bluuebunny/crossref_metadata_2025 huggingface dataset:
Vascular endothelial cell growth factor is an autocrine promoter of abnormal localized immature myeloid precursors and leukemia progenitor formation in myelodysplastic syndromes
Authors: Bellamy William T. , Richter Lynne , Sirjani Davuud , Roxas Concepcion , Glinsmann-Gibson Betty , Frutiger Yvette , Grogan Thomas M. , List Alan F.
Published: July 2002

Vascular endothelial growth factor (VEGF) is a potent angiogenic peptide with biologic effects that include regulation of hematopoietic stem cell development, extracellular matrix remodeling, and inflammatory cytokine generation. To delineate the potential role of VEGF in patients with myelodysplastic syndrome (MDS), VEGF protein and receptor expression and its functional significance in MDS bone marrow (BM) were evaluated. In BM clot sections from normal donors, low-intensity cytoplasmic VEGF expression was detected infrequently in isolated myeloid elements. However, monocytoid precursors in chronic myelomonocytic leukemia (CMML) expressed VEGF in an intense cytoplasmic pattern with membranous co-expression of the Flt-1 or KDR receptors, or both. In situ hybridization confirmed the presence of VEGF mRNA in the neoplastic monocytes. In acute myelogenous leukemia (AML) and other MDS subtypes, intense co-expression of VEGF and one or both receptors was detected in myeloblasts and immature myeloid elements, whereas erythroid precursors and lymphoid cells lacked VEGF and receptor expression. Foci of abnormal localized immature myeloid precursors (ALIP) co-expressed VEGF and Flt-1 receptor, suggesting autocrine cytokine interaction. Antibody neutralization of VEGF inhibited colony-forming unit (CFU)-leukemia formation in 9 of 15 CMML and RAEB-t patient specimens, whereas VEGF stimulated leukemia colony formation in 12 patients. Neutralization of VEGF activity suppressed the generation of tumor necrosis factor-α and interleukin-1β from MDS BM–mononuclear cells and BM–stroma and promoted the formation of CFU-GEMM and burst-forming unit-erythroid in methylcellulose cultures. These findings indicate that autocrine production of VEGF may contribute to leukemia progenitor self-renewal and inflammatory cytokine elaboration in CMML and MDS and thus provide a biologic rationale for ALIP and its adverse prognostic relevance in high-risk MDS.
Different expression of CD41 on human lymphoid and myeloid progenitors from adults and neonates
Authors: Debili Najet , Robin Catherine , Schiavon Valérie , Letestu Rémi , Pflumio Françoise , Mitjavila-Garcia Maria-Teresa , Coulombel Laure , Vainchenker William
Published: July 2002

The glycoprotein (Gp) IIb/IIIa integrin, also called CD41, is the platelet receptor for fibrinogen and several other extracellular matrix molecules. Recent evidence suggests that its expression is much wider in the hematopoietic system than was previously thought. To investigate the precise expression of the CD41 antigen during megakaryocyte (MK) differentiation, CD34+ cells from cord blood and mobilized blood cells from adults were grown for 6 days in the presence of stem cell factor and thrombopoietin. Two different pathways of differentiation were observed: one in the adult and one in the neonate cells. In the neonate samples, early MK differentiation proceeded from CD34+CD41− through a CD34−CD41+CD42− stage of differentiation to more mature cells. In contrast, in the adult samples, CD41 and CD42 were co-expressed on a CD34+ cell. The rare CD34+CD41+CD42− cell subset in neonates was not committed to MK differentiation but contained cells with all myeloid and lymphoid potentialities along with long-term culture initiating cells (LTC-ICs) and nonobese diabetic/severe combined immune-deficient repopulating cells. In the adult samples, the CD34+CD41+CD42−subset was enriched in MK progenitors, but also contained erythroid progenitors, rare myeloid progenitors, and some LTC-ICs. All together, these results demonstrate that the CD41 antigen is expressed at a low level on primitive hematopoietic cells with a myeloid and lymphoid potential and that its expression is ontogenically regulated, leading to marked differences in the surface antigenic properties of differentiating megakaryocytic cells from neonates and adults.
Endothelial cell activation by myeloblasts: molecular mechanisms of leukostasis and leukemic cell dissemination
Authors: Stucki Anne , Rivier Anne-Sophie , Gikic Milica , Monai Natacha , Schapira Marc , Spertini Olivier
Published: July 2002

Leukostasis and tissue infiltration by leukemic cells are poorly understood life-threatening complications of acute leukemia. This study has tested the hypothesis that adhesion receptors and cytokines secreted by blast cells play central roles in these reactions. Immunophenotypic studies showed that acute myeloid leukemia (AML) cells (n = 78) of the M0 to M5 subtypes of the French-American-British Cooperative Group expressed various amounts of adhesion receptors, including CD11a, b, c/CD18, CD49d, e, f/CD29, CD54, sCD15, and L-selectin. The presence of functional adhesion receptors was evaluated using a nonstatic adhesion assay. The number of blast cells attached to unactivated endothelium increased by 7 to 31 times after a 6-hour exposure of endothelium to tumor necrosis factor (TNF)-α. Inhibition studies showed that multiple adhesion receptors—including L-selectin, E-selectin, VCAM-1, and CD11/CD18—were involved in blast cell adhesion to TNF-α–activated endothelium. Leukemic cells were then cocultured at 37°C on unactivated endothelial cell monolayers for time periods up to 24 hours. A time-dependent increase in the number of blasts attached to the endothelium and a concomitant induction of ICAM-1, VCAM-1, and E-selectin were observed. Additional experiments revealed that endothelial cell activation by leukemic myeloblasts was caused by cytokine secretion by blast cells, in particular TNF-α and IL-1β, and direct contacts between adhesion receptors expressed by blast cells and endothelial cells. Thus, leukemic cells have the ability to generate conditions that promote their own adhesion to vascular endothelium, a property that may have important implications for the pathophysiology of leukostasis and tissue infiltration by leukemic blast cells.
Detection of viral interleukin-6 in Kaposi sarcoma–associated herpesvirus–linked disorders
Authors: Aoki Yoshiyasu , Yarchoan Robert , Wyvill Kathleen , Okamoto Shin-ichiro , Little Richard F. , Tosato Giovanna
Published: July 2002

