Clinicopathological and molecular characteristics of extramedullary acute myeloid leukaemia.

Aims: Myeloid sarcoma (MS) is a rare extramedullary neoplasm composed of immature myeloid precursor cells thought to be a unique clinical presentation of acute myeloid leukaemia (AML). Like AML, MS has a poor prognosis, but due to the rare nature of MS there are limited studies examining potential prognostic factors. We report our institutional experience, with the aim of investigating and establishing salient clinicopathological and molecular features of MS.

Clinical Utility and Biologic Implications of Phosphatase and Tensin Homolog (PTEN) and ETS-related Gene (ERG) in Prostate Cancer.

Phosphatase and tensin homolog (PTEN) and ETS-related gene (ERG) mutations are commonly found in prostate cancer. Although mouse studies have demonstrated that PTEN and ERG cooperatively interact during tumorigenesis, human studies examining these genes have been inconclusive. A systematic PubMed search including original articles assessing the pathogenesis of PTEN and ERG in prostate cancer was performed.

GATA3 expression in benign prostate glands with radiation atypia: a diagnostic pitfall.

Aims: Patients who have undergone prostate radiation are at increased risk for developing urothelial carcinoma. Radiation changes can cause significant cytological atypia in benign prostate glands that may mimic pagetoid spread of urothelial carcinoma. GATA3 is a common marker for differentiating prostatic adenocarcinoma from urothelial carcinoma.

Stem cell autotomy and niche interaction in different systems.

The best known cases of cell autotomy are the formation of erythrocytes and thrombocytes (platelets) from progenitor cells that reside in special niches. Recently, autotomy of stem cells and its enigmatic interaction with the niche has been reported from male germline stem cells (GSCs) in several insect species. First described in lepidopterans, the silkmoth, followed by the gipsy moth and consecutively in hemipterans, foremost the milkweed bug.

CDK4/6 Inhibitor PD 0332991 Sensitizes Acute Myeloid Leukemia to Cytarabine-Mediated Cytotoxicity.

Cyclin-dependent kinase (CDK)4 and CDK6 are frequently overexpressed or hyperactivated in human cancers. Targeting CDK4/CDK6 in combination with cytotoxic killing therefore represents a rational approach to cancer therapy. By selective inhibition of CDK4/CDK6 with PD 0332991, which leads to early G1 arrest and synchronous S-phase entry upon release of the G1 block, we have developed a novel strategy to prime acute myeloid leukemia (AML) cells for cytotoxic killing by cytarabine (Ara-C).

Predictors of repeat transarterial chemoembolization in the treatment of hepatocellular carcinoma.

Objectives: Repeat transarterial chemoembolization (TACE) is a common intervention performed for hepatocellular carcinoma (HCC). The aim of this study was to identify predictors of the need for repeat TACE.

Methods: Between 2008 and 2012, data on patient and tumour variables were collected for 262 patients treated with a first TACE procedure for HCC.

Chemoembolization outcomes for hepatocellular carcinoma in cirrhotic patients with compromised liver function.

Background: Transarterial chemoembolization (TACE) is recommended as a treatment for unresectable hepatocellular carcinoma (HCC) in patients with normal underlying liver function. The efficacy of TACE in cirrhotic patients with compromised liver function is unknown.

Methods: All ‘first’ TACE interventions for HCC performed at a single institution from 2008 to 2012 were retrospectively reviewed (n = 190).

Resource utilization associated with procurement of transplantable organs from donors that do not meet OPTN eligible death criteria.

Background: The strategy of evaluating every donation opportunity warrants an investigation into the financial feasibility of this practice. The purpose of this investigation is to measure resource utilization required for procurement of transplantable organs in an organ procurement organization (OPO).

Methods: Donors were stratified into those that met OPTN-defined eligible death criteria (ED donors, n=589) and those that did not (NED donors, n=703).

Computed tomography predictors of hepatocellular carcinoma tumour necrosis after chemoembolization.

Background: Radiographical features associated with a favourable response to trans-arterial chemoembolization (TACE) are poorly defined for patients with hepatocellular carcinoma (HCC).

Methods: From 2008 to 2012, all first TACE interventions for HCC performed at the University of Alabama at Birmingham (UAB) were retrospectively reviewed. Only patients with a pre-TACE and a post-TACE computed tomography (CT) scan were included in the analyses (n = 115).

Structural characterization and primary in vitro cell culture of locust male germline stem cells and their niche.

The establishment of in vitro culture systems to expand stem cells and to elucidate the niche/stem cell interaction is among the most sought-after culture systems of our time. To further investigate niche/stem cell interactions, we evaluated in vitro cultures of isolated intact male germline-niche complexes (i.e.

The effect of cantharidins on leukemic stem cells.

To identify an agent with specific activity against leukemic stem cells (LSCs), we evaluated compounds that targeted hepatic leukemia factor (HLF), a gene implicated in hematopoietic stem cell (HSCs) regulation, that we found overexpressed in LSCs. Cantharidin, a natural toxin from blister beetles, used as medicinal agent since antiquity, has been described to modulate the HLF competitor NFIL3 and is under clinical evaluation as an antitumor and antimetastatic agent. The molecule is not a substrate for multidrug resistant pumps and does not cause myelosuppression, and therefore it represents a promising compound for selective ablation of LSCs.

Quantification of the CD8+ T cell response against a mucin epitope in patients with breast cancer.

