Search

Background: The need to better understand the molecular underpinnings of the heterogeneous outcomes of patients with prostate cancer is a pressing global problem and a key research priority for Movember. To address this, the Movember Global Action Plan 1 Unique tissue microarray (GAP1-UTMA) project constructed a set of unique and richly annotated tissue microarrays (TMA) from prostate cancer samples obtained from multiple institutions across several global locations. Methods: Three separate TMA sets were built that differ by purpose and disease state. Results: The intended use of TMA1 (Primary Matched LN) is to validate biomarkers that help determine which clinically localized prostate cancers with associated lymph node metastasis have a high risk of progression to lethal castration-resistant metastatic disease, and to compare molecular properties of high-risk index lesions within the prostate to regional lymph node metastases resected at the time of prostatectomy. TMA2 (Pre vs. Post ADT) was designed to address questions regarding risk of castration-resistant prostate cancer (CRPC) and response to suppression of the androgen receptor/androgen axis, and characterization of the castration-resistant phenotype. TMA3 (CRPC Met Heterogeneity)'s intended use is to assess the heterogeneity of molecular markers across different anatomic sites in lethal prostate cancer metastases. Conclusions: The GAP1-UTMA project has succeeded in combining a large set of tissue specimens from 501 patients with prostate cancer with rich clinical annotation. Impact: This resource is now available to the prostate cancer community as a tool for biomarker validation to address important unanswered clinical questions around disease progression and response to treatment. [ABSTRACT FROM AUTHOR]

Purpose: Thanks to the introduction of more sensitive/specific imaging and minimally invasive treatment techniques, the oligometastatic state in prostate cancer (PCa) has attracted the interest of the uro-oncological community. We aim to identify and analyze trials across five registries to gain insights into the directions this field is moving. Methods: A systematic review of trials on oligometastatic PCa registered on ClinicalTrials.gov, ANZCTR, ISRCTN, Netherlands and UMIN Clinical Trials Registries was performed using the following keywords: 'prostate cancer' and 'oligo'. Data were extracted from ongoing/completed trials, with an unreported primary endpoint in a peer-reviewed journal, as of May until August, 2018. Results: We identified 41 trials on oligometastatic PCa. Twenty-four trials are conducted in North America and 14 in Europe. Up to 70% are phase I or II trials and < 10% (n = 4) are in phase III. Less than 50% (n = 17) are randomized controlled trials. Oligometastases are PET detected in 25 trials. Studies on synchronous oligometastatic (n = 12; 29%) or oligorecurrent (n = 14; 34%) PCa are equally represented, the remainder focus on mixed states (n = 15; 37%). The majority (n = 39; 95%) of trials investigate local treatment options (RP: 5; RT: 9; RP ± RT: 7; metastasis-directed therapy: 28) with (72%) or without (28%) systemic treatment. The remaining two are imaging studies. Progression-free (PFS; 17/41; 41%) or overall survival (OS; 3/41; 7%) is defined as primary endpoint in half of all trials, others are 'safety/toxicity' or 'PSA response'. Conclusions: With 41 ongoing trials, there is great interest in oligometastatic PCa. Most trials address local ablative treatments both for prostate and/or metastases, typically by radiotherapy, and several attempts to determine the benefit of adding systemic therapy. The field will hopefully have definitive answers after completion of four ongoing phase III trials. [ABSTRACT FROM AUTHOR]

Megakaryocytes, which mature from hematopoietic progenitors in the bone marrow, further differentiate by reorganizing their cytoplasm into long proplatelet extensions that release platelets into the circulation. The molecular mechanisms underlying this highly dynamic cytoplasmic and cytoskeletal remodeling process are only poorly understood. Here we report that sphin‐gosine 1‐phosphate receptor 4 (S1P4) is specifically up‐regulated during the development of human megakaryo‐cytes from progenitor cells and is expressed in mature murine megakaryocytes. Megakaryocytes generated from S1P4‐deficient murine bone marrow showed atypical and reduced formation of proplatelets in vitro. The recovery of platelet numbers after experimental thrombocytopenia was significantly delayed in S1p4−/− mice. Remarkably, overexpression and stimulation of S1P4 in human eryth‐roleukemia HEL cells promoted endomitosis, formation of cytoplasmic extensions, and subsequent release of platelet‐like particles. These observations indicate that S1P4 is involved in shaping the terminal differentiation of megakaryocytes.—Golfier, S., Kondo, S., Schulze, T., Takeuchi, T., Vassileva, G., Achtman, A. H., Graler, M. H., Abbondanzo, S. J., Wiekowski, M., Kremmer, E., Endo, Y., Lira, S. A., Bacon, K. B., Lipp, M. Shaping of terminal megakaryocyte differentiation and proplatelet development by sphingosine‐1‐phosphate receptor S1P4. FASEB J. 24, 4701–4710 (2010). www.fasebj.org [ABSTRACT FROM AUTHOR]