Expression of a viral interleukin-6 (vIL-6) has been detected in certain Kaposi sarcoma (KS)–associated herpesvirus positive (KSHV+) lesions. The release of vIL-6 systemically and its contribution to the pathogenesis of HIV-related malignancies was studied. Serum vIL-6 was detected in 13 (38.2%) of 34 HIV+ patients with KS, in 6 (85.7%) of 7 HIV+patients with primary effusion lymphoma (PEL) and/or multicentric Castleman disease (MCD), and in 18 (60.0%) of 30 HIV+, mostly homosexual, individuals without KS, MCD, or PEL. By contrast, serum vIL-6 was detected in only 3 (23.1%) of 13 patients with classic KS, 1 (2.5%) of 40 blood donors from the United States, and 4 (19.0%) of 21 blood donors from Italy. Circulating vIL-6 levels were associated with HIV+ status (P < .0001). However, within the HIV+ cohort, serum vIL-6 levels were not associated with the occurrence of KSHV-associated malignancies (P = .43).
Deoxygenation of sickle cells stimulates Syk tyrosine kinase and inhibits a membrane tyrosine phosphatase
Authors: Merciris Patrick , Hardy-Dessources Marie-Dominique , Giraud Françoise
Published: July 2002

Polymerization of hemoglobin S in sickle red cells, in deoxygenated conditions, is associated with K+ loss and cellular dehydration. It was previously reported that deoxygenation of sickle cells increases protein tyrosine kinase (PTK) activity and band 3 tyrosine phosphorylation and that PTK inhibitors reduce cell dehydration. Here, the study investigates which PTKs are involved and the mechanism of their activation. Deoxygenation of sickle cells induced a 2-fold increase in Syk activity, measured by autophosphorylation in immune complex assays, but had no effect on Lyn. Syk was not stimulated by deoxygenation of normal red cells, and stimulation was partly reversible on reoxygenation of sickle cells. Syk activation was independent of the increase in intracellular Ca++ and Mg2+ associated with deoxygenation. Lectins that promote glycophorin or band 3 aggregation did not activate Syk. In parallel to Syk stimulation, deoxygenation of sickle cells, but not of normal red cells, decreased the activity of both membrane-associated protein tyrosine phosphatase (PTPs) and membrane protein thiol content. In vitro pretreatment of Syk immune complexes with membrane PTP inhibited Syk autophosphorylation. It is suggested that Syk activation in vivo could be mediated by PTP inhibition, itself resulting from thiol oxidation, as PTPs are known to be inhibited by oxidants. Altogether these data indicate that Syk could be involved in the mechanisms leading to sickle cell dehydration.
Genetic variation in glycoprotein IIb/IIIa (GPIIb/IIIa) as a determinant of the responses to an oral GPIIb/IIIa antagonist in patients with unstable coronary syndromes
Authors: O'Connor Fiona F. , Shields Denis C. , Fitzgerald Anthony , Cannon Christopher P. , Braunwald Eugene , Fitzgerald Desmond J.
Published: July 2002

This study examined the influence of the PlApolymorphism of glycoprotein IIIa (GPIIIa) in determining the response to an oral GPIIb/IIIa antagonist, orbofiban, in patients with unstable coronary syndromes. Genotyping for the PlA polymorphism was performed in 1014 patients recruited into the OPUS-TIMI-16 (orbofiban in patients with unstable coronary syndromes–thrombolysis in myocardial infarction 16) trial, in which patients were randomized to low- or high-dose orbofiban or placebo for 1 year. The primary end point (n = 165) was a composite of death, myocardial infarction (MI), recurrent ischemia requiring rehospitalization, urgent revascularization, and stroke. Overall, orbofiban failed to reduce ischemic events when compared with placebo, but increased the rate of bleeding. In the whole population, PlA2 carriers had a significant increase in MI (n = 33) during follow up, with a relative risk (RR) of 2.71 (95% CI, 1.37 to 5.38; P = .004). There was a significant interaction between treatment (placebo and orbofiban) and the PlA polymorphism for bleeding (n = 187; P = .05). Thus, while orbofiban increased bleeding in noncarriers (RR = 1.87, 1.29 to 2.71;P < .001) in a dose-dependent fashion, it did not increase bleeding events in PlA2 carriers (RR = 0.87, 0.46 to 1.64). There was no interaction between treatment (placebo and orbofiban) and the PlA polymorphism for the primary end point (P = .10). However, in the patients receiving orbifiban there was a higher risk of a primary event (RR = 1.55, 1.03 to 2.34; P = .04) and MI (RR 4.27, 1.82 to 10.03;P < .001) in PlA2 carriers compared with noncarriers. In contrast, there was no evidence that PlA2influenced the rate of recurrent events in placebo-treated patients. In patients presenting with an acute coronary syndrome, the PlA polymorphism of GPIIb/IIIa may explain some of the variance in the response to an oral GPIIb/IIIa antagonist.
Vascular endothelial growth factor triggers signaling cascades mediating multiple myeloma cell growth and migration
Authors: Podar Klaus , Tai Yu-Tzu , Davies Faith E. , Lentzsch Suzanne , Sattler Martin , Hideshima Teru , Lin Boris K. , Gupta Deepak , Shima Yoshihito , Chauhan Dharminder , Mitsiades Constantine , Raje Noopur , Richardson Paul , Anderson Kenneth C.
Published: July 2002

