Search

MLN4924 (pevonedistat), an inhibitor of the Nedd8 activating enzyme (NAE), has exhibited promising clinical activity in acute myelogenous leukemia (AML). Here we demonstrate that MLN4924 induces apoptosis in AML cell lines and clinical samples via a mechanism distinct from those observed in other malignancies. Inactivation of E3 cullin ring ligases (CRLs) through NAE inhibition causes accumulation of the CRL substrate c-Myc, which transactivates the PMAIP1 gene encoding Noxa, leading to increased Noxa protein, Bax and Bak activation, and subsequent apoptotic changes. Importantly, c-Myc knockdown diminishes Noxa induction; and Noxa siRNA diminishes MLN4924-induced killing. Because Noxa also neutralizes Mcl-1, an anti-apoptotic Bcl-2 paralog often upregulated in resistant AML, further experiments have examined the effect of combining MLN4924 with BH3 mimetics that target other anti-apoptotic proteins. In combination with ABT-199 or ABT-263 (navitoclax), MLN4924 exerts a synergistic cytotoxic effect. Collectively, these results provide new insight into MLN4924-induced engagement of the apoptotic machinery that could help guide further exploration of MLN4924 for AML. [ABSTRACT FROM AUTHOR]

The signaling mediated by c-MET and its ligand, hepatocyte growth factor (HGF), has been implicated in malignant progression of cancer involving stimulation of proliferation, invasion and metastasis. We studied the c-MET/HGF axis as a mediator of tumor-stromal interaction in ovarian cancer and the value of targeting c-MET for the treatment of ovarian cancer. To assess c-MET signaling, we established in vitro models of the microenvironment using primary and immortalized human fibroblasts from normal ovary and tumor samples and epithelial ovarian cancer cell lines. We found that fibroblast from normal ovaries secreted high levels of HGF (1500-3800 pg/ml) as compared with tumor-derived fibroblasts (undetectable level) and could elicit cellular biological responses on c-MET-expressing ovarian cancer cells including increase of cell proliferation and migration (2- to 140-fold increase). HGF secreted by fibroblasts was also found sequestered within extracellular matrices (ECMs) and when degraded this ECM-derived HGF stimulated cancer cell migration (1.5- to 24-fold). In cells containing constitutive c-MET phosphorylation, recombinant HGF and fibroblast-derived HGF negligibly affect c-MET phosphorylation on Tyr1234 and Tyr1003. However, both sources of HGF increased the phosphorylation of c-MET on Tyr1349, the multi-substrate docking site, by more than sixfold and led to activation of downstream signaling transducers. DCC-2701 (Deciphera Pharmaceuticals, LLC), a novel c-MET/TIE-2/VEGFR inhibitor was able to effectively reduce tumor burden in vivo and block c-MET pTyr1349-mediated signaling, cell growth and migration as compared with a HGF antagonist in vitro. Importantly, DCC-2701's anti-proliferative activity was dependent on c-MET activation induced by stromal human fibroblasts and to a lesser extent exogenous HGF. Our data suggest for the first time that DCC-2701 may be superior to HGF antagonists that are in clinical trials and that pTyr1349 levels might be a good indicator of c-MET activation and likely response to targeted therapy as a result of signals from the microenvironment. [ABSTRACT FROM AUTHOR]

The development of effective treatment strategies for most forms of acute myeloid leukemia (AML) has languished for the past several decades. There are a number of reasons for this, but key among them is the considerable heterogeneity of this disease and the paucity of molecular markers that can be used to predict clinical outcomes and responsiveness to different therapies. The recent large-scale sequencing of AML genomes is now providing opportunities for patient stratification and personalized approaches to treatment that are based on individual mutational profiles. It is particularly notable that studies by The Cancer Genome Atlas and others have determined that 44% of patients with AML exhibit mutations in genes that regulate methylation of genomic DNA. In particular, frequent mutation has been observed in the genes encoding DNA methyltransferase 3A (DNMT3A), isocitrate dehydrogenase 1 (IDH1) and isocitrate dehydrogenase 2 (IDH2), as well as Tet oncogene family member 2. This review will summarize the incidence of these mutations, their impact on biochemical functions including epigenetic modification of genomic DNA and their potential usefulness as prognostic indicators. Importantly, the presence of DNMT3A, IDH1 or IDH2 mutations may confer sensitivity to novel therapeutic approaches, including the use of demethylating agents. Therefore, the clinical experience with decitabine and azacitidine in the treatment of patients harboring these mutations will be reviewed. Overall, we propose that understanding the role of these mutations in AML biology will lead to more rational therapeutic approaches targeting molecularly defined subtypes of the disease. [ABSTRACT FROM AUTHOR]

