http://www.jhoonline.org The most accessed research articles published by Journal of Hematology & Oncology 2012-05-08T00:00:00Z Mast cell activation disease comprises disorders characterized by accumulation of genetically altered mast cells and/or abnormal release of these cells' mediators, affecting functions in potentially every organ system, often without causing abnormalities in routine laboratory or radiologic testing. In most cases of mast cell activation disease, diagnosis is possible by relatively non-invasive investigation. Effective therapy often consists simply of antihistamines and mast cell membrane-stabilising compounds supplemented with medications targeted at specific symptoms and complications. Mast cell activation disease is now appreciated to likely be considerably prevalent and thus should be considered routinely in the differential diagnosis of patients with chronic multisystem polymorbidity or patients in whom a definitively diagnosed major illness does not well account for the entirety of the patient's presentation. http://www.jhoonline.org/content/4/1/10 Gerhard Molderings Stefan Brettner Jurgen Homann Lawrence Afrin Journal of Hematology & Oncology 2011, null:10 2011-03-22T00:00:00Z doi:10.1186/1756-8722-4-10 /content/figures/1756-8722-4-10-toc.gif Journal of Hematology & Oncology 1756-8722 ${item.volume} 10 2011-03-22T00:00:00Z XML Mesenchymal stem cells (MSC) have generated a great amount of enthusiasm over the pastdecade as a novel therapeutic paradigm for a variety of diseases. Currently, MSC basedclinical trials have been conducted for at least 12 kinds of pathological conditions, with manycompleted trials demonstrating the safety and efficacy. This review provides an overview ofthe recent clinical findings related to MSC therapeutic effects. Roles of MSCs in clinicaltrials conducted to treat graft-versus-host-disease (GVHD) and cardiovascular diseases arehighlighted. Clinical application of MSC are mainly attributed to their important fourbiological properties- the ability to home to sites of inflammation following tissue injurywhen injected intravenously; to differentiate into various cell types; to secrete multiplebioactive molecules capable of stimulating recovery of injured cells and inhibitinginflammation and to perform immunomodulatory functions. Here, we will discuss these fourproperties. Moreover, the issues surrounding clinical grade MSCs and principles for MSCtherapeutic approaches are also addressed on the transition of MSCs therapy from bench sideto bedside. http://www.jhoonline.org/content/5/1/19 Shihua Wang Xuebin Qu Robert Chunhua Zhao Journal of Hematology & Oncology 2012, null:19 2012-04-30T00:00:00Z doi:10.1186/1756-8722-5-19 /content/figures/1756-8722-5-19-toc.gif Journal of Hematology & Oncology 1756-8722 ${item.volume} 19 2012-04-30T00:00:00Z PDF Background: Tissue factor (TF), an initiator of blood coagulation, participates in cancer progression and metastasis. We recently found that inhibition of MAPK/ERK upregulated both full length TF (flTF) and soluble isoform TF (asTF) gene expression and cell-associated TF activity in breast cancer MDA-MB-231 cells. We explored the possible mechanisms, especially the possible interaction with EGFR and PI3K/Akt pathways. Methods: A plasmid containing TF promoter 2174 ~ +128 plus luciferase reporter gene was introduced into MDA-MB-231 cells to evaluate TF promoter activity. In order to study the interaction of these pathways, ERK inhibitor (PD98059), PI3K inhibitors (LY294002, wortmannin), Akt inhibitor (A6730), and EGFR inhibitor (erlotinib) as well as the corresponding siRNAs were used to treat MDA-MB-231 cells, and ovarian cancer OVCAR-3 and SKOV-3 cells. Quantitative PCR and western blot were used to determine TF expression. One stage clotting assays were used to measure pro-coagulation activity of the MDA-MB-231 cells. Results: We show that PI3K inhibitors LY294002, wortmannin and A6730 significantly inhibited TF promoter activity, and reduced TF mRNA and protein levels due to the inhibition of Akt phosphorylation. In contrast, ERK inhibitor PD98059 and ERK siRNA enhanced TF promoter activity by 2.5 fold and induced an increase in TF mRNA and protein levels in a dose dependent manner in these cells. The PI3K/Akt pathway was shown to be involved in PD98059-induced TF expression because the induction was inhibited by PI3K/Akt inhibitors. Most