bluuebunny/crossref_metadata_2025 huggingface dataset:
Cationic ordering in oxide glasses: the example of transition elements
Authors: Galoisy L. , Cormier L. , Rossano S. , Ramos A. , Calas G. , Gaskell P. , Le Grand M.
Published: July 2002

Structural data have been obtained on the cation surroundings in multi-component silicate and borosilicate glasses using chemically selective spectroscopic and scattering methods, such as extended X-ray absorption and neutron scattering with isotope substitution (NSIS). Transition elements such as Ni or Ti may occur in unusual 5-coordinated sites which coexist with other coordination numbers, depending on glass composition. Distribution of cationic sites in the glassy structure is responsible for unusual spectroscopic properties, as shown by Fe2+ Mössbauer spectroscopy. The environment of cations such as Zn, Zr or Mo, has been determined by EXAFS and discussed using the bond valence theory, which predicts the way to charge compensate the oxygen neighbours and which indicates the linkage of cationic sites with the silicate framework. Cation-cation correlations are given by NSIS up to ∼8 Á, indicating an extensive Medium Range Ordering (MRO) with corner- and edge-linked cationic polyhedra, for Ti and Ni-bearing glasses, respectively. This heterogeneous cationic distribution in glasses is consistent with the presence of two-dimensional domains in which cation mixing may occur, as shown in a Ca-Ni metasilicate glass. Three-dimensional domains have also been found by Ni-K edge EXAFS in the case of low alkali borate glasses, with a local structure which mimics some aspects of crystalline NiO. The presence of ordered cationic domains, clearly illustrated by Reverse Monte Carlo simulations helps to rationalize the physical properties of multi-component silicate glasses.
New data on welshite, e.g. Ca2Mg3.8Mn0.62+Fe0.12+Sb1.55+O2[Si2.8Be1.7Fe0.653+Al0.7As0.17O18], an aenigmatite-group mineral
Authors: Grew E. S. , Hålenius U. , Kritikos M. , Shearer C. K.
Published: July 2002

Electron and ion microprobe data on two samples of welshite from the type locality of Långban, Sweden, gave analytical totals of 99.38–99.57 wt.% and BeO contents of 4.82–5.11 wt.%, corresponding to 1.692–1.773 Be/20 O. Mössbauer and optical spectra of one of these samples gave [iv]Fe3+/ΣFe = 0.91, [vi]Fe2+/ΣFe = 0.09, and no evidence of Mn3+. The resulting formula for this sample is Ca2Mg3.8Mn0.62+Fe0.12+Sb1.55+O2[Si2.8Be1.7Fe0.653+Al0.7As0.17O18, and that for the second sample, Ca2Mg3.8Mn0.12+Fe0.12+Fe0.83+Sb1.25+O2[Si2.8Be1.8Fe0.653+Al0.5As0.25O18], is related by the substitution involving tetrahedral and octahedral sites: 0.59[vi,iv](Fe,Al)3+ ≈ 0.42[vi](Mg,Mn,Fe)2+ + 0.21([vi]Sb,[iv]As)5+, i.e. 3[vi,iv]M3+ = 2[vi]M2+ + [vi,iv]M5+. Welshite is distinctive among aenigmatite-group minerals in the high proportion of Fe3+ in tetrahedral coordination and is unique in its Be content, substantially exceeding 1Be per formula unit. Given the cation distributions in other minerals related to aenigmatite, we think it is reasonable to assume that at least one tetrahedral site is >50% occupied by Be and that one octahedral site is >50% occupied by Sb, so that welshite should be retained as a distinct species with its own name in the aenigmatite group.
Evidence for hibbingite–kempite solid solution
Authors: Saini-Eidukat Bernhardt , Rudashevsky Nikolai S. , Polozov Alexander G.
Published: July 2002

New occurrences of hibbingite, γ-Fe2(OH)3Cl, have been found associated with platinum-group minerals in the Noril'sk Complex, and with the Korshunovskoye iron ores of the southern Siberian platform. The Norils'k grains, which are up to 0. 6 mm in diameter, are associated with the platinumgroup minerals froodite, cabriite, urvantsevite and with native silver in massive pentlandite–cubanite– chalcopyrite ore. The Korshunovskoye iron ore sample in which hibbingite was found is composed of fine-grained magnetite ore associated with halite. Hibbingite, hematite and silver grains are found in cavities in halite; the reddish-brown hibbingite grains usually occur as encrustations in the cavities. The size of hibbingite and hematite grains is up to 100 µm.

Hibbingite from the Noril'sk Complex contains a significant kempite (Mn2(OH)3Cl) component; in some cases it contains over 50 mol. % Mn. These data suggest that at least a partial solid solution series exists between hibbingite and kempite. All known occurrences of hibbingite represent paragenetically late mineral assemblages. In the case of the Korshunovskoye deposits, the occurrences are associated with highly concentrated hydrothermal brines derived from the Lower Paleozoic saline sediments of the Siberian Platform cover.
Igneous layering in a dacite: on the origin and significance of Layer Cake Mountain, Kelowna, B.C., Canada
Authors: Greenough J. D. , Owen J. V.
Published: July 2002