The article discusses the gene expression of 65 potential leukemia-associated antigens (LAAs) in clinically annotated samples from diagnosed untreated acute myeloid leukemia (AML) patients using quantitative real-time polymerase chain reaction (PCR). It reveals the considerable heterogeneity in levels of RNA overexpression (OE) of putative LAAs compared with healthy donor tissues. It cites the list of genes overexpressed in AML for the selection of antigenic targets in adoptive T-cell therapy.

PurposeAlthough elevated urinary catecholamine levels have been reported in 90-95% of patients with neuroblastoma, more recent studies of pediatric Horner syndrome caused by an underling neuroblastoma have reported normal values at presentation. The purpose of this population-based study is to report the percentage of cases of neuroblastoma with elevated urinary catecholamine levels at presentation and to suggest a recommended work-up for cases of idiopathic pediatric Horner syndrome.MethodsThe medical records of all pediatric (<19 years) residents of Olmsted County, Minnesota diagnosed with neuroblastoma from 1 January 1969 through 31 December 2008 were retrospectively reviewed.ResultsA total of 14 patients <19 years of age were diagnosed with neuroblastoma as residents of Olmsted County, Minnesota, during the 40-year study period. A total of 10 (71%) of the 14 cases manifested elevated urinary catecholamine metabolites at the initial presentation. Urinary vanillylmandelic acid (VMA) levels were greater than twice the upper limit of normal in eight (57%) of 14 cases, whereas homovanillic acid (HVA) levels were greater than two times the upper limit of normal in 10 (71%) of the 14 cases. Three (75%) of the four cases without significantly elevated urinary VMA or HVA levels were diagnosed with stage IV disease, whereas one (25%) had stage II neuroblastoma.ConclusionUrinary catecholamine levels were significantly elevated at presentation in 10 (71%) of the 14 neuroblastoma cases during the 40-year study period, suggesting that greater emphasis be placed on performing a thorough physical examination and obtaining warranted imaging studies in cases of idiopathic pediatric Horner syndrome. [ABSTRACT FROM AUTHOR]

We report the results of a phase I dose escalation trial of the multikinase inhibitor sorafenib in relapsed and refractory acute leukemia patients using an intermittent dosing regimen. Fifteen patients with advanced leukemia (12 with acute myeloid leukemia, 2 with acute lymphoblastic leukemia, 1 with biphenotypic) and a median age of 63 (range 37-85) years were enrolled and treated on a dose escalation trial. Toxicities >or=grade 3 were present in 55% of cycles and the maximum tolerated dose (MTD) was determined to be 400 mg b.i.d. x 21 days in a 28-day cycle. Plasma inhibitory assays of kinase targets extracellular signal-regulated kinase (ERK) and FLT3-internal tandem duplication (ITD) showed excellent target inhibition, with FLT3-ITD silencing occurring below the MTD. The N-oxide metabolite of sorafenib seemed to be a more potent inhibitor of FLT3-ITD than the parent compound. Despite marked ex vivo FLT-3 ITD inhibition, no patients met the criteria for complete or partial response in this monotherapy study. Out of 15 patients, 11 experienced stable disease as best response. Although sorafenib showed only modest clinical activity as a single agent in this heavily treated population, robust inhibition of FLT3 and ERK suggests that there may be a potential important role in combination therapies. [ABSTRACT FROM AUTHOR]

Graft failure after allogeneic blood or marrow transplantation, although generally uncommon, can be a devastating complication. This report includes the outcome of nine patients who received a salvage transplant for failure to engraft after one (n=8) or 2 (n=1) prior transplants. Eight patients received allografts from the original donor. All received fludarabine 30 mg/m2 i.v. and alemtuzumab 20 mg i.v. daily from days −6 to −2. Daily CYA was begun on day −2, and the allograft was infused on day 0. The therapy was well tolerated with low toxicity, and all nine patients engrafted, recovering neutrophils at a median of 12 days after transplant. Four patients died: two of relapse, one of a fungal infection in the setting of GVHD and one of multiple sclerosis. The combination of fludarabine and alemtuzumab is an effective and well-tolerated salvage conditioning regimen for patients who experience graft failure after blood or marrow transplants.Bone Marrow Transplantation (2009) 43, 477–480; doi:10.1038/bmt.2008.353; published online 3 November 2008 [ABSTRACT FROM AUTHOR]