Introduction: Mucin 1, encoded by the MUC1 gene, is a tumor-associated antigen expressed on the surface of breast cancer cells. It would be of interest to see whether there is a naturally existing T cell immune response against mucin epitopes in cancer patients.

Materials And Methods: Using tetramer and interferon-gamma assays, the immune response to one MUC1 peptide epitope in the peripheral blood of breast cancer patients was quantified.

Structural polarity and dynamics of male germline stem cells in an insect (milkweed bug Oncopeltus fasciatus).

Knowing the structure opens a door for a better understanding of function because there is no function without structure. Male germline stem cells (GSCs) of the milkweed bug (Oncopeltus fasciatus) exhibit a very extraordinary structure and a very special relationship with their niche, the apical cells. This structural relationship is strikingly different from that known in the fruit fly (Drosophila melanogaster) -- the most successful model system, which allowed deep insights into the signaling interactions between GSCs and niche.

Cellular and humoral immunogenicity of hamster polyomavirus-derived virus-like particles harboring a mucin 1 cytotoxic T-cell epitope.

In this study, we examined hamster polyomavirus (HaPyV) major capsid protein VP1-derived virus-like particles (VLPs) as a carrier for a human tumor-associated cytotoxic T lymphocyte (CTL) epitope. The VP1 tolerated the insertion of an HLA-*A2-restricted CTL epitope from human mucin 1 (MUC1) into two sites independently and simultaneously, without interfering with assembly of chimeric VLPs. Chimeric VLPs did not differ in the entry pathway or maturation potential of human dendritic cells (hDCs) compared to unmodified VLPs.

Apoptosis of male germ-line stem cells after laser ablation of their niche.

Male germ-line stem cells (GSCs) and their niche-the apical cells or hub cells-display a unique feature at the apices of insect testicular follicles. In the locust, Locusta migratoria, the niche consists of only one large apical cell surrounded by about 60 GSCs. The apical cell can be readily identified in the intact follicle.

Constitutive activation of Flt3 and STAT5A enhances self-renewal and alters differentiation of hematopoietic stem cells.

Objective: To model human leukemogenesis by transduction of human hematopoietic stem cells (HSC) with genes associated with leukemia and expressed in leukemic stem cells.

Methods: Constitutive activation of Flt3 (Flt3-ITD) has been reported in 25 to 30% of patients with acute myeloid leukemia (AML). Retroviral vectors expressing constitutively activated Flt3 and STAT5A were used to transduce human cord blood CD34(+) cells and HSC cell self-renewal and differentiation were evaluated.

Tumor cell specific toxicity of Inula helenium extracts.

The aim of the research program was to identify botanical extracts with antineoplastic activity. In this respect extracts prepared from Inula helenium roots showed a remarkable activity. As evidenced by the MTT assay, the Inula helenium extract revealed a highly selective toxicity toward four different tumor cell lines (HT-29, MCF-7, Capan-2 and G1), but a much lower toxicity against healthy human peripheral blood lymphocytes (PBLs) from two donors.

Virus-like particles derived from major capsid protein VP1 of different polyomaviruses differ in their ability to induce maturation in human dendritic cells.

As polyomavirus major capsid protein VP1-derived virus-like particles (VLPs) have been demonstrated to be highly immunogenic, we studied their interaction with human dendritic cells (hDCs). Exposure of hDCs to VLPs originating from murine (MPyV) or hamster polyomavirus (HaPyV) induced hDC maturation. In contrast, exposure of hDCs to VLPs derived from human polyomaviruses (BK and JC) and simian virus 40 (SV40) only marginally induced DC maturation.

Hematopoiesis controlled by distinct TIF1gamma and Smad4 branches of the TGFbeta pathway.

Tissue homeostasis in mammals relies on powerful cytostatic and differentiation signals delivered by the cytokine TGFbeta and relayed within the cell via the activation of Smad transcription factors. Formation of transcription regulatory complexes by the association of Smad4 with receptor-phosphorylated Smads 2 and 3 is a central event in the canonical TGFbeta pathway. Here we provide evidence for a branching of this pathway.

The migrastatin family: discovery of potent cell migration inhibitors by chemical synthesis.

The first asymmetric total synthesis of (+)-migrastatin (1), a macrolide natural product with anti-metastatic properties, has been accomplished. Our concise and flexible approach utilized a Lewis acid-catalyzed diene aldehyde condensation (LACDAC) to install the three contiguous stereocenters and the trisubstituted (Z)-alkene of migrastatin (2 + 3 --> 21). Construction of the two remaining stereocenters and incorporation of the glutarimide-containing side chain was achieved by an anti-selective aldol addition of propionyl oxazolidinone 28 to angelic aldehyde 27, followed by a Horner-Wadsworth-Emmons (HWE) coupling of 32 with glutarimide aldehyde 5.

Enforced expression of an Flt3 internal tandem duplication in human CD34+ cells confers properties of self-renewal and enhanced erythropoiesis.

To investigate the role of constitutively active internal tandem duplication (ITD) mutants of the Fms-like tyrosine kinase 3 (Flt3) receptor in leukemogenesis, we introduced the Flt3-ITD, W51, into human cord blood CD34+ cells and evaluated their phenotype in diverse hematopoietic assays. W51 expression resulted in a strong proliferative advantage and enhanced erythropoiesis as determined by immunophenotyping, colony assays, and molecular analyses. In MS-5 stromal cocultures, numerous early cobblestone areas (CAs) were generated within 10 to 14 days.