A Tertiary, dacitic volcanic land-form in Kelowna, British Columbia, shows layering that has not been recognized elsewhere. Layering is expressed as thin (0.5 m) layers separated by thick (4.5 m) layers exposed along a weathered fault scarp. The major elements show that both thick and thin layers are dacitic and geochemically very similar. Trace element modelling indicates that thin layers formed from thick layers via crystal fractionation involving removal of plagioclase, biotite and magnetite in the proportions 75:20:5, and with only 12% fractionation. The thin layers represent segregation veins generated during crystallization of the dacite. They formed when the crystal mush at the bottom of the upper crust successively, thermally contracted, fractured and foundered, siphoning evolved interstitial liquid from the mush into the horizontal crack. Cooling of the segregation veins led to further fracturing. Later, fluids following these fractures altered the thin layers and precipitated secondary carbonate minerals. The altered thin layers weather preferentially, thus visually accentuating the small primary chemical differences between thick and thin layers. The scale of layering, mode of formation and differentiation mechanisms appear different from those in felsic magma chambers and it is unclear how common this phenomenon is. However, similar layering is more easily identified and commonly developed in mafic lava flows.
Combined effect of all-trans retinoic acid and arsenic trioxide in acute promyelocytic leukemia cells in vitro and in vivo
Authors: Jing Yongkui , Wang Long , Xia Lijuan , Chen Guo-qiang , Chen Zhu , Miller Wilson H. , Waxman Samuel
Published: July 2002

All-trans retinoic acid (tRA) and arsenic trioxide (As2O3) induce non–cross-resistant complete clinical remission in patients with acute promyelocytic leukemia with t(15;17) translocation and target PML-RARα, the leukemogenic protein, by different pathways suggesting a possible therapeutic synergism. To evaluate this possibility, this study examined the effect of As2O3 on tRA-induced differentiation and, conversely, the effect of tRA on As2O3-induced apoptosis. As2O3 at subapoptotic concentrations (0.5 μM) decreased tRA-induced differentiation in NB4 cells but synergized with atRA to induce differentiation in tRA-resistant NB4 subclones MR-2 and R4 cells as measured by nitroblue tetrazolium reduction and tRA-inducible genes (TTGII, RARβ, RIG-E). tRA cleaved PML-RARα into distinct fragments in NB4 but not in tRA-resistant MR-2 or R4 cells, whereas As2O3 completely degraded PML-RARα in all 3 cell lines. As2O3-induced apoptosis was decreased by tRA pretreatment of NB4 cells but not of R4 cells and was associated with a strong induction of Bfl-1/A1 expression, a Bcl-2 protein family member. Severe combined immunodeficient mice bearing NB4 cells showed an additive survival effect after sequential treatment, but a toxic effect was observed after simultaneous treatment with tRA and As2O3. These data suggest that combined As2O3 and tRA treatment may be more effective than single agents in tRA-resistant patients. Although in vitro data do not always translate to in vivo response, toxicity and potential drug antagonism may be diminished by decreasing the concentration of As2O3 when given at the same time with therapeutic levels of tRA.
Lutheran blood group glycoprotein and its newly characterized mouse homologue specifically bind α5 chain-containing human laminin with high affinity
Authors: Parsons Stephen F. , Lee Gloria , Spring Frances A. , Willig Thiebaut-Noel , Peters Luanne L. , Gimm J. Aura , Tanner Michael J. A. , Mohandas Narla , Anstee David J. , Chasis Joel Anne
Published: July 2002

Lutheran blood group glycoproteins (Lu gps) are receptors for the extracellular matrix protein, laminin. Studies suggest that Lu gps may contribute to vaso-occlusion in sickle cell disease and it has recently been shown that sickle cells adhere to laminin isoforms containing the α5 chain (laminin 10/11). Laminin α5 is present in the subendothelium and is also a constituent of bone marrow sinusoids, suggesting a role for the Lu/laminin interaction in erythropoiesis. The objectives of the current study were to define more precisely the molecular interactions of the extracellular and intracellular regions of human Lu and to clone and characterize a mouse homologue. To this end, complementary DNA and genomic clones for the mouse homologue were sequenced and the mouse Lu gene mapped to a region on chromosome 7 with conserved synteny with human 19q13.2. Mouse and human Lu gps are highly conserved (72% identity) at the amino acid sequence level and both mouse and human Lu gps specifically bind laminin 10/11 with high affinity. Furthermore, the first 3, N-terminal, immunoglobulin superfamily domains of human Lu are critical for this interaction. The results indicated that the cytoplasmic domain of BRIC 221-labeled human Lu gp is linked with the spectrin-based skeleton, affording the speculation that this interaction may be critical for signal transduction. These results further support a role for Lu gps in sickle cell disease and indicate the utility of mouse models to explore the function of Lu gp-laminin 10/11 interaction in normal erythropoiesis and in sickle cell disease.
Primary chromosomal rearrangements of leukemia are frequently accompanied by extensive submicroscopic deletions and may lead to altered prognosis
Authors: Kolomietz Elena , Al-Maghrabi Jaudah , Brennan Shawn , Karaskova Jana , Minkin Solomon , Lipton Jeffrey , Squire Jeremy A.
Published: July 2002

BCR/ABL fluorescent in situ hybridization study of chronic myeloid leukemia (CML) and Philadelphia+(Ph+) acute lymphoid leukemia (ALL) indicated that approximately 9% of patients exhibited an atypical hybridization pattern consistent with a submicroscopic deletion of the 5′ region ofABL and the 3′ region of the BCR genes on the 9q+ chromosome. The CML patients with deletions had a shorter survival time and a high relapse rate following bone marrow transplant. Since deletions are associated with both Ph+CML and ALL, it seemed probable that other leukemia-associated genomic rearrangements may also have submicroscopic deletions. This hypothesis was confirmed by the detection of deletions of the 3′ regions of theCBFB and the MLL genes in AML M4 patients with inv(16) and in patients with ALL and AML associated withMLL gene translocations, respectively. In contrast, analysis of the AML M3 group of patients and AML M2 showed that similar large deletions were not frequently associated with the t(15;17) or t(8;21) translocations. Analysis of sequence data from each of the breakpoint regions suggested that large submicroscopic deletions occur in regions with a high overall density of Alu sequence repeats. These findings are the first to show that the process of deletion formation is not disease specific in leukemia and also implicate that the presence of repetitive DNA in the vicinity of breakpoint regions may facilitate the generation of submicroscopic deletions. Such deletions could lead to the loss of one or more genes, and the associated haploinsufficiency may result in the observed differences in clinical behavior.
Differential requirement for the transcription factor PU.1 in the generation of natural killer cells versus B and T cells
Authors: Colucci Francesco , Samson Sandrine I. , DeKoter Rodney P. , Lantz Olivier , Singh Harinder , Di Santo James P.
Published: July 2002