Myeloid leukemias, although a heterogeneous group of hematopoietic stem cell neoplasms, are arguably among the most suited for active specific immunotherapy. Nevertheless, clinical development of myeloid leukemia vaccine lagged behind similar approaches in other solid and hematological malignancies. The recent identification of apparently specific leukemia antigens and advances in understanding the fundamentals of tumor immunology have helped initiate a number of early phase clinical studies evaluating the safety and clinical efficacy of this approach. Here we review the recently identified and characterized putative leukemia antigens, the main vaccination strategies employed by most investigators and the results of clinical studies of immunotherapy of myeloid leukemias. Although these studies are early and often difficult to interpret, they offer evidence that effective immunity to leukemia could be induced following vaccination, and that clinical benefit can sometimes be observed, thus setting the stage for future development of this strategy and in the combinatorial approaches to treatment of myeloid leukemias that incorporate immunotherapy. [ABSTRACT FROM AUTHOR]

Most cases of acute leukemia can be assigned to the myeloid, B or T lineage. In a few cases, definitive assignment cannot be achieved because blasts express antigens of more than one lineage. A subset of these, referred to as acute bilineal leukemias (aBLLs), is characterized by the presence of more than one population of blasts, each comprising a single lineage. We identified 19 cases of aBLL, including 10 mixed T and myeloid (T-My) and nine mixed B and myeloid (B-My); no mixed B and T cases were identified. Cytogenetic data were available for 16 patients. Three of seven patients with B-My had a t(9;22)(q34q11.2), two had 11q23 translocations and one had del(9). Two of nine patients with T-My had 2p13 translocations; five had other unrelated abnormalities. Of 16 patients with outcome data, only six achieved complete remission and only two remain free of disease 2.5 and 4.5 years after chemotherapy or stem cell transplantation. aBLL is a rare disease that combines B or T and myeloid blasts. Cytogenetic abnormalities of t(9;22) and 11q23 are common in, and may be restricted to, B-My cases, while T-My cases have frequent but generally non-recurring abnormalities. Both types of aBLL are associated with poor outcome.Leukemia (2007) 21, 2264–2270; doi:10.1038/sj.leu.2404848; published online 5 July 2007 [ABSTRACT FROM AUTHOR]

Despite extensive study in many malignancies, maintenance therapy has clinically benefited only two diseases: acute lymphocytic leukemia (ALL) and acute promyelocytic leukemia (APL). ALL maintenance therapy utilizes low-dose 6-mercaptopurine (6MP) and methotrexate (MTX), while maintenance in APL primarily consists of all-trans-retinoic acid (ATRA). 6MP and MTX as used in ALL are also now usually added to maintenance ATRA for APL, based on data suggesting an improved disease-free survival. Although the mechanism of action of MTX and 6MP as maintenance is unknown, low-dose cytotoxic agents are potent inducers of differentiation in vitro. Thus, we studied whether maintenance therapy in ALL, like ATRA in APL, may be inducing terminal differentiation of ALL progenitors. The APL cell line NB4, the ALL cell lines REH and RS4;11, and patients' ALL blasts were incubated with ATRA, 6MP, and MTX in vitro. All three drugs inhibited the clonogenic growth of the APL and ALL cell lines without inducing immediate apoptosis, but associated with induction of phenotypic differentiation. The three drugs similarly upregulated lymphoid antigen expression, while decreasing CD34 expression, on patients' ALL blasts. These data suggest that induction of leukemia progenitor differentiation plays an important role in the mechanism of action of maintenance therapy in ALL. [ABSTRACT FROM AUTHOR]