Multiple myeloma (MM) remains incurable, with a median survival of 3 to 4 years. This study shows direct effects of vascular endothelial growth factor (VEGF) upon MM and plasma cell leukemia (PCL) cells. The results indicate that VEGF triggers tumor cell proliferation via a protein kinase C (PKC)–independent Raf-1–MEK–extracellular signal-regulated protein kinase pathway, and migration via a PKC-dependent pathway. These observations provide the framework for novel therapeutic strategies targeting VEGF signaling cascades in MM.
High production of interferon γ but not interleukin-2 by human T-lymphotropic virus type I–infected peripheral blood mononuclear cells
Authors: Hanon Emmanuel , Goon Peter , Taylor Graham P. , Hasegawa Hitoshi , Tanaka Yuetsu , Weber Jonathan N. , Bangham Charles R. M.
Published: July 2002

The transactivator protein of human T-lymphotropic virus I (HTLV-I), Tax, has been associated with the up-regulation of several host cell genes, including interleukin 2 (IL-2), the IL-2 receptor-α(IL-2Rα) chain (CD25), interferon γ(IFN-γ), and tumor necrosis factor (TNF). It has been proposed that an IL-2/CD25 autocrine loop plays a part in maintaining the very high proviral loads often found in HTLV-I infection. Furthermore, abnormal production of inflammatory cytokines might contribute to the pathogenesis of the inflammatory diseases associated with HTLV-I infection. However, there has been no study of the expression of these genes in freshly isolated peripheral blood mononuclear cells (PBMCs) naturally infected with HTLV-I. In the present study, flow cytometry was used to determine which cytokines are produced by freshly isolated PBMCs that spontaneously express the HTLV-I Tax protein. Surprisingly, the results show that intracellular Tax expression is associated with rapid up-regulation of IFN-γ but not TNF or IL-2. A proportion of HTLV-I–infected cells express both IFN-γ and the surface markers of effector memory cells. Such cells are capable of migration through peripheral tissues and could therefore contribute to the inflammation seen in diseases such as HTLV-I–associated myelopathy/tropical spastic paraparesis.
The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents, IV: the mechanisms involved in inhibiting cell-cycle progression
Authors: Gao Jin , Richardson Des R.
Published: July 2002

Some chelators of the pyridoxal isonicotinoyl hydrazone class have antiproliferative activity that is far greater than desferrioxamine (DFO). In this study, DFO was compared with one of the most active chelators (311) on the expression of molecules that play key roles in cell-cycle control. This was vital for understanding the role of iron (Fe) in cell-cycle progression and for designing chelators to treat cancer. Incubating cells with DFO, and especially 311, resulted in a decrease in the hyperphosphorylated form of the retinoblastoma susceptibility gene product (pRb). Chelators also decreased cyclins D1, D2, and D3, which bind with cyclin-dependent kinase 4 (cdk4) to phosphorylate pRb. The levels of cdk2 also decreased after incubation with DFO, and especially 311, which may be important for explaining the decrease in hyperphosphorylated pRb. Cyclins A and B1 were also decreased after incubation with 311 and, to a lesser extent, DFO. In contrast, cyclin E levels increased. These effects were prevented by presaturating the chelators with Fe. In contrast to DFO and 311, the ribonucleotide reductase inhibitor hydroxyurea increased the expression of all cyclins. Hence, the effect of chelators on cyclin expression was not due to their ability to inhibit ribonucleotide reductase. Although chelators induced a marked increase in WAF1 and GADD45 mRNA transcripts, there was no appreciable increase in their protein levels. Failure to translate these cell-cycle inhibitors may contribute to dysregulation of the cell cycle after exposure to chelators.
Gene expression screening of human mast cells and eosinophils using high-density oligonucleotide probe arrays: abundant expression of major basic protein in mast cells
Authors: Nakajima Toshiharu , Matsumoto Kenji , Suto Hajime , Tanaka Kazuko , Ebisawa Motohiro , Tomita Hisashi , Yuki Keisuke , Katsunuma Toshio , Akasawa Akira , Hashida Ryoichi , Sugita Yuji , Ogawa Hideoki , Ra Chisei , Saito Hirohisa
Published: July 2002

Mast cells (MCs) and eosinophils are thought to play important roles in evoking allergic inflammation. Cell-type–specific gene expression was screened among 12 000 genes in human MCs and eosinophils with the use of high-density oligonucleotide probe arrays. In comparison with other leukocytes, MCs expressed 140 cell-type–specific transcripts, whereas eosinophils expressed only 34. Among the transcripts for expected MC-specific proteins such as tryptase, major basic protein (MBP), which had been thought to be eosinophil specific, was ranked fourth in terms of amounts of increased MC-specific messenger RNA. Mature eosinophils were almost lacking this transcript. MCs obtained from 4 different sources (ie, lung, skin, adult peripheral blood progenitor–derived and cord blood progenitor–derived MCs, and eosinophils) were found to have high protein levels of MBP in their granules with the use of flow cytometric and confocal laser scanning microscopic analyses. The present finding that MCs can produce abundant MBP is crucial because many reports regarding allergic pathogenesis have been based on earlier findings that MBP was almost unique to eosinophils and not produced by MCs.
The Notch ligand, Delta-1, inhibits the differentiation of monocytes into macrophages but permits their differentiation into dendritic cells
Authors: Ohishi Kohshi , Varnum-Finney Barbara , Serda Rita E. , Anasetti Claudio , Bernstein Irwin D.
Published: July 2002