PU.1 is a member of the Ets family of transcription factors required for the development of various lymphoid and myeloid cell lineages, but its role in natural killer (NK) cell development is not known. The study shows that PU.1 is expressed in NK cells and that, on cell transfer into alymphoid Rag2/γc−/−mice, hematopoietic progenitors of PU.1−/−fetal liver cells could generate functional NK cells but not B or T cells. Nevertheless, the numbers of bone marrow NK cell precursors and splenic mature NK cells were reduced compared to controls. Moreover,PU.1−/− NK cells displayed reduced expression of the receptors for stem cell factor and interleukin (IL)-7, suggesting a nonredundant role for PU.1 in regulating the expression of these cytokine receptor genes during NK cell development.PU.1−/− NK cells also showed defective expression of inhibitory and activating members of the Ly49 family and failed to proliferate in response to IL-2 and IL-12. Thus, despite the less stringent requirement for PU.1 in NK cell development compared to B and T cells, PU.1 regulates NK cell differentiation and homeostasis.
Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy
Authors: Rawstron Andy C. , Kennedy Ben , Evans Paul A. S. , Davies Faith E. , Richards Stephen J. , Haynes Andy P. , Russell Nigel H. , Hale Geoff , Morgan Gareth J. , Jack Andrew S. , Hillmen Peter
Published: July 2002

Previous studies have suggested that the level of residual disease at the end of therapy predicts outcome in chronic lymphocytic leukemia (CLL). However, available methods for detecting CLL cells are either insensitive or not routinely applicable. A flow cytometric assay was developed that can differentiate CLL cells from normal B cells on the basis of their CD19/CD5/CD20/CD79b expression. The assay is rapid and can detect one CLL cell in 104 to 105leukocytes in all patients. We have compared this assay to conventional assessment in 104 patients treated with CAMPATH-1H and/or autologous transplant. During CAMPATH-1H therapy, circulating CLL cells were rapidly depleted in responding patients, but remained detectable in nonresponders. Patients with more than 0.01 × 109/L circulating CLL cells always had significant (> 5%) marrow disease, and blood monitoring could be used to time marrow assessments. In 25 out of 104 patients achieving complete remission by National Cancer Institute (NCI) criteria, the detection of residual bone marrow disease at more than 0.05% of leukocytes in 6 out of 25 patients predicted significantly poorer event-free (P = .0001) and overall survival (P = .007). CLL cells are detectable at a median of 15.8 months (range, 5.5-41.8) posttreatment in 9 out of 18 evaluable patients with less than 0.05% CLL cells at end of treatment. All patients with detectable disease have progressively increasing disease levels on follow-up. The use of sensitive techniques, such as the flow assay described here, allow accurate quantitation of disease levels and provide an accurate method for guiding therapy and predicting outcome. These results suggest that the eradication of detectable disease may lead to improved survival and should be tested in future studies.
Blockade of adenosine diphosphate receptors P2Y12 and P2Y1 is required to inhibit platelet aggregation in whole blood under flow
Authors: Turner Nancy A. , Moake Joel L. , McIntire Larry V.
Published: July 2002

Using heparinized whole blood and flow conditions, it was shown that adenosine 5′-diphosphate (ADP) receptors P2Y12 and P2Y1 are both important in direct shear-induced platelet aggregation and platelet aggregation subsequent to initial adhesion onto von Willebrand factor (vWf)–collagen. In the viscometer, whole blood was subjected to shear rates of 750, 1500, and 3000 s−1 for 30 seconds at room temperature. The extent of aggregation was determined by flow cytometry. The P2Y12antagonist AR-C69 931MX (ARMX) reduced shear-induced aggregation at these rates by 56%, 54%, and 16%, respectively, compared to control samples. Adenosine 3′,5′-diphosphate (A3P5P; P2Y1antagonist) inhibited shear-induced aggregation by 40%, 30% and 29%, respectively, compared to control samples. Blockade of both ADP receptors at 3000 s−1 with ARMX plus A3P5P further reduced the platelet aggregation by 41% compared to the addition of ARMX alone (57% compared to control samples). Using a parallel-plate flow chamber, whole blood was perfused over bovine collagen type 1 at a wall shear rate of 3000 s−1 for 60 seconds. Platelet deposition was quantified with epifluorescence video microscopy and digital image processing. Blockade of P2Y12 alone or blockade of P2Y1 alone did not reduce thrombus formation on vWf–collagen. In contrast, blockade of both P2Y12 and P2Y1 reduced platelet deposition by 72%. These results indicate that combinations of antagonists of the ADP receptors P2Y12 and P2Y1 are effective inhibitors of direct shear-induced platelet aggregation and of platelet aggregation subsequent to initial adhesion under flow conditions. Inhibitors of these pathways are potentially useful as antiarterial thrombotic agents.
Myeloablation and autologous peripheral blood stem cell rescue results in hematologic and clinical responses in patients with myeloid metaplasia with myelofibrosis
Authors: Anderson Jeanne E. , Tefferi Ayalew , Craig Fiona , Holmberg Leona , Chauncey Thomas , Appelbaum Frederick R. , Guardiola Philippe , Callander Natalie , Freytes Cesar , Gazitt Yair , Razvillas Betty , Deeg H. Joachim
Published: July 2002

