julilili42/papers huggingface dataset:
Hematopoietic Progenitor Cell Transplantation from Parental Donors for Children with Sickle Cell Anemia and Stroke.
2007-11-16

Although allogeneic hematopoietic progenitor cell transplantation (HPCT) can be curative for sickle cell anemia (SCA), most patients lack an HLA matched sibling donor or matched unrelated donor. A 2002 multidisciplinary conference held at St. Jude Children’s Research Hospital reached consensus that pilot studies using parental donors were reasonable and ethical. Subsequently, eight children with a history of clinically overt stroke were transplanted on two sequential pilot studies. Peripheral blood progenitor cells were obtained from parents with sickle cell trait. Conditioning was i.v. busulfan (targeted to Css 900 ng/ml) q 6 hours x 4 days, fludarabine 150–200 mg/m2, and OKT3/methylprednisolone and infusion of CD34+ HPCT for 3 patients. Five patients received i.v. busulfan (targeted to Css 900 ng/ml) x 4 days, cyclophosphamide 200 mg/kg, thiotepa 10 mg/kg, OKT3/methylprednisolone, and infusion of both CD34+ cells and CD3+ cells with a fixed T-cell addback of 1.0–1.5 x 105 CD3+ cells/kg. Six children received pre-transplant immunosuppression with hydroxyurea and azathioprine. The median follow-up of eight patients is 1.4 years (range 2 months–4 years). Five of eight had durable donor engraftment,4 of whom are alive and free of SCA post-HPCT. Rejection occurred in 4 patients and was successfully reversed with additional CD34+ cells in one of three patients. GVHD occurred in patients receiving a fixed T-cell addback or DLI: two patients had grade II acute graft-versus-host disease (aGVHD), one grade III aGVHD, and three patients developed chronic GVHD, including a fatal case of bronchiolitis obliterans organizing pneumonia (BOOP) and fungal sepsis. One engrafted patient developed medulloblastoma 2 years post-HPCT and is in remission after treatment. Further investigation revealed that this child inherited a novel germline p53 mutation. In this preliminary experience, haploidentical HPCT for children with SCA and stroke was associated with significant graft rejection and chronic GVHD. The addition of pre-transplant hydroxyurea and azathioprine, increased intensity of conditioning, and the use of T-cell addback to the graft did not improve engraftment in the second cohort. While offering the possibility of cure, haploidentical HPCT for SCA as performed in this experience is associated with significant toxicity and should only be pursued in the context of a rigorously designed and controlled prospective clinical trial.
Imatinib Inhibits Proteasomal Activity in CML Cells.
2007-11-16

Abstract Imatinib mesylate (Gleevec) is a specific tyrosine kinase inhibitor, which inhibits phosphorylation of downstream proteins involved in BCR-ABL signal transduction. In the treatment of CML it has become indispensable and shows few side effects. Nevertheless, imatinib has been described to influence the function and differentiation of APCs, inhibit the effector function of T lymphocytes and decrease the immunogenicity of CML cells. In the present study, we analyzed the possible effects of imatinib on proteasomal activity in CML cells. Proteasomal activity was determined using a biotinylated active site-directed probe which, depending on their activity, covalently binds and labels proteasomal subunits beta-1, beta-2 and beta-5. We show that Imatinib treatment leads to a decreased activity of the proteasome in BCR-ABL positive cells. Imatinib sensitive K-562 cells as well as HLA-A2 transfected K-562 cells displayed a profound downregulation of proteasome activity at sub-therapeutic concentrations of imatinib. This effect was not due to downregulation of the protein expression of proteasome subunits or the induction of apoptosis. In imatinib resistant K-562R cells a higher concentration of imatinib was required for a detectable inhibition of proteasomal activity corresponding to a higher expression of BCR-ABL in these cells. Interestingly, the use of specific siRNA against the BCR-ABL fusion site b3a2 to downregulate the expression of the protein in K-562 and K-562R cells did not influence the activity of the proteasome indicating that this effect is independent of the expression and activity of BCR-ABL. In line with these results transfection of BaF/3 cells with BCR-ABL had no effect on proteasomal activity. To further analyze the mechanisms involved in proteasome inhibition by imatinib we performed activity assays with isolated 20S and 26S proteasomes. Incubation of both proteasome subtypes with imatinib resulted in a reduced acitivity in a concentration dependent manner as shown by reduced proteolytic cleavage of fluorogenic substrates. As the reduction in activity was seen in the ATP-independent 20S proteasome as well as the ATP-dependent 26S proteasome, a competition of imatinib with ATP similar to the mechanism of BCR-ABL inhibition is not responsible for this effect. In order to expand these studies, we additionally examined HLA class I expression on the cell surface to determine the influence of imatinib and subsequent proteasome inhibition on antigen presentation. Correlating with the inhibition of proteasome activity, HLA class I expression was strongly reduced on HLA-A2 transfected K-562 cells after imatinib treatment. Taken together these findings show that imatinib directly affects proteasomal activity in vitro. This effect is more pronounced in BCR-ABL positive cells, which might be due to BCR-ABL mediated deregulation of cellular pathways, but seems to be, however, independent of BCR-ABL.
Role of Glucocorticoid-Induced TNF-Related Protein (GITR) Ligand in the Interaction of Acute Myeloid Leukemia with NK Cells.
2007-11-16