Notch-mediated cellular interactions are known to regulate cell fate decisions in various developmental systems. A previous report indicated that monocytes express relatively high amounts of Notch-1 and Notch-2 and that the immobilized extracellular domain of the Notch ligand, Delta-1 (Deltaext-myc), induces apoptosis in peripheral blood monocytes cultured with macrophage colony-stimulating factor (M-CSF), but not granulocyte-macrophage CSF (GM-CSF). The present study determined the effect of Notch signaling on monocyte differentiation into macrophages and dendritic cells. Results showed that immobilized Deltaext-myc inhibited differentiation of monocytes into mature macrophages (CD1a+/−CD14+/− CD64+) with GM-CSF. However, Deltaext-myc permitted differentiation into immature dendritic cells (CD1a+CD14−CD64−) with GM-CSF and interleukin 4 (IL-4), and further differentiation into mature dendritic cells (CD1a+CD83+) with GM-CSF, IL-4, and tumor necrosis factor-α (TNF-α). Notch signaling affected the differentiation of CD1a−CD14+macrophage/dendritic cell precursors derived in vitro from CD34+ cells. With GM-CSF and TNF-α, exposure to Deltaext-myc increased the proportion of precursors that differentiated into CD1a+CD14− dendritic cells (51% in the presence of Deltaext-myc versus 10% in control cultures), whereas a decreased proportion differentiated into CD1a−CD14+ macrophages (6% versus 65%). These data indicate a role for Notch signaling in regulating cell fate decisions by bipotent macrophage/dendritic precursors.
Discrepancies between genotype and phenotype in hematology: an important frontier
Authors: Beutler Ernest
Published: July 2002

An African American male infant with sickle cell disease has a devastating stroke; an African American soldier is surprised when he is informed that he has sickle cell disease. They are both homozygous for the same mutation. An Ashkenazi Jewish woman with Gaucher disease has a huge spleen and severe thrombocytopenia; her older brother, homozygous for the same 1226G glucocerebrosidase mutation, is found on routine examination to have a barely palpable spleen tip. The fact that clinical manifestations of genetic diseases can vary widely among patients has been recognized for many decades. In the past, however, it could often be attributed to the pleomorphic nature of mutations of the same gene: the patient with severe disease, it was averred, must have a different mutation than the one with mild disease. Even before a precise definition of mutations could be achieved at the DNA level, such an explanation did not serve to clarify the differences that existed between siblings with the same autosomal recessive disease. Such siblings must surely be carrying the same 2 disease-producing alleles. With the advent of sequence analysis of genes, the great extent of phenotype variation in patients with the same genotype has come to be more fully appreciated, but understanding of why it occurs continues to be meager. It is the purpose of this review to explore some of the variations in phenotype seen by hematologists in patients with identical mutations, to indicate where some progress has been made, and to suggest how understanding in this important area may be expanded.
Human T-cell leukemia virus type 2 induces survival and proliferation of CD34+ TF-1 cells through activation of STAT1 and STAT5 by secretion of interferon-γ and granulocyte macrophage–colony-stimulating factor
Authors: Bovolenta Chiara , Pilotti Elisabetta , Mauri Massimiliano , Turci Marco , Ciancianaini Paolo , Fisicaro Paola , Bertazzoni Umberto , Poli Guido , Casoli Claudio
Published: July 2002

Human T-cell leukemia–lymphoma virus (HTLV) type-2 can induce the survival and proliferation of CD34+ TF-1 cells deprived of interleukin (IL)-3. This effect did not require productive infection and occurred when HTLV-2 was produced from T cells (CMo), but not from B cells (BMo), unless the latter virus was complexed with anti–HLA-DR monoclonal antibodies (mAbs). Cellular and molecular mechanisms triggered by HTLV-2 interaction with TF-1 cells were here investigated. Activation of signal transducer and activator of transcription (STAT) 5 protein occurred in TF-1 cells incubated either with IL-3 or with HTLV-2/CMo; in addition the virus, but not IL-3, activated STAT1. The effect of HTLV-2 required several hours, suggesting dependence on the induction of cellular factors. By screening a panel of secreted factors, granulocyte macrophage–colony-stimulating factor (GM-CSF), interferon (IFN)-γ, and stem cell factor (SCF) were found induced by HTLV-2 in TF-1 cells. Of note is the fact that these molecules induce a variety of biologic effects through the activation of STAT proteins, including STAT1 and STAT5. Neutralization experiments indicated that GM-CSF and IFN-γ, but not SCF, were responsible for HTLV-2–induced STAT activation, whereas anti–GM-CSF antibodies greatly inhibited TF-1 cell proliferation. Finally, incubation of BMo virus with anti–HLA-DR mAb rescued TF-1 cell survival in the absence of IL-3. Thus, HTLV-2 interaction with CD34+ precursor cells may lead to the expression of cytokines that, by inducing autocrine activation of STATs, may influence the host's regenerative capacity and immune response to HTLV-2 and to other infectious agents.
Distinct bone marrow findings in T-cell granular lymphocytic leukemia revealed by paraffin section immunoperoxidase stains for CD8, TIA-1, and granzyme B
Authors: Morice William G. , Kurtin Paul J. , Tefferi Ayalew , Hanson Curtis A.
Published: July 2002