Current therapeutic options for myeloid metaplasia with myelofibrosis (MMM) are limited. A pilot study was conducted of autologous peripheral blood stem cell (PBSC) collection in 27, followed by transplantation in 21 patients with MMM. The median age was 59 (range 45-75) years. PBSCs were mobilized at steady state (n = 2), after granulocyte colony-stimulating factor (G-CSF) alone (n = 17), or after anthracycline-cytarabine induction plus G-CSF (n = 8). A median of 11.6 × 106 (range 0 to 410 × 106) CD34+ cells per kilogram were collected. Twenty-one patients then underwent myeloablation with oral busulfan (16 mg/kg) and PBSC transplantation. The median times to neutrophil and platelet recovery after transplantation were 21 (range 10-96) and 21 (range, 13 to ≥ 246) days, respectively. Five patients received back-up PBSC infusion because of delayed neutrophil or platelet recovery. The median follow-up is 390 (range 70-1623) days after transplantation, and the 2-year actuarial survival is 61%. After transplantion, 6 patients died: 3 of nonrelapse causes (1 within 100 days of PBSC infusion) and 3 of disease progression. Erythroid response (hemoglobin ≥ 100 g/L [10 gm/dL] without transfusion for ≥ 8 weeks) occurred in 10 of 17 anemic patients. Four of 8 patients with a platelet count less than 100 × 109/L (100 000/μL) responded with a durable platelet count more than 100 × 109/L (100 000/μL). Symptomatic splenomegaly improved in 7 of 10 patients. It is concluded that (1) PBSC collection was feasible and stable engraftment occurred after transplantation in most patients with MMM, (2) myeloablation with busulfan was associated with acceptable toxicity, (3) a significant proportion of patients derived clinical benefit after treatment, and (4) further investigation of this novel approach is warranted.
Calcium signaling inhibits interleukin-12 production and activates CD83+ dendritic cells that induce Th2 cell development
Authors: Faries Mark B. , Bedrosian Isabelle , Xu Shuwen , Koski Gary , Roros James G. , Moise Mirielle A. , Nguyen Hung Q. , Engels Friederike H. C. , Cohen Peter A. , Czerniecki Brian J.
Published: July 2002

Mature dendritic cells (DCs), in addition to providing costimulation, can define the Th1, in contrast to the Th2, nature of a T-cell response through the production of cytokines and chemokines. Because calcium signaling alone causes rapid DC maturation of both normal and transformed myeloid cells, it was evaluated whether calcium-mobilized DCs polarize T cells toward a Th1 or a Th2 phenotype. After human monocytes were cultured for 24 hours in serum-free medium and granulocyte-macrophage colony-stimulating factor to produce immature DCs, additional overnight culture with either calcium ionophore (CI) or interferon γ (IFN-γ), tumor necrosis factor-α (TNF-α), and soluble CD40L resulted in phenotypically mature DCs that produced interleukin-8 (IL-8) and displayed marked expression of CD80, CD86, CD40, CD54, CD83, DC-LAMP, and RelB. DCs matured by IFN-γ, TNF-α, and soluble CD40L were additionally distinguished by undetectable CD4 expression, marked secretion of IL-12, IL-6, and MIP-1β, and preferential ability to promote Th1/Tc1 characteristics during T-cell sensitization. In contrast, DCs matured by CI treatment were distinguished by CD4 expression, modest or absent levels of IL-12, IL-6, and MIP-1β, and preferential ability to promote Th2/Tc2 characteristics. Calcium signaling selectively antagonized IL-12 production by mature DCs activated with IFN-γ, TNF-α, and soluble CD40L. Although the activation of DCs by calcium signals is largely mediated through calcineurin phosphatase, the inhibition of IL-12 production by calcium signaling was independent of this enzyme. Naturally occurring calcium fluxes in immature DCs, therefore, negatively regulate Dc1 differentiation while promoting Dc2 characteristics and Th2/Tc2 polarization. Calcium-mobilized DCs may have clinical usefulness in treating disease states with excessive Th1/Tc1 activity, such as graft-versus-host disease or autoimmunity.
Persistent preswitch clonotypic myeloma cells correlate with decreased survival: evidence for isotype switching within the myeloma clone
Authors: Reiman Tony , Seeberger Karen , Taylor Brian J. , Szczepek Agnieszka J. , Hanson John , Mant Michael J. , Coupland Robert W. , Belch Andrew R. , Pilarski Linda M.
Published: July 2002

Multiple myeloma (MM) is identified by unique immunoglobulin heavy chain (IgH) variable diversity joining region gene rearrangements, termed clonotypic, and an M protein termed the “clinical” isotype. Transcripts encoding clonotypic pre and postswitch IgH isotypes were identified in MM peripheral blood mononuclear cells (PBMCs), bone marrow (BM), and mobilized blood. For 29 patients, 38 BM, 17 mobilized blood, and 334 sequential PBMC samples were analyzed at diagnosis, before and after transplantation for 2 to 107 months. The clinical clonotypic isotype was readily detectable and persisted throughout treatment. Eighty-two percent of BM and 38% of PBMC samples also expressed nonclinical clonotypic isotypes. Clonotypic immunoglobulin M (IgM) was detectable in 68% of BM and 25% of PBMC samples. Nonclinical clonotypic isotypes were detected in 41% of mobilized blood samples, but clonotypic IgM was detected in only 12%. Patients with persistent clonotypic IgM expression had adverse prognostic features at diagnosis (lower hemoglobin, higher β2-microglobulin) and higher numbers of BM plasma cells compared with patients with infrequent/absent clonotypic IgM. Patients with persistent clonotypic IgM expression had significantly poorer survival than patients with infrequent IgM expression (P < .0001). In a multivariate analysis, persistent clonotypic IgM expression in the blood correlated independently with poor survival (P = .01). In nonobese diabetic severe combined immunodeficiency mice, xenografted MM cells expressed clinical and nonclinical postswitch clonotypic isotypes. MM expressing clonotypic IgM engrafted both primary and secondary mice, indicating their persistence within the murine BM. This study demonstrates that MM clonotypic cells expressing preswitch transcripts are tied to disease burden and outcomes. Because MM pathology involves postswitch plasma cells, this raises the possibility that IgH isotype switching in MM may accompany worsening disease.
Treatment of von Willebrand disease with a high-purity factor VIII/von Willebrand factor concentrate: a prospective, multicenter study
Authors: Mannucci Pier M. , Chediak Juan , Hanna Wahid , Byrnes John , Ledford Marlies , Ewenstein Bruce M. , Retzios Anastassios D. , Kapelan Barbara A. , Schwartz Richard S. , Kessler Craig ,   the Alphanate Study Group
Published: July 2002

