received PBS for 14 days post transplantation. The results showed that PBI-1402 treatment significantly diminished post-transplant erythropenia in a dose dependent manner. Similarly, determination of haemoglobin (Hb) demonstrated a significant attenuation of Hb loss and additionally, significantly accelerated post-transplantation recovery with the highest dose of PBI-1402. A significantly higher number of platelets was observed with the highest dose of PBI-1402. In addition, similar results were obtained with analysis of white blood cell (WBC) recovery. To determine if the observed effect of PBI-1402 treatment on red blood cell cytopenia and Hb recovery is the consequence of increased erythrocyte progenitor response to Epo, we performed an Epo dose response experiment on CFU-E bone marrow samples obtained from treated and control mice at different time points post transplantation. The results indicated that erythroid progenitors from treated and control mice responded similarly to Epo. However, PBI-1402 treated mice contained significantly higher number of CFU-E. Interestingly, analysis of more primitive Sca1+ progenitors revealed a significant increase in the number of Sca1+ cells from the bone marrow of mice treated with PBI-1402 (p 〈 0.05). These results demonstrate that PBI-1402 treatment significantly reduced irradiation induced erythropenia with concomitant acceleration in erythroid and Hb recovery. Additionally, treatment with PBI-1402 accelerated WBC recovery and platelet recovery and increased more primitive Sca1+ progenitors. PBI-1402 may offer protection from myeloabaltive therapy or accelerate recovery from remaining resident or transplanted stem cells.

Description: The B-cell lymphoma/leukaemia 11A (BCL11A) gene was first identified in the rare t(2;14)(p16;q32.3) translocation involving the IGH locus in aggressive B-cell chronic lymphocytic leukaemia (CLL) and, together with REL, is a candidate for the 2p16 chromosomal amplifications in B-cell malignancies. BCL11A encodes a Kruppel zinc finger transcription factor essential for pre-B-cell development and thymocyte maturation. Alternative RNA splicing generates at least three BCL11A transcripts encoding proteins that share a common N-terminus with the BCL11AXL transcript being the most abundant BCL11A transcript in normal tissues. We have produced a murine monoclonal antibody (BCL11A/123, isotype IgG1) specific for the BCL11AXL protein and, using this reagent, provide the first description of BCL11AXL protein distribution in normal and malignant human tissues. Initial studies using another antibody to the common N-terminus indicated the BCL11AXL protein to be the dominant isoform. In lymph node, tonsil and spleen, BCL11AXL expression was detected in B-cell nuclei in the mantle zone, germinal centers, interfollicular areas, splenic marginal zones and in tonsillar epithelium, but not in plasma cells or T cells. The differential expression of BCL11AXL in B-cell populations suggests its downregulation might be a requirement for plasma cell differentiation and is consistent with reports that BCL11A is transcriptionally repressed by Blimp-1. A subpopulation of cells, mostly B-cells, in the thymic medulla and scattered cells in the cortex were BCL11AXL+. Labeling of a very small number of CD3+ T-cells in the cortex and epithelial cells around the cortical periphery was also observed. Labeling of B-cell follicles in rat spleen demonstrated the BCL11A/123 epitope to be conserved across species. Another important finding was the high level expression of BCL11AXL in CD74+CD68+CD123+ plasmacytoid dendritic cells (pDCs). Publicly available microarray expression data are consistent with these findings, showing BCL11A transcripts to be present at high levels in peripheral blood B cells, in tonsil, lymph node and fetal brain with the highest expression in pDCs. BCL11AXL therefore represents an additional marker for the identification of pDCs and may be important in the differentiation and/or functional activity of this cell type. BCL11AXL was commonly detected in B-cell lymphomas, including diffuse large B-cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia and a subgroup of Hodgkin’s lymphomas, with the exception of multiple myeloma. Tumor cells in a small number of T-cell lymphomas (3/29) also expressed BCL11AXL. In a tissue microarray, comprising 107 cases of de novo DLBCL at diagnosis, BCL11AXL expression correlated with that of its interaction partner BCL6 and showed a trend towards increased overall survival. The study of this molecule should provide additional invaluable information concerning the possible role of BCL11A in lymphomagenesis.