interestingly, the EGFR inhibitor erlotinib and EGFR siRNA also significantly suppressed PD98059- or ERK siRNA-induced TF promoter activity and TF protein expression. Similar results were found with ovarian cancer cells SKOV-3 and OVCAR-3. Furthermore, in MDA-MB-231, mRNA levels of asTF were regulated in a similar way to that of TF in response to the cell treatment. Conclusions: This study showed a regulatory mechanism in which MAPK/ERK signals inhibit EGFR/PI3K/Akt-mediated TF expression in breast cancer MDA-MB-231 cells. The same regulation was observed in ovarian cancer OVCAR-3 and SKOV-3 cells. Interestingly, we observed that both flTF and asTF could be regulated in a parallel manner in MDA-MB-231. As the PI3K/Akt pathway and EGFR regulate TF expression in cancer cells, targeting these signaling components is expected to potentially inhibit TF expression-associated tumor progression. http://www.jhoonline.org/content/5/1/16 Chaoquan Hu Limin Huang Caroline Gest Xiaodong Xi Anne Janin Claudine Soria Hong Li He Lu Journal of Hematology & Oncology 2012, null:16 2012-04-25T00:00:00Z doi:10.1186/1756-8722-5-16 /content/figures/1756-8722-5-16-toc.gif Journal of Hematology & Oncology 1756-8722 ${item.volume} 16 2012-04-25T00:00:00Z PDF The discovery of CD117 mutation in almost all gastrointestinal stromal tumors (GISTs)marked a milestone. Other spindle cell neoplasms arising from the GI tract including lipoma,schwannoma, hemangioma, leiomyoma, and leiomyosarcoma are typically CD117-negative.GIST research and clinical care now represent a paradigm of translating discoveries in themolecular pathogenesis of cancer into highly effective targeted therapies that selectivelyinhibit etiologic "driver" pathways, leading to dramatically improved clinical outcomes. Aseries of investigations and trials are underway to develop novel and effective ways to treatpatients with GIST. In this review, we discuss the highlights of recent advances and novelagents for GIST therapy. http://www.jhoonline.org/content/5/1/21 Gurpreet Lamb Samir Ambrale Byung Lee Ridhi Gupta Shamudheen Rafiyath Delong Liu Journal of Hematology & Oncology 2012, null:21 2012-05-08T00:00:00Z doi:10.1186/1756-8722-5-21 /content/figures/1756-8722-5-21-toc.gif Journal of Hematology & Oncology 1756-8722 ${item.volume} 21 2012-05-08T00:00:00Z PDF Non-prescriptional use of medicinal herbs among cancer patients is common around the world. The alleged anti-cancer effects of most herbal extracts are mainly based on studies derived from in vitro or in vivo animal experiments. The current information suggests that these herbal extracts exert their biological effect either through cytotoxic or immunomodulatory mechanisms. One of the active compounds responsible for the immune effects of herbal products is in the form of complex polysaccharides known as β-glucans. β-glucans are ubiquitously found in both bacterial or fungal cell walls and have been implicated in the initiation of anti-microbial immune response. Based on in vitro studies, β-glucans act on several immune receptors including Dectin-1, complement receptor (CR3) and TLR-2/6 and trigger a group of immune cells including macrophages, neutrophils, monocytes, natural killer cells and dendritic cells. As a consequence, both innate and adaptive response can be modulated by β-glucans and they can also enhance opsonic and non-opsonic phagocytosis. In animal studies, after oral administration, the specific backbone 1→3 linear β-glycosidic chain of β-glucans cannot be digested. Most β-glucans enter the proximal small intestine and some are captured by the macrophages. They are internalized and fragmented within the cells, then transported by the macrophages to the marrow and endothelial reticular system. The small β-glucans fragments are eventually released by the macrophages and taken up by other immune cells leading to various immune responses. However, β-glucans of different sizes and branching patterns may have significantly variable immune potency. Careful selection of appropriate β-glucans is essential if we wish to investigate the effects of β-glucans clinically. So far, no good quality clinical trial data is available on assessing the effectiveness of purified β-glucans among cancer patients. Future effort should direct at performing well-designed clinical trials to verify the actual clinical efficacy of β-glucans or β-glucans containing