Among patients with von Willebrand disease (VWD) who are unresponsive to desmopressin therapy, replacement with plasma-derived concentrates is the treatment of choice. Because prospective studies are lacking, such treatment has been largely empirical. A multicenter, prospective study has been conducted in 81 patients with VWD (15 patients with type 1, 34 with type 2, and 32 with type 3 disease) to investigate the efficacy of a high-purity factor VIII/von Willebrand factor (FVIII/VWF) concentrate for treatment of bleeding and surgical prophylaxis. Two preparations of the concentrate—one virally inactivated with solvent detergent, the other with an additional heat-treatment step—were evaluated. Pharmacokinetic parameters were similar for both preparations. Using pre-established dosages based on the results of pharmacokinetic studies, 53 patients were administered either preparation for the treatment of 87 bleeding episodes, and 39 patients were treated prophylactically for 71 surgical or invasive procedures. Sixty-five (74.7%) and 10 (11.5%) of the bleeding episodes were controlled with 1 or 2 infusions, respectively. Patients with severe type 3 VWD typically required more infusions and higher doses, at shorter time intervals, than did patients with generally milder types 1 and 2. Among patients undergoing surgical procedures, blood loss was lower than that predicted prospectively, and losses exceeding the predicted value did not correlate with the postinfusion skin bleeding time. In conclusion, the concentrate effectively stopped active bleeding and provided adequate hemostasis for surgical or invasive procedures, even in the absence of bleeding time correction.
Resistance of leukemic cells to 2-chlorodeoxyadenosine is due to a lack of calcium-dependent cytochrome c release
Authors: Chandra Joya , Mansson Emma , Gogvadze Vladimir , Kaufmann Scott H. , Albertioni Freidoun , Orrenius Sten
Published: July 2002

The purine nucleoside 2-chlorodeoxyadenosine (CdA) is often used in leukemia therapy. Its efficacy, however, is compromised by the emergence of resistant cells. In the present study, 3 CdA-resistant cell lines were generated and characterized. Their ability to accumulate 2-chloroadenosine triphosphate (CdATP) varied, reflecting differences in activities of deoxycytidine kinase (dCK) and deoxyguanosine kinase (dGK). Nonetheless, the selected lines were uniformly resistant to CdA-induced apoptosis, as assessed by caspase activation and DNA fragmentation. In contrast, cytosols from resistant cells were capable of robust caspase activation when incubated in the presence of cytochrome c and dATP. Moreover, replacement of dATP with CdATP also resulted in caspase activation in the parental and some of the resistant cell lines. Strikingly, CdA-induced decreases in mitochondrial transmembrane potential and release of cytochrome c from mitochondria were observed in the parental cells but not in any resistant lines. The lack of cytochrome c release correlated with an increased ability of mitochondria from resistant cells to sequester free Ca2+. Consistent with this enhanced Ca2+buffering capacity, an early increase in cytosolic Ca2+after CdA treatment of parental cells but not resistant cells was detected. Furthermore, CdA-resistant cells were selectively cross-resistant to thapsigargin but not to staurosporine- or Fas-induced apoptosis. In addition, CdA-induced caspase-3 activation and DNA fragmentation were inhibited by the Ca2+ chelator BAPTA-AM in sensitive cells. Taken together, the data indicate that the mechanism of resistance to CdA may be dictated by changes in Ca2+-sensitive mitochondrial events.
A broad T-cell repertoire diversity and an efficient thymic function indicate a favorable long-term immune reconstitution after cord blood stem cell transplantation
Authors: Talvensaari Kimmo , Clave Emmanuel , Douay Corinne , Rabian Claire , Garderet Laurent , Busson Marc , Garnier Federico , Douek Daniel , Gluckman Eliane , Charron Dominique , Toubert Antoine
Published: July 2002

Cord blood (CB) is used increasingly as a source of hematopoietic stem cells because of a lower risk of acute and chronic graft-versus-host disease (GVHD). However, there is some concern regarding the ability to adequately reconstitute host immune response due to the immaturity and naivety of CB T cells. This study was designed to evaluate T-cell reconstitution using combined approaches of phenotyping, analysis of αβ T-cell receptor (TCR) diversity, and assessment of ex vivo thymic function by measuring TCR rearrangement excision circles (TRECs). Ten patients who underwent CB transplantation for high-risk hematologic disorders were compared to a reference group of 19 age- and GVHD-matched patients who underwent transplantation with non-T cell-depleted bone marrow from an HLA-identical sibling donor. TREC values correlated with the relative number of naive T cells and with TCR repertoire polyclonality. During the first year after transplantation, TCR repertoires were highly abnormal and TREC values low in both groups. Notably, 2 years after transplantation onward TREC values as well as TCR diversity were higher in CB recipients than in recipients of bone marrow transplants. These data indicate an efficient thymic regeneration pathway from CB lymphoid progenitors despite the low number of cells infused compared to bone marrow, arguing for a complete clinical immune recovery after CB transplantation.
Dendritic cells exposed to extracellular adenosine triphosphate acquire the migratory properties of mature cells and show a reduced capacity to attract type 1 T lymphocytes
Authors: la Sala Andrea , Sebastiani Silvia , Ferrari Davide , Di Virgilio Francesco , Idzko Marco , Norgauer Johannes , Girolomoni Giampiero
Published: July 2002