Abstract NK cells play an important role in the reciprocal interaction of tumor cells with the immune system and participate in the surveillance and eradication of hematological malignancies. The activity of NK cells is governed by a balance of activating and inhibitory surface receptors. Glucocorticoid-induced TNF-related protein (GITR) and its ligand (GITRL) are members of the TNF/TNF receptor (TNFR) superfamily, which mediates multiple cellular functions including proliferation, differentiation, and cell death. Recently we reported that NK cells express GITR while cancer cells express GITRL and GITR-GITRL interaction down regulates NK cell-mediated anti-tumor immunity (Baltz et al., FASEB J 2007). Here we demonstrate that GITRL is expressed on 6 of 7 investigated acute myeloid leukemia (AML) cell lines and on primary AML cells in 30 of 52 (59%) patients, while no GITRL expression was detected on CD34+ cells of healthy donors (n=5). GITRL expression was not restricted to a specific French-American-British (FAB) subtype, but was significantly (p&amp;lt;0.05, one-way ANOVA) associated with monocytic (FAB M4, M5) differentiation. In addition, no association with a particular cytogenetic abnormality or with expression of MHC class I was observed. Reverse signaling via GITRL led to phosphorylation of ERK and JNK resulting in significantly (p&amp;lt;0.05, Mann-Whitney U-test) enhanced production of IL-10 and TNF by patient AML cells (n=10). In line, specific inhibitors for JNK and ERK1/2 blocked the cytokine release by AML cells demonstrating that activation of MAP kinases is responsible for the production of the immunoregulatory cytokines following GITRL stimulation. Importantly, blocking GITR-GITRL interaction in cocultures of AML and NK cells significantly (both &amp;lt;0.05 Mann-Whitney U-test) increased cellular cytotoxicity about 70% and IFN-γ production about 60%, and this was due to restored NK cell NF-κB activity. Thus, GITRL substantially influences immunoediting by AML cells and enables the escape of AML cells from NK cell-mediated immune surveillance. The correlation found between GITRL expression and NK cell susceptibility may provide useful information for NK cell-based immunotherapy.
NFAT signaling in neural development and axon growth
2007-11-17

Abstract The NFAT (nuclear factor of activated T‐cells) family of transcription factors functions as integrators of multiple signaling pathways by binding to chromatin in combination with other transcription factors and coactivators to regulate genes central for many developmental systems. Recent experimental evidence has shown that the calcineurin/NFAT signaling pathway is important in axonal growth and guidance during vertebrate development. In fact, studies with triple NFATc2/c3/c4 mutant mice demonstrate that the extension and organization of sensory axon projection and commissural axon growth are both dependent upon NFAT activity. Neurotrophin and L‐type calcium channel signaling modulate intracellular calcium levels to regulate the nuclear import and transcriptional activity of NFAT by activating the phosphatase calcineurin. The rephosphorylation and subsequent export of NFAT from the nucleus is mediated by several kinases, including GSK‐3β, which contribute to the fine tuning of NFAT transcriptional activity in neurons. However, currently, no direct transcriptional targets for NFAT have been identified in a chromatin environment in the nervous system. Undiscovered are also the binding partners of NFAT that might combinatorially regulate specific genes important for neuronal development. This review will discuss the current knowledge related to NFAT signaling in the nervous system development and the potential for future research directions.
Chromatin modifications induced by PML-RARα repress critical targets in leukemogenesis as analyzed by ChIP-Chip
2007-11-17