compounds. http://www.jhoonline.org/content/2/1/25 Godfrey Chi-Fung Chan Wing Keung Chan Daniel Man-Yuen Sze Journal of Hematology & Oncology 2009, null:25 2009-06-10T00:00:00Z doi:10.1186/1756-8722-2-25 /content/figures/1756-8722-2-25-toc.gif Journal of Hematology & Oncology 1756-8722 ${item.volume} 25 2009-06-10T00:00:00Z XML Immunomodulatory drugs lenalidomide and pomalidomide are synthetic compounds derived by modifying the chemical structure of thalidomide to improve its potency and reduce its side effects. Lenalidomide is a 4-amino-glutamyl analogue of thalidomide that lacks the neurologic side effects of sedation and neuropathy and has emerged as a drug with activity against various hematological and solid malignancies. It is approved by FDA for clinical use in myelodysplastic syndromes with deletion of chromosome 5q and multiple myeloma. Lenalidomide has been shown to be an immunomodulator, affecting both cellular and humoral limbs of the immune system. It has also been shown to have anti-angiogenic properties. Newer studies demonstrate its effects on signal transduction that can partly explain its selective efficacy in subsets of MDS. Even though the exact molecular targets of lenalidomide are not well known, its activity across a spectrum of neoplastic conditions highlights the possibility of multiple target sites of action. http://www.jhoonline.org/content/2/1/36 Venumadhav Kotla Swati Goel Sangeeta Nischal Christoph Heuck Kumar Vivek Bhaskar Das Amit Verma Journal of Hematology & Oncology 2009, null:36 2009-08-12T00:00:00Z doi:10.1186/1756-8722-2-36 /content/figures/1756-8722-2-36-toc.gif Journal of Hematology & Oncology 1756-8722 ${item.volume} 36 2009-08-12T00:00:00Z XML Background: Recombinant human arginase (rhArg) has been developed for arginine deprivation therapy in cancer, and is currently under clinical investigation. During pre-clinical evaluation, rhArg has exhibited significant anti-proliferative activity in cancer cells deficient in the expression of ornithine carbamoyl transferase (OCT). Interestingly, a variety of cancer cells such as melanoma and prostate cancer deficient in argininosuccinate synthetase (ASS) are sensitive to arginine deprivation by arginine deiminase. In this study, we investigated levels of gene expression of OCT and ASS, and the effects of rhArg in human prostate cancer cells: LNCaP (androgen-dependent), PC-3 and DU-145 (both androgen-independent). Results: Quantitative real-time PCR showed minimal to absent gene expression of OCT, but ample expression of ASS expression in all 3 cell lines. Cell viability assay after 72-h exposure of rhArg showed all 3 lines had half maximal inhibitory concentration less than or equal to 0.02 U/ml. Addition of ornithine to cell culture media failed to rescue these cells from rhArg-mediated cytotoxicity.Decreased phosphorylation of 4E-BP1, a downstream effector of mammalian target of rapamycin (mTOR), was noted in DU-145 and PC-3 after exposure to rhArg. Moreover, there was no significant apoptosis induction after arginine deprivation by rhArg in all 3 prostate cancer cell lines. Conclusion: rhArg causes significant cytotoxicity in LNCaP, DU-145 and PC-3 prostate cancer cells which all demonstrate decreased OCT expression. Inhibition of mTOR manifested by hypophosphorylation of 4E-BP1 suggests autophagy is involved as alternative cell death mechanism. rhArg demonstrates a promising novel agent for prostate cancer treatment. http://www.jhoonline.org/content/5/1/17 Eddy Hsueh Stephanie Knebel Wai-Hung Lo Yun-Chung Leung Paul Ning-Man Cheng Chung-Tsen Hsueh Journal of Hematology & Oncology 2012, null:17 2012-04-30T00:00:00Z doi:10.1186/1756-8722-5-17 /content/figures/1756-8722-5-17-toc.gif Journal of Hematology & Oncology 1756-8722 ${item.volume} 17 2012-04-30T00:00:00Z PDF Background: Ezatiostat, a glutathione S-transferase P1-1 inhibitor, promotes the maturation ofhematopoietic progenitors and induces apoptosis in cancer cells. Results: Ezatiostat was administered to 19 patients with non-deletion(5q) myelodysplastic syndrome(MDS) at one of two doses (2000 mg or 2500 mg/day) in combination with 10 mg oflenalidomide on days 1-21 of a 28-day cycle. No unexpected toxicities occurred and theincidence and severity of adverse events (AEs) were consistent with that expected for eachdrug alone. The most common non-hematologic AEs related to ezatiostat in combination