We previously reported that chronic stimulation with low, noncytotoxic doses of extracellular adenosine triphosphate (ATP) induced a distorted maturation of dendritic cells (DCs) and impaired their capacity to initiate T-helper (Th) 1 responses in vitro. Here, we examined the effects of ATP on chemokine-receptor expression and chemokine production by DCs. ATP strongly induced expression of CXC chemokine receptor 4 on both immature and lipopolysaccharide (LPS)–stimulated DCs and slightly up-regulated CC chemokine receptor (CCR) 7 on both DC types. In contrast, ATP reduced CCR5 expression on immature DCs. These effects were confirmed at both the messenger RNA and protein levels and were not produced by uridine triphosphate (UTP). Consistent with the changed receptor expression, ATP increased migration and intracellular calcium of immature and mature DCs to stromal-derived factor 1 (CXC ligand [CXCL] 12) and macrophage inflammatory protein [MIP] 3β (CC ligand [CCL] 19), whereas responses to MIP-1β (CCL4) were reduced. DCs are an important source of chemokines influencing recruitment of distinct T-lymphocyte subsets. ATP, but not UTP, significantly reduced LPS-induced production of interferon-inducible protein 10 (CXCL10) and regulated upon activation, normal T-cell expressed and secreted chemokine (CCL5); increased secretion of macrophage-derived chemokine (CCL22); and did not change production of thymus and activation-regulated chemokine (CCL17). Consistent with these findings, supernatants from ATP-treated mature DCs attracted Th1 and T-cytotoxic 1 cells less efficiently, whereas migration of Th2 and T cytotoxic 2 cells was not affected. Our data suggest that ATP provides a signal for enhanced lymph node localization of DCs but that it may, at the same time, diminish the capacity of DCs to amplify type 1 immune responses.
Voice Rehabilitation After Total Laryngectomy and Postoperative Radiation Therapy
Authors: Mendenhall William M. , Morris Christopher G. , Stringer Scott P. , Amdur Robert J. , Hinerman Russell W. , Villaret Douglas B. , Robbins K. Thomas
Published: July 2002

PURPOSE: The purpose of this study was to evaluate voice rehabilitation after laryngectomy and postoperative irradiation for patients with squamous cell carcinoma of the larynx and hypopharynx.

PATIENTS AND METHODS: Between December 1983 and December 1998, 173 patients underwent a total laryngectomy and postoperative irradiation and had follow-up from 3 to 188 months (median, 38 months). Three patients were lost to follow-up at 63, 39, and 4 months after treatment. All other living patients had follow-up for 2 years or longer. Twelve (7%) patients had incomplete data pertaining to voice rehabilitation.

RESULTS: Data pertaining to voice rehabilitation were available at 2 to 3 years and longer and 5 years and longer after treatment for 118 and 69 patients, respectively. The methods of voice rehabilitation at 2 to 3 years and longer and 5 years and longer were as follows: tracheoesophageal, 27% and 19%; artificial larynx, 50% and 57%; esophageal, 1% and 3%; nonvocal, 17% and 14%; and no data, 5% and 7%, respectively.

CONCLUSION: The most common form of voice rehabilitation after total laryngectomy and postoperative radiation therapy is the artificial larynx. Although the tracheoesophageal puncture is a technique frequently promoted by clinicians as a superior method, a relatively small subset of patients are successfully rehabilitated long-term. However, of those who undergo a tracheoesophageal puncture, approximately half will use this method of voice rehabilitation long term.
Phase II Trial of Weekly Single-Agent Paclitaxel in Platinum/Paclitaxel-Refractory Ovarian Cancer
Authors: Markman Maurie , Hall James , Spitz Daniel , Weiner Sheldon , Carson Linda , Van Le Linda , Baker Mark
Published: July 2002

PURPOSE: We wished to critically examine the level of activity of weekly paclitaxel in a patient population with well-characterized platinum/paclitaxel-resistant (3-week schedule) ovarian cancer.

PATIENTS AND METHODS: Eligibility criteria for this phase II trial included the following: ovarian and fallopian tube cancers or primary carcinoma of the peritoneum; prior initial therapy with platinum/paclitaxel; and failure to respond to treatment (progression or stable disease as best response), or a response duration of less than 3 months, or if the response was more than 3 months, retreatment with both agents required and failure to respond a second time or the response duration was less than 3 months. Measurable or assessable disease (CA-125 response criteria) was required. Patients received weekly paclitaxel (80 mg/m2) until disease progression, unacceptable toxicity developed, or they elected to discontinue treatment.

RESULTS: Fifty-three patients (52 assessable for toxicity and 51 for response) were entered onto this multi-institution trial. Of 248 total cycles (887 doses), only 13 (1%) were modified (dose reduction or treatment delay) because of side effects. Therapy was discontinued in five patients because of toxicity (four because of peripheral neuropathy, and one because of painful fingernail beds). Thirteen patients (25%; 95% confidence interval, 13.5% to 37.5%) achieved an objective response (four by CA-125 criteria, and nine by ≥ 50% reduction of measurable disease).