The translocation t(15;17) generates the chimeric PML-RARα transcription factor that is the initiating event of acute promyelocytic leukemia. A global view of PML-RARα transcriptional functions was obtained by genome-wide binding and chromatin modification analyses combined with genome-wide expression data. Chromatin immunoprecipitation (ChIP)–chip experiments identified 372 direct genomic PML-RARα targets. A subset of these was confirmed in primary acute promyelocytic leukemia. Direct PML-RARα targets include regulators of global transcriptional programs as well as critical regulatory genes for basic cellular functions such as cell-cycle control and apoptosis. PML-RARα binding universally led to HDAC1 recruitment, loss of histone H3 acetylation, increased tri-methylation of histone H3 lysine 9, and unexpectedly increased trimethylation of histone H3 lysine 4. The binding of PML-RARα to target promoters and the resulting histone modifications resulted in mRNA repression of functionally relevant genes. Taken together, our results reveal that the transcription factor PML-RARα regulates key cancer-related genes and pathways by inducing a repressed chromatin formation on its direct genomic target genes.
Early treatment after a symptomatic event is not associated with an increased risk of stroke in patients undergoing carotid stenting
2007-11-17

A recently symptomatic carotid artery stenosis carries a high risk of subsequent ischaemic events and thus requires rapid treatment. We investigated the influence of the time delay between the last symptomatic event of a carotid stenosis and subsequent carotid artery stenting (CAS) with respect to the combined 30‐day outcome of stroke and death. In a group of 320 patients undergoing CAS the median delay before the intervention was 19 days (interquartile range 10–36) and the combined 30‐day complication rate was 8.4%. Time delay was not significantly associated with peri‐procedural complications, regardless of whether this variable was dichotomized (&lt;14 days and ≥14 days), separated into interquartile ranges or analysed as a continuous variable. Our results indicate that early CAS is not associated with an increased complication rate in patients with a recently symptomatic carotid stenosis. Thus, if CAS has been selected as the treatment modality for a patient, it should be performed as soon as possible to maximize the benefit of the intervention in reducing the risk of stroke.
Short Article: Knowing When to Hear Aids What to Hear
2007-11-17

Temporal preparation often has been assumed to influence motor stages of information processing. Recent studies, however, challenge this notion and provide evidence for a facilitation of visual processing. The present study was designed to investigate whether perceptual processing in the auditory domain also benefits from temporal preparation. To this end, we employed a pitch discrimination task. In Experiment 1, discrimination performance was clearly improved when participants were temporally prepared. This finding was confirmed in Experiment 2, which ruled out possible influences of short-term memory. The results support the notion that temporal preparation enhances perceptual processing not only in the visual, but also in the auditory, modality.
Installation of a network for patients with congenital melanocytic nevi in German‐speaking countries
2007-11-17

Summary In 2005, an Internet‐based network for the support of patients with congenital melanocytic nevi in German‐speaking countries was started ( http://www.naevus‐netzwerk.de ). Along with detailed information for patients and parents, the home‐page includes a nevus registry which is based on an electronic questionnaire and which aims at providing data on the long‐term course of nevi estimated to reach &gt; 10 cm in largest diameter. In the past, congenital melanocytic nevi have been subject to various mythological interpretations (“ Tierfellnävus ”, lit.”animal coat nevus”;” Muttermal ”). Today an increasing body of reliable scientific data allows a differentiated reflection of the risk of malignant transformation and has led to progress in the diagnostic and therapeutic management. Recent findings from the literature and considerations from scientific meetings are reviewed.
Phosphatidylethanolamine critically supports internalization of cell-penetrating protein C inhibitor
2007-11-19