Unlike other leukemia types in which the bone marrow findings are diagnostic, the bone marrow pathology of T-cell granular lymphocytic leukemia (GLL) is subtle and ill-defined. In this study, bone marrow biopsy specimens from 36 patients with T-cell GLL and from 25 control patients with cytopenias and relative or absolute increases in blood large granular lymphocytes were studied by immunohistochemistry using antibodies to the cytolytic lymphocyte antigens CD8, CD56, CD57, TIA-1, and granzyme B. The goals were to clarify the bone marrow pathology of T-cell GLL and to refine the diagnostic criteria for T-cell GLL. Most bone marrow specimens from the T-cell GLL patients contained interstitially distributed clusters of at least 8 CD8+(83%) or TIA-1+ (75%) lymphocytes or clusters of at least 6 granzyme B+ (50%) lymphocytes. Interstitial clusters of CD8+, TIA-1+, or granzyme B+ cells were present in 36%, 12%, and 0%, respectively, of the control bone marrows (all values significantly different, P < .001). An additional T-cell GLL disease-specific finding was the presence of linear arrays of intravascular CD8+, TIA-1+, or granzyme B+ lymphocytes, found in 67% of cases of T-cell GLL and in none of the 25 control samples (P < .001). Staining for CD56 and CD57 was noncontributory. These findings clarify the bone marrow histopathology of T-cell GLL and provide an additional tool by which the discrete, abnormal lymphocyte population required for a diagnosis of T-cell GLL can be identified.
Dramatic increase in lymph node dendritic cell number during infection by the mouse mammary tumor virus occurs by a CD62L-dependent blood-borne DC recruitment
Authors: Martı́n Pilar , Ruiz Sara Ruiz , del Hoyo Gloria Martı́nez , Anjuère Fabienne , Vargas Héctor Hernández , López-Bravo Marı́a , Ardavı́n Carlos
Published: July 2002

Despite the information dealing with the differential phenotype and function of the main mouse dendritic cell (DC) subpopulations, namely, CD8α− and CD8α+ DCs, their origin and involvement in antiviral immune responses in vivo are still largely unknown. To address these issues, this study used the changes occurring in DC subpopulations during the experimental infection by the Swiss (SW) strain of the mouse mammary tumor virus (MMTV). MMTV(SW) induced an 18-fold increase in lymph node DCs, which can be blocked by anti-CD62L treatment, concomitant with the presence of high numbers of DCs in the outer cortex, in close association with high endothelial venules. These data suggest that the DC increase caused by MMTV(SW) infection results from the recruitment of blood-borne DCs via high endothelial venules, by a CD62L-dependent mechanism. In addition, skin sensitization assays indicate that MMTV(SW) infection inhibits epidermal Langerhans cell migration to the draining lymph node. Moreover, data on the kinetics of MMTV(SW)-induced expansion of the different DC subsets support the hypothesis that CD8− and CD8+ DCs represent different maturation stages of the same DC population, rather than myeloid- and lymphoid-derived DCs, respectively, as previously proposed. Finally, the fact that DCs were infected by MMTV(SW) suggests their participation in the early phases of infection.
Requirement of Gab2 for mast cell development and KitL/c-Kit signaling
Authors: Nishida Keigo , Wang Lin , Morii Eiichi , Park Sung Joo , Narimatsu Masahiro , Itoh Shousaku , Yamasaki Satoru , Fujishima Masahiro , Ishihara Katsuhiko , Hibi Masahiko , Kitamura Yukihiko , Hirano Toshio
Published: July 2002

Mast cells are thought to participate in a variety of immune responses, such as parasite resistance and the allergic reaction. Mast cell development depends on stem cell factor (Kit ligand) and its receptor, c-Kit. Gab2 is an adaptor molecule containing a pleckstrin homology domain and potential binding sites for SH2 and SH3 domains. Gab2 is phosphorylated on tyrosine after stimulation with cytokines and growth factors, including KitL. Gab2-deficient mice were created to define the physiological requirement for Gab2 in KitL/c-Kit signaling and mast cell development. In Gab2-deficient mice, the number of mast cells was reduced markedly in the stomach and less severely in the skin. Bone marrow–derived mast cells (BMMCs) from the Gab2-deficient mice grew poorly in response to KitL. KitL-induced ERK MAP kinase and Akt activation were impaired in Gab2-deficient BMMCs. These data indicate that Gab2 is required for mast cell development and KitL/c-Kit signaling.
Practical applications of uniqueness theorems in gravimetry: Part II—Pragmatic incorporation of concrete geologic information
Authors: Barbosa Valéria C. F. , Silva João B. C. , Medeiros Walter E.
Published: July 2002

We illustrate the importance of establishing solution uniqueness through mathematical restrictions reflecting a source attribute. We also illustrate the validity and utility of a guideline derived in an accompanying paper for constructing sound gravity inversion methods for the class of sources presenting either homogeneous or depth‐independent density distributions. The two‐part guideline is (1) to introduce a priori information favoring uniqueness, either by assuming that a nonnull density distribution depending only on x and y is confined to the interior of a horizontal slab with known position or by limiting the class of possible solutions to homogeneous, simply connected polygons (or polyhedra) with known density, displaying no fancy shapes and no curling apophyses at their borders, and (2) to introduce information favoring solution stability by estimating only the features of the source which may be resolved by the data.