CONCLUSION: Weekly paclitaxel (80 mg/m2) is generally well tolerated and is an active second-line regimen against ovarian cancer that has demonstrated resistance to platinum/paclitaxel delivered on an every-3-week schedule.
Debarking harvesters simultaneously combat the European spruce bark beetle (Ips typographus) and conserve non‐target beetle diversity
Authors: Zarges Sebastian , Wohlert Jan , Kamp Johannes , Thorn Simon , Müller Jörg , Hagge Jonas
Published: July 2024

In the face of climate change, the European Spruce Bark Beetle (Ips typographus) breeding predominantly in Norway spruce (Picea abies) led to exceptional amounts of damaged timber in European forests. Up to now, if pest control is applied, damaged or weakened P. abies trees are either extracted by salvage logging or, when quantities are low, made unsuitable for breeding by manual debarking techniques. Both pest control interventions are costly, are often limited by the short timeframe of effectiveness and come with negative impacts on the non‐target biodiversity.

As alternatives for timely removal, a debarking head for harvesters for large scale disturbances and a bark gouging device for motor‐manual treatment have been developed in recent years to make breeding material unsuitable for bark beetles and reduce existing larvae.

Based on data from an experimental design with infested Norway spruce logs, we show that the harvester debarking head and the motor‐manual bark gouging regulate I. typographus populations efficiently, whereas a conventional harvester did not reduce the emerging bark beetles. Species assemblages of non‐target beetles living in the infested Norway spruce logs were altered from the natural species assemblages in control logs by processing logs with the debarking head or the bark gouging device but not by the conventional harvester. None of the bark treatments reduced non‐target beetle species richness in this experiment.

Practical implication. We endorse the debarking head and bark gouging as alternatives to salvage logging and manual debarking. This uncouples pest control from in‐time dependencies on the availability of transport capacities. The debarking head and bark gouging open up the opportunity to retain dead wood biomass in the forest, supporting ecological benefits and conservation goals. Particularly for protected areas these two new management options better balance requirements of pest control and biodiversity conservation.
The Changes of Mitochondria during Aging and Regeneration
Authors: Li Anqi , Qin Yuan , Gong Guohua
Published: July 2024

Aging and regeneration are opposite cellular processes. Aging refers to progressive dysfunction in most cells and tissues, and regeneration refers to the replacement of damaged or dysfunctional cells or tissues with existing adult or somatic stem cells. Various studies have shown that aging is accompanied by decreased regenerative abilities, indicating a link between them. The performance of any cellular process needs to be supported by the energy that is majorly produced by mitochondria. Thus, mitochondria may be a link between aging and regeneration. It should be interesting to discuss how mitochondria behave during aging and regeneration. The changes of mitochondria in aging and regeneration discussed in this review can provide a timely and necessary study of the causal roles of mitochondrial homeostasis in longevity and health.
DNA Tetrahedron Delivering miR‐21‐5p Promotes Senescent Bone Defects Repair through Synergistic Regulation of Osteogenesis and Angiogenesis
Authors: Qi Lei , Hong Shebin , Zhao Tong , Yan Jinge , Ge Weiwen , Wang Jing , Fang Xin , Jiang Weidong , Shen Steve GF , Zhang Lei
Published: July 2024

Compromised osteogenesis and angiogenesis is the character of stem cell senescence, which brought difficulties for bone defects repairing in senescent microenvironment. As the most abundant bone‐related miRNA, miRNA‐21‐5p plays a crucial role in inducing osteogenic and angiogenic differentiation. However, highly efficient miR‐21‐5p delivery still confronts challenges including poor cellular uptake and easy degradation. Herein, TDN‐miR‐21‐5p nanocomplex is constructed based on DNA tetrahedral (TDN) and has great potential in promoting osteogenesis and alleviating senescence of senescent bone marrow stem cells (O‐BMSCs), simultaneously enhancing angiogenic capacity of senescent endothelial progenitor cells (O‐EPCs). Of note, the activation of AKT and Erk signaling pathway may direct regulatory mechanism of TDN‐miR‐21‐5p mediated osteogenesis and senescence of O‐BMSCs. Also, TDN‐miR‐21‐5p can indirectly mediate osteogenesis and senescence of O‐BMSCs through pro‐angiogenic growth factors secreted from O‐EPCs. In addition, gelatin methacryloyl (GelMA) hydrogels are mixed with TDN and TDN‐miR‐21‐5p to fabricate delivery scaffolds. TDN‐miR‐21‐5p@GelMA scaffold exhibits greater bone repair with increased expression of osteogenic‐ and angiogenic‐related markers in senescent critical‐size cranial defects in vivo. Collectively, TDN‐miR‐21‐5p can alleviate senescence and induce osteogenesis and angiogenesis in senescent microenvironment, which provides a novel candidate strategy for senescent bone repair and widen clinical application of TDNs‐based gene therapy.
M6A‐mediated upregulation of lncRNA TUG1 in liver cancer cells regulates the antitumor response of CD8+ T cells and phagocytosis of macrophages
Authors: Xi Qing , Yang Guangze , He Xue , Zhuang Hao , Li Li , Lin Bing , Wang Lingling , Wang Xianyang , Fang Chunqiang , Chen Qiurui , Yang Yongjie , Yu Zhaoan , Zhang Hao , Cai Wenqian , Li Yan , Shen Han , Liu Li , Zhang Rongxin
Published: July 2024