Aplastic anemia (AA) and hypoplastic myelodysplastic syndromes (hMDS) are often difficult to distinguish. However, an accurate diagnosis is important because the prognosis and treatment of these diseases may differ. CD34+ hematopoietic progenitors are central to the pathogenesis of both disorders; they are the targets of the autoimmune attack in AA and neoplastic transformation in MDS. The aim of this study was to assess whether bone marrow CD34+ cell numbers could be used in differentiating between AA and hMDS. The percentage of bone marrow CD34+ cells was normal or increased (mean −3.5+0.5%, range 1–7%) in 15 of 35 patients studied, and low (mean −0.13±0.02%, range 0.02−0.36%) in 20 of 35 patients. All patients with a normal or increased percentage of CD34+ cells were ultimately diagnosed with hMDS based on the detection of clonal cytogenetic abnormalities or progression to refractory anemia with excess blasts/acute myeloid leukemia. All patients with low marrow CD34+ cell numbers met standard clinical criteria for AA and have not demonstrated neoplastic transformation with follow-up. Quantification of marrow CD34+ cells may serve as an important tool for distinguishing between AA and hMDS.Leukemia (2006) 20, 458–462. doi:10.1038/sj.leu.2404119; published online 26 January 2006 [ABSTRACT FROM AUTHOR]

The comparative kinetics of the accumulation of the trace metals copper, zinc and cadmium have been measured in the estuarine burrowing polychaete worm Nereis (Hediste) diversicolor from two sites: (a) a metalrich site, Restronguet Creek, Cornwall, UK, which hosts a copper- and zinc-tolerant population of worms, and (b) the Blackwater estuary, Essex, UK as a control site. A sediment transfer experiment showed that the Blackwater worms responded to the increased copper bioavailability in Restronguet Creek sediment by accumulating significantly increasing copper concentrations over 50 days. The Restronguet Creek worms showed no significant change in copper concentration over 50 days in sediment from either site or in sand. Nevertheless, electron microscopy showed that some Restronguet Creek worms do appear to excrete accumulated copper, probably in association with renewal of the cuticle over a long time scale. The Blackwater worms did not accumulate extra zinc from the zinc-rich Restronguet Creek sediment, in probable reflection of the regulation of body zinc concentration by N. diversicolor. Radiolabelled zinc and cadmium were accumulated from labelled sediment and labelled solution by worms from both sites. The rate of uptake of labelled zinc from sediment was significantly greater in the Restronguet Creek worms, as was the rate of uptake of labelled cadmium from 10 μg 1-1 dissolved exposure; other rates of uptake did not differ between populations. Mucus, which is secreted by Restronguet Creek worms in response to enhanced copper exposure, adsorbed very small proportions of zinc and cadmium present in solution, indicating that the mucus does not act as an adsorption barrier against excessive metal uptake by these worms. [ABSTRACT FROM AUTHOR]

The barnacle Balanus improvisus and the mussel Mytilus trossulus have been used as biomonitors of the trace metals Cu, Zn, Cd, Fe, Pb, Mn and Ni at five sublittoral sites in the Gulf of Gdansk (Baltic Sea) between February 2000 and September 2001. The study has established a benchmark against which future biomonitoring programmes will be able to establish changes in local metal pollution, particularly if metal loadings in the river Vistula (draining into the Gulf) alter in the future. The study highlighted differences in trace metal bioavailabilities to both barnacles and mussels, geographically and over time. Accumulated metal concentrations of Cu, Zn, Fe, Pb and Ni, but not Cd or Mn, were correlated in the barnacles and mussels, suggesting that the bioavailabilities of the former metals to the two biomonitors were similar. The barnacles showed greater discriminatory power than the mussels as trace metal biomonitors. Concentrations of trace metals in surficial sediments (<63 μm) did not correlate significantly with accumulated metal concentrations in either barnacles or mussels, indicating that sediment metal concentrations are not necessarily good proxy measures of ambient trace metal bioavailabilities to the local coastal filter feeders. [ABSTRACT FROM AUTHOR]

Bioaccumulation of cadmium, copper, and zinc was examined in common ragworms Hediste diversicolor from control (Bay of Somme, Blackwater) and metal-rich (Seine estuary, Boulogne harbor, Restronguet Creek) sites in France and the United Kingdom. The degree of exposure in the field was assessed by considering both total concentrations in superficial sediment and the quantities of metals which may be released in vitro at different pH levels. Among the three contaminated sites, release of the three metals was not detectable in Boulogne harbor, in correlation with limited enhancement of the metal concentrations in the common ragworms from this site. Even at those sites where zinc could be released in vitro from the sediment, zinc concentrations were not enhanced in common ragworms, in agreement with previous findings indicating that the body content of this metal is regulated in H. diversicolor. At all the studied sites, bioaccumulated zinc was mainly in cytosolic form. The distribution of cadmium and copper varied according to the origin of the common ragworms, the insoluble fraction increasing with the degree of contamination (cadmium in the Restronguet Creek, copper in the Seine estuary, and even more in Restronguet Creek). In the cytosolic fraction, metals were partly linked to cytosolic heat-stable thiolic compounds (CHSTC) with molecular masses (5–6 kDa and about 12 kDa) consistent with metallothionein-like proteins (MTLP). Metal-binding to MTLP varied with the degree of contamination and with the metal studied. In contrast to many invertebrates, the presence of metal-binding CHSTC (MM about 2 kDa) other than MTLP seems to be a peculiar feature of H. diversicolor.RID="" ID="" Correspondence to: J. C. Amiard; email: Jean-Claude.Amiard@isomer.univ-nantes.fr [ABSTRACT FROM AUTHOR]