Following the guideline, we apply different methods to gravity data using interpretation models consisting of a grid of cells on the x‐y and x‐z planes. In both cases the estimates are very close to the true synthetic source. The data produced by the distribution varying with x and z are also inverted using the method, which minimizes the norm of the first‐order derivative of the density. This constraint does not reflect a true source attribute but is strong enough to stabilize the solution and to guarantee its uniqueness. Because of the strong bias imposed to the solution, the estimated distribution, although unique and stable, is far from the true source, concentrating most of the anomalous mass at the surface. Finally, we present an alternative method which redistributes the estimated anomalous mass downward. To be effective, this technique requires prior knowledge about the source depth to the top. In addition, the source should not be too small and deep. Although being able to produce good results, this alternative method requires a great dose of the interpreter's art.
Airborne gravity measurements over mountainous areas by using a LaCoste & Romberg air‐sea gravity meter
Authors: Verdun Jérôme , Bayer Roger , Klingelé Emile E. , Cocard Marc , Geiger Alain , Halliday Mark E.
Published: July 2002

This paper introduces a new approach to airborne gravity data reduction well‐suited for surveys flown at high altitude with respect to gravity sources (mountainous areas). Classical technique is reviewed and illustrated in taking advantage of airborne gravity measurements performed over the western French Alps by using a LaCoste & Romberg air‐sea gravity meter. The part of nongravitational vertical accelerations correlated with gravity meter measurements are investigated with the help of coherence spectra. Beam velocity has proved to be strikingly correlated with vertical acceleration of the aircraft. This finding is theoretically argued by solving the equation of the gravimetric system (gravity meter and stabilized platform). The transfer function of the system is derived, and a new formulation of airborne gravity data reduction, which takes care of the sensitive response of spring tension to observable gravity field wavelengths, is given. The resulting gravity signal exhibits a residual noise caused by electronic devices and short‐wavelength Eötvös effects. The use of dedicated exponential filters gives us a way to eliminate these high‐frequency effects. Examples of the resulting free‐air anomaly at 5100‐m altitude along one particular profile are given and compared with free‐air anomaly deduced from the classical method for processing airborne gravity data, and with upward‐continued ground gravity data. The well‐known trade‐off between accuracy and resolution is discussed in the context of a mountainous area.
Advanced Statistics:Statistical Methods for Analyzing Cluster and Cluster‐randomized Data
Authors: Wears Robert L.
Published: July 2002

Abstract. Sometimes interventions in randomized clinical trials are not allocated to individual patients, but rather to patients in groups. This is called cluster allocation, or cluster randomization, and is particularly common in health services research. Similarly, in some types of observational studies, patients (or observations) are found in naturally occurring groups, such as neighborhoods. In either situation, observations within a cluster tend to be more alike than observations selected entirely at random. This violates the assumption of independence that is at the heart of common methods of statistical estimation and hypothesis testing. Failure to account for the dependence between individual observations and the cluster to which they belong can have profound implications on the design and analysis of such studies. Their p‐values will be too small, confidence intervals too narrow, and sample size estimates too small, sometimes to a dramatic degree. This problem is similar to that caused by the more familiar “unit of analysis error” seen when observations are repeated on the same subjects, but are treated as independent. The purpose of this paper is to provide an introduction to the problem of clustered data in clinical research. It provides guidance and examples of methods for analyzing clustered data and calculating sample sizes when planning studies. The article concludes with some general comments on statistical software for cluster data and principles for planning, analyzing, and presenting such studies.
AspergillusGalactomannan Detection in the Diagnosis of Invasive Aspergillosis in Cancer Patients
Authors: Herbrecht Raoul , Letscher-Bru Valérie , Oprea Corina , Lioure Bruno , Waller Jocelyn , Campos France , Villard Odile , Liu Kun-Lun , Natarajan-Amé Shanti , Lutz Patrick , Dufour Patrick , Bergerat Jean-Pierre , Candolfi Ermanno
Published: July 2002

PURPOSE: To assess the Aspergillus galactomannan enzyme-linked immunosorbent assay (ELISA) in the diagnosis of invasive aspergillosis (IA) in adult and pediatric oncohematologic patients.

PATIENTS AND METHODS: The study was conducted in four patient groups: those with fever of unknown origin (FUO) during neutropenia, suspected pulmonary infection (PI), or nonpulmonary aspergillosis (NPA) and those undergoing surveillance (S) after hematopoietic stem-cell transplantation (HSCT). IA was classified as definite, probable, or possible, according to European Organization for Research and Treatment of Cancer/Mycosis Study Group definitions.

RESULTS: A total of 3,294 serum samples were collected during 797 episodes (FUO, 261; PI, 297; NPA, 28; and surveillance, 211), and 153 episodes of IA were diagnosed (31 definite, 67 probable, and 55 possible). Three episodes were first suspected from galactomannan ELISA; the remaining 150 cases were diagnosed from clinical or radiologic evidence. Sensitivity of the ELISA was 64.5%, 16.4%, and 25.5% in definite, probable, and possible episodes of IA, respectively, and was lower in patients positive for anti-Aspergillus antibodies than in antibody-negative patients. Most false-positive results occurred in children and in allogeneic HSCT (allo-HSCT) patients. Overall specificity of the ELISA was 94.8%. It was lower in children compared with adults (P < .0001) and in allo-HSCT patients compared with non–allo-HSCT adults (P = .0002). Lowering the ELISA cutoff value from 1.500 to 0.700 seemed more relevant for non–allo-HSCT adults (sensitivity, 73.1%, 44.3%, and 44.7% in definite, probable, and possible IA, respectively; specificity, 94%).

CONCLUSION: Galactomannan ELISA seems less sensitive than previously described, and sensitivity can be further reduced by the presence of anti-Aspergillus antibodies. A new cutoff value for the ELISA of 0.700 is proposed for non–allo-HSCT adults.
Prospective Randomized Trial Comparing Mitomycin, Cisplatin, and Protracted Venous-Infusion Fluorouracil (PVI 5-FU) With Epirubicin, Cisplatin, and PVI 5-FU in Advanced Esophagogastric Cancer
Authors: Ross P. , Nicolson M. , Cunningham D. , Valle J. , Seymour M. , Harper P. , Price T. , Anderson H. , Iveson T. , Hickish T. , Lofts F. , Norman A.
Published: July 2002

PURPOSE: We report the results of a prospectively randomized study that compared the combination of epirubicin, cisplatin, and protracted venous-infusion fluorouracil (PVI 5-FU) (ECF) with the combination of mitomycin, cisplatin, and PVI 5-FU (MCF) in previously untreated patients with advanced esophagogastric cancer.