withlenalidomide were mostly grade 1 and 2 fatigue, anorexia, nausea, diarrhea, and vomiting;hematologic AEs due to lenalidomide were thrombocytopenia, neutropenia, and anemia. Oneof 4 evaluable patients (25%) in the 2500/10 mg dose group experienced an erythroidhematologic improvement (HI-E) response by 2006 MDS International Working Group(IWG) criteria. Four of 10 evaluable patients (40%) in the 2000 mg/10 mg dose groupexperienced an HI-E response. Three of 7 (43%) red blood cell (RBC) transfusion-dependentpatients became RBC transfusion independent, including one patient for whom priorlenalidomide monotherapy was ineffective. Three of 5 (60%) thrombocytopenic patients hadan HI-platelet (HI-P) response. Bilineage HI-E and HI-P responses occurred in 3 of 5 (60%),1 of 3 with HI-E and HI-N (33%), 3 of 5 with HI-E and HI-P (60%), and 1 of 3 with HI-Nand HI-P (33%). One of 3 patients (33%) with pancytopenia experienced a completetrilineage response. All multilineage responses were observed in the 2000/10 mg dosesrecommended for future studies. Conclusions: The tolerability and activity profile of ezatiostat co-administered with lenalidomide supportsthe further development of ezatiostat in combination with lenalidomide in MDS and alsoencourages studies of this combination in other hematologic malignancies wherelenalidomide is active.Trial registrationClinicaltrials.gov: NCT01062152 http://www.jhoonline.org/content/5/1/18 Azra Raza Naomi Galili Deborah Mulford Scott Smith Gail Brown David Steensma Roger Lyons Ralph Boccia Mikkael Sekeres Garcia-Manero Guillermo Ruben Mesa Journal of Hematology & Oncology 2012, null:18 2012-04-30T00:00:00Z doi:10.1186/1756-8722-5-18 /content/figures/1756-8722-5-18-toc.gif Journal of Hematology & Oncology 1756-8722 ${item.volume} 18 2012-04-30T00:00:00Z PDF MicroRNA (miRs) represent a class of small non-coding regulatory RNAs playing a major role in the control of gene expression by repressing protein synthesis at the post-transcriptional level. Studies carried out during the last years have shown that some miRNAs plays a key role in the control of normal and malignant hgematopoiesis. In this review we focus on recent progress in analyzing the functional role of miR-146a in the control of normal and malignant hematopoiesis. On the other hand, this miRNA has shown to impact in the control of innate immune responses. Finally, many recent studies indicate a deregulation of miR-146 in many solid tumors and gene knockout studies indicate a role for this miRNA as a tumor suppressor. http://www.jhoonline.org/content/5/1/13 Catherine Labbaye Ugo Testa Journal of Hematology & Oncology 2012, null:13 2012-03-27T00:00:00Z doi:10.1186/1756-8722-5-13 /content/figures/1756-8722-5-13-toc.gif Journal of Hematology & Oncology 1756-8722 ${item.volume} 13 2012-03-27T00:00:00Z XML We reviewed preclinical data and clinical development of MDM2 (murine double minute 2), ALK (anaplastic lymphoma kinase) and PARP (poly [ADP-ribose] polymerase) inhibitors. MDM2 binds to p53, and promotes degradation of p53 through ubiquitin-proteasome degradation. JNJ-26854165 and RO5045337 are 2 small-molecule inhibitors of MDM2 in clinical development. ALK is a transmembrane protein and a member of the insulin receptor tyrosine kinases. EML4-ALK fusion gene is identified in approximately 3-13% of non-small cell lung cancer (NSCLC). Early-phase clinical studies with Crizotinib, an ALK inhibitor, in NSCLC harboring EML4-ALK have demonstrated promising activity with high response rate and prolonged progression-free survival. PARPs are a family of nuclear enzymes that regulates the repair of DNA single-strand breaks through the base excision repair pathway. Randomized phase II study has shown adding PARP-1 inhibitor BSI-201 to cytotoxic chemotherapy improves clinical outcome in patients with triple-negative breast cancer. Olaparib, another oral small-molecule PARP inhibitor, demonstrated encouraging single-agent activity in patients with advanced breast or ovarian cancer. There are 5 other PARP inhibitors currently under active clinical investigation. http://www.jhoonline.org/content/4/1/16 Yuan Yuan Yu-Min Liao Chung-Tsen Hsueh Hamid Mirshahidi Journal of Hematology & Oncology 2011, null:16 2011-04-20T00:00:00Z doi:10.1186/1756-8722-4-16 /content/figures/1756-8722-4-16-toc.gif Journal of Hematology & Oncology 1756-8722 ${item.volume} 16 2011-04-20T00:00:00Z XML