Description: B-cell lymphomaleukaemia 11B (BCL11B), the human homologue of murine Bcl11b/Rit-1/CTIP2, was originally identified as a novel tumor suppressor gene in a study of gamma-radiation induced thymic lymphomas in mice. Later studies, however, showed Bcl11b to have a vital role in T cell development and survival, with BCL11B translocations involving a variety of partner genes being reported in both T-cell and myeloid leukemias. The human BCL11B gene, located at 14q32.2, encodes an 832aa Kruppel C2H2 zinc finger protein that is functionally uncharacterized but likely to act as a transcriptional regulator. Analysis of publically available normal tissue Affymetrix microarray expression data indicates an expression pattern restricted to hematopoietic cells, with high levels of BCL11B transcripts being present only in peripheral blood T cells, NK cells, thymus and tonsil. We have used two rabbit polyclonal anti-BCL11B antibodies to study the distribution of BCL11B protein in both normal and neoplastic human cells. These reagents, raised against two distinct regions of the murine Bcl11b protein (zinc finger and C-terminus), recognized the human BCL11B protein. While neither antibody stained B-cells in tonsil, one was crossreactive with the highly homologous BCL11AXL protein by Western blotting. In normal tissues, BCL11B protein expression was confined to the nuclei of the vast majority of T cells in thymus (foetal and adult) and tonsil. High levels of BCL11B were detected in T-cell lines, including the Molt-4, CCRF-CEM and Jurkat T-cell acute lymphoblastic leukaemia (T-ALL) derived cell lines. No expression was detected in any B-cell derived (pre-B to plasma cell stage) or myeloid cell lines studied. These results are consistent with the microarray gene expression data. In T-cell malignancies, BCL11B protein was only detected in a proportion of tumors, including 5/6 T-ALLs (one being weakly stained) and 2/8 peripheral T-cell lymphomas (weak cytoplasmic staining only). Interestingly, no expression was detected in ALK-positive anaplastic large cell lymphoma lines or tumors. Further studies of a larger series of T-cell malignancies are in progress. All other tumors studied, including B-ALL, chronic lymphocytic leukaemia, diffuse large B-cell lymphoma, mantle cell lymphoma, Burkitt’s lymphoma, follicular lymphoma, myeloma and Hodgkin’s lymphoma, were unlabelled. In conclusion, the distribution pattern of the BCL11B protein in a wide range of both normal and neoplastic tissues is described for the first time. The study of BCL11B expression is an invaluable first step towards elucidating the role of this protein in T-cell biology and the significance of its differential expression in T-cell malignancies.

Description: Erythropoiesis is regulated by an intricated network of transcription factors and other molecules that mediate differentiation of stem cell progenitors into erythroid lineage. PBI-1402 is a non-toxic, well-defined chemo- and radio-protective orally active small molecule which stimulates erythropoiesis. In vivo studies demonstrate that PBI-1402 has an immunorestorative effect in anemia induced by phenylhydrazine or lethal irradiation. In phenylhydrazine-induced anemia, PBI-1402 treated mice had an increased number of hematopoietic progenitor cells compared to the control mice. This increase was more pronounced in the erythroid lineage (BFU-E and CFU-E). In myeloablated mice that received a syngeneic bone marrow transplant, oral treatment with PBI-1402 resulted in a significant increase in peripheral erythrocyte count and hemoglobin concentration. In conclusion, these results indicate that PBI-1402 plays an important role in the formation of red blood cells. Therefore, PBI-1402 may be useful for the treatment of anemia associated with chemotherapy, radiotherapy, bone marrow transplantation and cancer.

Description: PBI-1402 is an orally active low molecular weight synthetic compound which is currently in a phase Ib/II clinical trial in patients with anemia associated with cancer and/or chemotherapy. PBI-1402 stimulates the in vitro/ex vivo proliferation and maturation of hematopoietic progenitors (erythroid and myeloid populations) with an activity comparable to EPO. Furthermore, an additive effect is observed in combination with EPO. PBI-1402 enhances the differentiation of pluripotent stem cells: CFU-GEMM, CFU-GM with a predominant effect on BFU-E. Clinical phase I study showed that PBI-1402 is devoid of significant side effects. In addition, the clinical phase I results showed statistical increase (100%, p

Description: PBI-1402 is a non-toxic, well-defined low molecular weight synthetic hematopoietic growth stimulant. PBI-1402 promotes the proliferation and maturation of hematopoietic progenitors (myeloid and erythroid populations) yielding a biological efficacy comparable to G-CSF, GM-CSF and EPO in in vitro human bone marrow cell proliferation and colony formation assays. An additive effect is observed when PBI-1402 is combined with G-CSF, GM-CSF and EPO. In human bone marrow colony assay, PBI-1402 enhances the differentiation of pluripotent stem cells: CFU-GEMM, CFU-GM with a predominant effect on BFU-E. Furthermore, PBI-1402 exerts its activity via a different mechanism of action than EPO and stem cell factor (SCF) and at an earlier stage on more immature hematopoietic progenitors. PBI-1402 is targeted as an adjunct to cancer chemo/radiotherapy, bone marrow transplantation and diseases involving neutropenia and anemia.