PATIENTS AND METHODS: Five hundred eighty patients with adenocarcinoma, squamous carcinoma, or undifferentiated carcinoma were randomized to receive either ECF (epirubicin 50 mg/m2 every 3 weeks, cisplatin 60 mg/m2 every 3 weeks and PVI 5-FU 200 mg/m2/d) or MCF (mitomycin 7 mg/m2 every 6 weeks, cisplatin 60 mg/m2 every 3 weeks, and PVI 5-FU 300 mg/m2/d) and analyzed for survival, response, toxicity, and quality of life (QOL).

RESULTS: The overall response rate was 42.4% (95% confidence interval [CI], 37% to 48%) with ECF and 44.1% (95% CI, 38% to 50%) with MCF (P = .692). Toxicity was tolerable, and there were only two toxic deaths. ECF resulted in more grade 3/4 neutropenia and grade 2 alopecia, but MCF caused more thrombocytopenia and plantar-palmar erythema. Median survival was 9.4 months with ECF and 8.7 months with MCF (P = .315); at 1 year, 40.2% (95% CI, 34% to 46%) of ECF and 32.7% (95% CI, 27% to 38%) of MCF patients were alive. Median failure-free survival was 7 months with both regimens. Global QOL scores were better with ECF at 3 and 6 months.

CONCLUSION: This study confirms response, survival, and QOL benefits of ECF observed in a previous randomized study. The equivalent efficacy of MCF was demonstrated, but QOL was superior with ECF. ECF remains one of the reference treatments for advanced esophagogastric cancer.
Assessment of Molecular Markers of Clinical Sensitivity to Single-Agent Taxane Therapy for Metastatic Breast Cancer
Authors: Van Poznak Catherine , Tan Lee , Panageas Katherine S. , Arroyo Crispinita D. , Hudis Clifford , Norton Larry , Seidman Andrew D.
Published: July 2002

PURPOSE: The taxanes affect tubulin polymerization and interfere with mitotic transition. A checkpoint blockade at the G1-S boundary would be expected to promote taxane-induced apoptotic cell death through a mechanism that may involve p27. Other proposed determinants of clinical taxane sensitivity/resistance include p53, members of the epidermal growth factor receptor (EGFR) superfamily (eg, HER2, EGFR), and estrogen receptors and progesterone receptors. These molecular markers and their correlation with clinical taxane sensitivity are investigated in this retrospective clinicopathologic study.

PATIENTS AND METHODS: We performed immunohistochemistry (IHC) for estrogen receptors, progesterone receptors, HER2, EGFR, p53, and p27 on 144 breast tumor specimens from patients treated for metastatic breast cancer on a series of clinical trials of single-agent taxane chemotherapy for correlation with clinical response (complete or partial response). Patient characteristics that could influence response (ie, performance status, extent of disease, and prior therapy) were also examined.

RESULTS: In univariate analysis, Karnofsky performance status ≥ 90% and no prior history of anthracycline therapy correlated with a good clinical response to single-agent taxane (P = .003 and P = .041, respectively). None of the IHC variables tested were predictive of clinical response to taxane therapy, although p27 negativity showed a trend toward significance (P = .075). Concordance between the polyclonal antibody with HercepTest (DAKO, Carpinteria, CA) and the monoclonal antibody CB-11 (BioGenex, San Ramon, CA) was noted (kappa = 0.943); however, neither univariate nor multivariate analysis demonstrated an association between HER2 status and response to taxane chemotherapy.

CONCLUSION: The IHC biomarkers studied were not predictive of response to single-agent taxane chemotherapy in patients with metastatic breast cancer. Identification of molecular correlates of taxane response remains an important goal.
Enhancement of Circularly Polarized Light Detection Through Ortho‐Substitution in Chiral Perylene Diimides
Authors: Li Zhenping , Shen Xianfeng , Zhao Wenkai , Gao Ke , Wang Zhiwei , Zhuo Huagui , Liu Jinhang , Wang Zhuofan , Yang Lei , Zheng Xinglong , Yan Yang , Fang Yunsheng , Chen Feng , Wan Li , Long Guankui , Li Rongjin , Ma Wei , Zhang Mingming , Shang Xiaobo
Published: November 2024

Chiral organic small molecules are promising for circularly polarized light (CPL) detection due to their easy modifiability, strong intermolecular interactions, and straightforward manipulation of the transition dipole moments. However, they often exhibit a low absorption asymmetry factor (gabs) since their magnetic transition dipole moment (m) is overshadowed by the electric transition dipole moment (μ), and their alignment (θ) is not optimized, limiting the performance of CPL photodetectors. This study introduces an ortho‐substitution strategy to significantly enhance CPL detection in chiral perylene diimides (PDIs) by tuning the crystal packing motif. Incorporating a cyano group at the ortho‐position markedly reduces the angle (θ) between m and μ within the crystal, thus amplifying the gabs. The fabricated chiral organic single‐crystal film devices of (R)‐4CN‐PDI‐Ph demonstrated superior photodetecting performance, with a photocurrent asymmetry factor (gph) of 0.362 — three times larger than that of its counterpart (R)‐4PH‐PDI‐Ph. These findings underscore the pivotal role of ortho‐substitution in tuning molecular stacking, enhancing CPL detection, and deepening the understanding of the structure‐performance relationship in chiral organic optoelectronics.
Interfacial Coupling Induced Discrete Orientation of Epitaxial Graphene on High‐Index Cu Substrates
Authors: Lou Shuang , Ma Xiuqing , Wang Zhong , Wang Weizhi , Song Lu , Sun Xiaoli , Ding Yumei , Yin Wan‐jian , Yang Weimin , Tan Jing , Sun Xiucai , Liu Zhongfan
Published: November 2024