Polychaete worms (Hediste diversicolor) originating from a strongly metal-contaminated area (Restronguet Creek) and a relatively clean site (Blackwater estuary) were exposed to a range of experimental doses of Ag, Cd, Cu and Zn. Specimens from both populations were compared to assess their relative sensitivity to metal stress and the physiological mechanisms involved in their respective adaptive strategies for coping with increased metal exposures. Taking into account the LC50 values, increased tolerance to Cd, Cu and Zn of the Restronguet Creek worms over that of the Blackwater was demonstrated, whereas the opposite was shown for Ag. An abundant secretion of mucus in response to toxicants was observed, possibly reducing metal availability for uptake, at least under laboratory conditions. This mechanism was particularly active in specimens from Restronguet Creek exposed to Ag and Cu. Unexpectedly, of the two worm populations, Blackwater worms contained significantly higher concentrations of cytosolic heat-stable compounds (CHSTC), a category of cytosolic components that includes metallothioneins, the detoxificatory role of which is well documented, and other compounds binding trace metals via sulphur bonds. However, the concentration of such compounds is not totally representative in itself of their involvement in metal detoxification, because a high rate of their turnover in metal-exposed worms might be responsible for (at least) the Cu storage associated with S in lysosomes as a consequence of the breakdown of Cu-thionein. Cu-containing lysosomes were abundant in epidermal cells of Restronguet Creek worms, but were lacking in Blackwater worms. Extracellular granules present in the epicuticle also contained S and Cu, their number and size being much more important in Restronguet Creek worms, and they appear to be a major detoxificatory store for accumulated Cu. Spherocrystals in cells of the gut wall seem to be the major detoxified store of Zn in Restronguet Creek worms, whereas in specimens from the Blackwater they were also present but contained only S and Ca at detectable levels. Evidence was also found for the presence of detoxificatory intracellular structures containing other metals and metalloids in the tegument and gut epithelium of Restronguet Creek worms. [ABSTRACT FROM AUTHOR]

The exoskeleton of the stone crab Paralomis granulosa (Decapoda: Lithodidae) is one of the substrates on which the barnacle Notobalanus flosculus settles in the Beagle Channel of Tierra del Fuego, Argentina (~55°S 67°W). The presence of such an epibiont can be useful for estimating the intermolt period of pre-recruit and recruited crabs to the legal, fishable stock of crab. We undertook an investigation of the timing of N. flosculus settlement on P. granulosa exoskeletons, and their subsequent loss during molting, as a step toward forecasting fishable stock biomass. Between December 1996 and December 1998, 10–15 male P. granulosa with the epibiont N. flosculus were sampled each month in the fishery catches. Almost every month from 1995 to 1998 we evaluated the carapace age of 30,051 crabs, as judged from the degree and type of epibionts. We supplemented our fishery-based investigation with an overlapping investigation of the timing of N. flosculus settlement on artificial collectors. In September 1996, we deployed 240 clay tiles as collectors which were checked monthly for the presence of newly settled N. flosculus. From 1995 to 1997 the prevalence of N. flosculus as an epibiont of P. granulosa was ~20% in male crabs >80 mm carapace length (CL). P. granulosa molted in December, yet the frequency of molted crabs >80 mm CL decreased with size and the prevalence of barnacles was significantly greater than on crabs <80 mm CL. N.flosculus grew well as an epibiont on P. granulosa and remained on crab exoskeletons for 13 months. Our observation that the densest settlements of barnacle cohorts on the artificial collectors occurred previously or simultaneously with the molting period of male P. granulosa provides evidence that P. granulosa carrying N. flosculus between January and November skipped their molt. Moreover, barnacle cohorts of December, February and March seemed not to settle onto crab carapaces. Our conclusion can help us calculate the proportion of skip-molters in the population, and subsequently explain or forecast changes in the fishable stock biomass of crab after each molting season. [ABSTRACT FROM AUTHOR]