Tumor immune evasion relies on the crosstalk between tumor cells and adaptive/innate immune cells. Immune checkpoints play critical roles in the crosstalk, and immune checkpoint inhibitors have achieved promising clinical effects. The long non‐coding RNA taurine‐upregulated gene 1 (TUG1) is upregulated in hepatocellular carcinoma (HCC). However, how TUG1 is upregulated and the effects on tumor immune evasion are incompletely understood. Here, METTL3‐mediated m6A modification led to TUG1 upregulation is demonstrated. Knockdown of TUG1 inhibited tumor growth and metastasis, increased the infiltration of CD8+ T cells and M1‐like macrophages in tumors, promoted the activation of CD8+ T cells through PD‐L1, and improved the phagocytosis of macrophages through CD47. Mechanistically, TUG1 regulated PD‐L1 and CD47 expressions by acting as a sponge of miR‐141 and miR‐340, respectively. Meanwhile, TUG1 interacted with YBX1 to facilitate the upregulation of PD‐L1 and CD47 transcriptionally, which ultimately regulated tumor immune evasion. Clinically, TUG1 positively correlated with PD‐L1 and CD47 in HCC tissues. Moreover, the combination of Tug1‐siRNA therapy with a Pdl1 antibody effectively suppressed tumor growth. Therefore, the mechanism of TUG1 in regulating tumor immune evasion is revealed and can inform existing strategies targeting TUG1 for enhancing HCC immune therapy and drug development.
Spike‐Based Neuromorphic Hardware for Dynamic Tactile Perception with a Self‐Powered Mechanoreceptor Array
Authors: Lee Sang‐Won , Yun Seong‐Yun , Han Joon‐Kyu , Nho Young‐Hoon , Jeon Seung‐Bae , Choi Yang‐Kyu
Published: July 2024

A self‐powered mechanoreceptor array is demonstrated using four mechanoreceptor cells for recognition of dynamic touch gestures. Each cell consists of a triboelectric nanogenerator (TENG) for touch sensing and a bi‐stable resistor (biristor) for spike encoding. It produces informative spike signals by sensing a force of an external touch and encoding the force into the number of spikes. An array of the mechanoreceptor cells is utilized to monitor various touch gestures and it successfully generated spike signals corresponding to all the gestures. To validate the practicality of the mechanoreceptor array, a spiking neural network (SNN), highly attractive for power consumption compared to the conventional von Neumann architecture, is used for the identification of touch gestures. The measured spiking signals are reflected as inputs for the SNN simulations. Consequently, touch gestures are classified with a high accuracy rate of 92.5%. The proposed mechanoreceptor array emerges as a promising candidate for a building block of tactile in‐sensor computing in the era of the Internet of Things (IoT), due to the low cost and high manufacturability of the TENG. This eliminates the need for a power supply, coupled with the intrinsic high throughput of the Si‐based biristor employing complementary metal–oxide–semiconductor (CMOS) technology.
Unexpected Molecular Sieving of Xylene Isomer Using Tethered Ligand in Polymer‐Metal–Organic Frameworks (polyMOFs)
Authors: Hyun Taehoon , Park Junkil , So Jungseob , Kim Jihan , Koh Dong‐Yeun
Published: July 2024

Promising advances in adsorption technology can lead to energy‐efficient solutions in industrial sectors. This work presents precise molecular sieving of xylene isomers in the polymer‐metal‐oragnic framework (polyMOF), a hybrid porous material derived from the parent isoreticular MOF‐1 (IRMOF‐1). PolyMOFs are synthesized by polymeric ligands bridged by evenly spaced alkyl chains, showing reduced pore sizes and enhanced stabilities compared to its parent material due to tethered polymer bridge within the pores while maintaining the original rigid crystal lattice. However, the exact configuration of the ligands within the crystals remain unclear, posing hurdles to predicting the adsorption performances of the polyMOFs. This work reveals that the unique pore structure of polyIRMOF‐1‐7a can discriminate xylene isomers with sub‐angstrom size differences, leading to highly selective adsorption of p‐xylene over other isomers and alkylbenzenes in complex liquid mixtures (αpX/OM = 15 and αpX/OME = 9). The structural details of the polyIRMOF‐1‐7a are elucidated through computational studies, suggesting a plausible configuration of alkyl chains within the polyMOF crystal, which enable a record‐high p‐xylene selectivity and stability in liquid hydrocarbon. With this unprecedented molecular selectivity in MOFs, “polymer‐MOF” hybridization is expected to meet rigorous requirements for high‐standard molecular sieving through precisely tunable and highly stable pores.
Construction of H‐Doped PdB Nanocrystals as Electrocatalysts to Modulate Formic Acid Oxidation
Authors: Li Huiling , Zhou Shangqi , Liu Jiewen , Wang Weibin , Chen Ankang , Sheng LiBo , Zhao Jingxiang , Li Yan , Sui Yongming , Zou Bo
Published: July 2024

The strong ligand effect in B‐doped Pd‐based (PdB) catalysts renders them a promising anode for constructing formic acid fuel cells (FAFCs) exhibiting high power density and outstanding stability. However, the enhancement of the oxidation barrier is unavoidable in this alloy system owing to the electron transfer (ET) from B to Pd. In this study, a hydrogen doping strategy is employed to open charge freedom in PdB compounds and boost their formic acid oxidation reaction (FAOR) activity by suppressing the ET process. The resulting hydrogen‐doped PdB (PdBH) exhibits an ultrahigh mass activity of up to 1.2A mg−1Pd, which is 3.23 times that of the PdB catalyst and 9.55 times that of Pd black. Detailed experimental and theoretical studies show that the interstitial hydrogen leads to enhanced orbital hybridization and reduced electron density around Pd. This optimized ligand effect weakens the carbon monoxide adsorption and increases the direct pathway preference of PdBH, resulting in its outstanding catalytic activity for the FAOR. The development of this high‐performance hydrogen‐doped PdB catalyst is an important step toward the construction of advanced light element co‐doped metal catalysts.