Controlled and precise synthesis of materials has been a central pursuit in academia and industry. With the rise of twistronics research, there is growing demand for synthesizing orientation‐controlled 2D materials with atomic precision. Previous theories for 2D materials can predict graphene (Gr) growth on low‐index metal substrates but fail to explain the discrete orientations on most high‐index substrates, inconsistent with experimental data. Using density functional theory (DFT) and ab‐initio molecular dynamics (AIMD), this study explores graphene growth on high‐index substrates, showing that atomic steps do not dominate in trapping C atoms or driving preferential graphene nucleation at high temperatures. Thus, the possibility of intrinsic atomic steps in inducing graphene orientation on high‐index substrates is ruled out. Interfacial coupling strength between graphene and substrates is quantified using a close contact index (CCI), linking atomic structure and electronic states. The coupling between graphene and high‐index Cu surfaces is generally weak, reducing substrate anchoring and increasing graphene orientation dispersion. The extension of this theory to bilayer graphene (BLG) reveals competition between Gr/Cu interfacial coupling and Gr/Gr interlayer coupling, offering insights for controlling twist angles. This theory explains the discrete orientations on high‐index substrates, providing a theoretical basis for synthesizing orientation‐controlled graphene.
Bacteriophage‐Activated DNAzyme Hydrogels Combined with Machine Learning Enable Point‐of‐Use Colorimetric Detection of Escherichia coli
Authors: Mann Hannah , Khan Shadman , Prasad Akansha , Bayat Fereshteh , Gu Jimmy , Jackson Kyle , Li Yingfu , Hosseinidoust Zeinab , Didar Tohid F. , Filipe Carlos D. M.
Published: November 2024

Developing cost‐effective, consumer‐accessible platforms for point‐of‐use environmental and clinical pathogen testing is a priority, to reduce reliance on laborious, time‐consuming culturing approaches. Unfortunately, a system offering ultrasensitive detection capabilities in a form that requires little auxiliary equipment or training has remained elusive. Here, a colorimetric DNAzyme‐crosslinked hydrogel sensor is presented. In the presence of a target pathogen, DNAzyme cleavage results in hydrogel dissolution, yielding the release of entrapped gold nanoparticles in a manner visible to the naked eye. Recognizing that Escherichia coli holds high relevance within both environmental and clinical environments, an E. coli‐responsive DNAzyme is incorporated into this platform. Through the optimization of the hydrogel polymerization process and the discovery of bacteriophage‐induced DNAzyme signal amplification, 101 CFU mL−1 E. coli is detected within real‐world lake water samples. Subsequent pairing with an artificial intelligence model removed ambiguity in sensor readout, offering 96% true positive and 100% true negative accuracy. Finally, high sensor specificity and stability results supported clinical use, where 100% of urine samples collected from patients with E. coli urinary tract infections are accurately identified. No false positives are observed when testing healthy samples. Ultimately, this platform stands to significantly improve population health by substantially increasing pathogen testing accessibility.
Versatile Biopolymers for Advanced Lithium and Zinc Metal Batteries
Authors: Li Shimei , Zhi Chunyi
Published: November 2024

Lithium (Li) and zinc (Zn) metals are emerging as promising anode materials for next‐generation rechargeable metal batteries due to their excellent electronic conductivity and high theoretical capacities. However, issues such as uneven metal ion deposition and uncontrolled dendrite growth result in poor electrochemical stability, limited cycle life, and rapid capacity decay. Biopolymers, recognized for their abundance, cost‐effectiveness, biodegradability, tunable structures, and adjustable properties, offer a compelling solution to these challenges. This review systematically and comprehensively examines biopolymers and their protective mechanisms for Li and Zn metal anodes. It begins with an overview of biopolymers, detailing key types, their structures, and properties. The review then explores recent advancements in the application of biopolymers as artificial solid electrolyte interphases, electrolyte additives, separators, and solid‐state electrolytes, emphasizing how their structural properties enhance protection mechanisms and improve electrochemical performance. Finally, perspectives on current challenges and future research directions in this evolving field are provided.
Biopolymeric Ionotronics Based on Biodegradable Wool Keratin
Authors: Zhu Shuihong , Chen Shaohua , Jiang Feng , Fu Cong , Fu Tianqi , Lin Da , Meng Zhaohui , Lin Youhui , Lee Pooi See
Published: November 2024

The advent of ionotronics has revealed significant potential in flexible transistors, energy harvesting, and unconventional circuits. However, most ionotronic devices, often centered around synthetic polymers, involve complex grafting or synthesis that raise legitimate concerns about their environmental sustainability. Herein, a simple yet versatile approach for developing single‐composition ionotronic devices using wool keratin (WK), a biodegradable and pH‐responsive natural polymer is presented. By employing facile pH regulation processes, WK molecules with opposing polarities are successfully modified, which are combined to form an ionic heterojunction through entropically driven depletion. This ionic heterojunction functions as an ionic diode, enabling efficient rectification of alternating current signals (with a rectification ratio of up to 199). Furthermore, the application of this biopolymeric ionotronic device is extended to mechanical energy harvesting, self‐powered sensing, and ionic logic circuit. The biodegradability and renewability of WK offer a viable alternative to synthetic materials, highlighting its potential for sustainable applications.