The oyster Crassostrea rhizophorae has been used as a biomonitor of trace metal contamination in two Brazilian coastal systems. C. rhizophorae were collected in January 1998 from 15 stations (from 4 coastal inlets (including 1 estuary) and 1 coastal beach) near Macau, Rio Grande do Norte (RN), Brazil, a region affected by the activities of the oil industry and salt manufacture in coastal salt ponds; oysters were also collected in September 1999 from 8 stations in the Curimatau estuary (RN), an estuary becoming increasingly affected by shrimp farming activities. C. rhizophorae is a net accumulator of trace metals and can be used as a biomonitor, the accumulated soft tissue concentrations representing integrated records of bioavailable metal over the life of the oyster. At Macau, significant differences in oyster accumulated concentrations (and hence bioavailabilities to the oyster) of Fe, Zn, Cu, and Mn were found between stations; raised zinc availabilities at the coastal site are in close proximity to oil industry activities but the very high availabilities of Fe, Cu and Mn in the Rio dos Cavalos estuary originate from an unknown source. In the Curimatau estuary, bioavailabilities of Mn, Pb and Cd, but particularly of Cu and Zn, to the oysters are raised at the two most downstream sites, the only sites below the effluent of a large shrimp farming enterprise. The oysters also act as a local food source, and concentrations of Zn, Cu and Pb of some of the oysters are above typical public health recommended limits. [ABSTRACT FROM AUTHOR]

Aberrant expression of homeobox genes has been described in primary leukemia blasts. We recently cloned a new cDNA, BP1, which is a member of the homeobox gene family. BP1 expression was investigated in bone marrow samples from acute myeloid leukemia (AML), acute T cell lymphocytic leukemia (ALL) and pre-B cell ALL. Expression levels of two apparent isoforms of BP1, DLX7 and DLX4, were measured in the same samples. They are weakly if at all detectable in normal bone marrow, PHA-stimulated T cells or B cells. BP1 RNA was highly expressed in 63% of AML cases, including 81% of the pediatric and 47% of the adult cases, and in 32% of T-ALL cases, but was not found in any of the pre-B ALL cases. Coexpression of BP1, DLX7 and DLX4 occurred in a significant number of leukemias. Our data, including co-expression of BP1 with c-myb and GATA-1, markers of early progenitors, suggest that BP1 expression occurs in primitive cells in AML. Analysis of CD34+ and CD34- normal bone marrow cells revealed BP1 is expressed in CD34- cells and virtually extinguished in CD34+ cells. Ectopic expression of BP1 in the leukemia cell line K562 increased clonogenicity, consistent with a role for BP1 in leukemogenesis. The presence of BP1 RNA in leukemic blasts may therefore be a molecular marker for primitive cells and/or may indicate that BP1 is an important upstream factor in an oncogenic pathway. [ABSTRACT FROM AUTHOR]

Excess calcium binding affects the shape and dynamics of cellular deformation of human erythrocytes. It may be hypothesized that incorporation of calcium may modify cellular deformability by processes which include specific cross-linking of membrane proteins with resultant changes in cell shape and deformability. Since previous studies indicate that accumulation of calcium ions causes development of gamma-glutamyl-epsilon-lysine bridges in membrane proteins, under control of a membrane transamidating enzyme which specifically requires calcium ions for activation, experiments were devised to examine the relationship between cross-linking and deformability and to determine the effects of specific inhibitor of membrane protein cross-linking on the calcium-dependent modification of erythrocyte to the echinocytic shape. The elastic shear modulus of the membrane was not significantly affected by calcium-induced cross-linking, indicating that induced shape change, not altered elasticity, causes the observed reduction in cellular deformability. These findings support the interpretation that Ca++-induced and transamidase-catalyzed cross-linking of membrane proteins contributes to fixation of altered cellular shape and decreased cellular deformability. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "Quantification of marrow CD34p cells: an important tool for distinguishing between hypoplastic myelodysplastic syndromes and aplastic anemia," byW. H. Matsui, Brodsky in the September 14, 2006 online publication issue.

A correction to the article "DNMT3A and IDH mutations in acute myeloid leukemia and other myeloid malignancies: associations with prognosis and potential treatment strategies" that was published in the volume 28, 2014 issue is presented.