Megakaryocytes, which mature from hematopoietic progenitors in the bone marrow, further differentiate by reorganizing their cytoplasm into long proplatelet extensions that release platelets into the circulation. The molecular mechanisms underlying this highly dynamic cytoplasmic and cytoskeletal remodeling process are only poorly understood. Here we report that sphigosine 1-phosphate receptor 4 (S1P4) is specifically up-regulated during the development of human megakaryocytes from progenitor cells and is expressed in mature murine megakaryocytes. Megakaryocytes generated from S1P44-deficient murine bone marrow showed atypical and reduced formation of proplatelets in vitro. The recovery of platelet numbers after experimental thrombocytopen was significantly delayed in S1p4-1- mice. Remarkabl overexpression and stimulation of S1P4 in human erythroleukemia HEL cells promoted endomitosis, formation of cytoplasmic extensions, and subsequent release of platelet-like particles. These observations indicate that S1P is involved in shaping the terminal differentiation of megakaryocytes. [ABSTRACT FROM AUTHOR]

Megakaryocytes, which mature from hematopoietic progenitors in the bone marrow, further differentiate by reorganizing their cytoplasm into long proplatelet extensions that release platelets into the circulation. The molecular mechanisms underlying this highly dynamic cytoplasmic and cytoskeletal remodeling process are only poorly understood. Here we report that sphin‐gosine 1‐phosphate receptor 4 (S1P4) is specifically up‐regulated during the development of human megakaryo‐cytes from progenitor cells and is expressed in mature murine megakaryocytes. Megakaryocytes generated from S1P4‐deficient murine bone marrow showed atypical and reduced formation of proplatelets in vitro. The recovery of platelet numbers after experimental thrombocytopenia was significantly delayed in S1p4−/− mice. Remarkably, overexpression and stimulation of S1P4 in human eryth‐roleukemia HEL cells promoted endomitosis, formation of cytoplasmic extensions, and subsequent release of platelet‐like particles. These observations indicate that S1P4 is involved in shaping the terminal differentiation of megakaryocytes.—Golfier, S., Kondo, S., Schulze, T., Takeuchi, T., Vassileva, G., Achtman, A. H., Graler, M. H., Abbondanzo, S. J., Wiekowski, M., Kremmer, E., Endo, Y., Lira, S. A., Bacon, K. B., Lipp, M. Shaping of terminal megakaryocyte differentiation and proplatelet development by sphingosine‐1‐phosphate receptor S1P4. FASEB J. 24, 4701–4710 (2010). www.fasebj.org [ABSTRACT FROM AUTHOR]

Megakaryocytes, which mature from hematopoietic progenitors in the bone marrow, further differentiate by reorganizing their cytoplasm into long proplatelet extensions that release platelets into the circulation. The molecular mechanisms underlying this highly dynamic cytoplasmic and cytoskeletal remodeling process are only poorly understood. Here we report that sphigosine 1-phosphate receptor 4 (S1P4) is specifically up-regulated during the development of human megakaryocytes from progenitor cells and is expressed in mature murine megakaryocytes. Megakaryocytes generated from S1P44-deficient murine bone marrow showed atypical and reduced formation of proplatelets in vitro. The recovery of platelet numbers after experimental thrombocytopen was significantly delayed in S1p4-1- mice. Remarkabl overexpression and stimulation of S1P4 in human erythroleukemia HEL cells promoted endomitosis, formation of cytoplasmic extensions, and subsequent release of platelet-like particles. These observations indicate that S1P is involved in shaping the terminal differentiation of megakaryocytes. [ABSTRACT FROM AUTHOR]

Anemia is a common condition in HIV-infected children; however, its pathophysiology and the contribution of frequent causes of anemia such as iron deficiency (ID) and malaria are poorly understood. We carried out an ancillary study on the effect of HIV on anemia as part of a case-control study on risk factors of anemia among Mozambican children aged 1-59 months with documented HIV status. Of them, 390 children were admitted to the hospital with anemia (hemoglobin [Hb] < 11 g/dL), whereas 272 children without anemia (Hb ≥ 11 g/dL) were recruited in the community. We assessed differences by HIV status in the presentation of anemia etiological factors and the effect of HIV infection on the association of each factor with anemia. Among the 99 HIV-infected and 563 uninfected children included, HIV-infected anemic children had an increased risk of undernutrition (P < 0.0001), Epstein-Barr virus infection (P < 0.0001), bacteremia (P = 0.0060), a decreased risk of malaria (P < 0.0001), and a similar risk of ID (P = 0.7371) compared with anemic-uninfected children. HIV-infected children were significantly less likely to have anemia associated with Plasmodium falciparum hyperparasitemia (P = 0.0444) and had a lower prevalence of parasitemia in the bone marrow (BM) (P < 0.0001) than anemic-uninfected children. Levels of BM erythropoiesis and dyserythropoiesis were comparable between groups. These findings suggest that the pathophysiology of anemia among HIV-infected malaria-exposed children is not related to HIV-specific effects. For unclear reasons, HIV-infected children had reduced risk of malaria infection, whereas ID prevalence was comparable in HIV-infected and uninfected children, suggesting that iron supplementation recommendations should not be different in HIV-infected children.