Although their contribution remains unclear, lipids may facilitate noncanonical routes of protein internalization into cells such as those used by cell-penetrating proteins. We show that protein C inhibitor (PCI), a serine protease inhibitor (serpin), rapidly transverses the plasma membrane, which persists at low temperatures and enables its nuclear targeting in vitro and in vivo. Cell membrane translocation of PCI necessarily requires phosphatidylethanolamine (PE). In parallel, PCI acts as a lipid transferase for PE. The internalized serpin promotes phagocytosis of bacteria, thus suggesting a function in host defense. Membrane insertion of PCI depends on the conical shape of PE and is associated with the formation of restricted aqueous compartments within the membrane. Gain- and loss-of-function mutations indicate that the transmembrane passage of PCI requires a branched cavity between its helices H and D, which, according to docking studies, precisely accommodates PE. Our findings show that its specific shape enables cell surface PE to drive plasma membrane translocation of cell-penetrating PCI.
Cerebrocortical Beta Activity in Overweight Humans Responds to Insulin Detemir
2007-11-20

Despite cerebrocortical resistance to human insulin, insulin detemir increased beta activity in overweight human subjects similarly as human insulin in lean subjects. These data suggest that the decreased cerebral beta activity response in overweight subjects can be restored by insulin detemir.
Regulation of the epithelial calcium channel TRPV6 by the serum and glucocorticoid‐inducible kinase isoforms SGK1 and SGK3
2007-11-20

Epithelial calcium (re)absorption is mediated by TRPV5 and TRPV6 channels. TRPV5 is modulated by the SGK1 kinase, a process requiring the PDZ‐domain containing scaffold protein NHERF2. The present study explored whether TRPV6 is similarly regulated by SGKs and the scaffold proteins NHERF1/2. In Xenopus oocytes, SGKs activate TRPV6 by increasing its plasma membrane abundance. Deletion of the putative PDZ binding motif on TRPV6 did not abolish channel activation by SGKs. Furthermore, coexpression of neither NHERF1 nor NHERF2 affected TRPV6 or potentiated the SGKs stimulating effect. The present observations disclose a novel TRPV6 regulatory mechanism which presumably participates in calcium homeostasis.
Special conditions allow binding of the siderophore salmochelin to siderocalin (NGAL-lipocalin)
2007-11-20

Siderocalin is part of the innate immune system and is secreted by epithelial cells in the early stages of inflammation. This protein binds catecholate siderophores such as enterobactin with high affinity. As a consequence, the iron supply and growth of the siderophore-producing bacteria is disturbed. Recombinant siderocalin isolated from strains of Escherichia coli K-12 contained bound enterobactin. Very low amounts of siderocalin were isolated from another K-12 strain unable to produce enterobactin, which indicated that enterobactin might stabilize the recombinant protein. Siderocalin isolated from E. coli strain Nissle 1917, which produces the glucosylated enterobactin salmochelin, contained a mixture of bound salmochelin (55%) and enterobactin (45%). The growth of an enterobactin-producing E. coli K-12 strain but not of the same strain carrying a plasmid encoding iroBCDEN and therefore able to produce salmochelin was suppressed when siderocalin was added to the medium, which indicated that salmochelin is bound by siderocalin before siderocalin folds into its final conformation in the cell, and that binding of salmochelin to matured siderocalin is not possible. Salmochelin is mainly produced by pathogenic enterobacteria. Glucosylation of enterobactin may be a mechanism by which these bacteria evade trapping of the enterobactin by siderocalin.
World stress map published
2007-11-20

The World Stress Map (WSM), published in April 2007 by the Commission for the Geological Map of the World and the Heidelberg Academy of Sciences and Humanities, displays the tectonic regime and the orientation of the contemporary maximum horizontal compressional stress at more than 12,000 locations within the Earth's crust. The Mercator projection is a scale of 1:46,000,000. The WSM provides insight into large‐scale patterns of stress orientations (i.e., first‐order stress patterns due to plate boundary forces and second‐order stress patterns due to topography), large lateral density variations, and deglaciation effects. Furthermore, the WSM contains a number of regions with high data resolution that enable users to investigate variations in stress orientations on local scales and to discuss factors controlling third‐order stress patterns such as active faults, local inclusions, detachment horizons, and density contrasts. Forces resulting from these geological subsurface structures control the stress field orientations especially when magnitudes of the horizontal stresses are close to each other.
Licofelone, a dual COX/5-LOX inhibitor, induces apoptosis in HCA-7 colon cancer cells through the mitochondrial pathway independently from its ability to affect the arachidonic acid cascade
2007-11-21

Nowadays, no data are available concerning the potential use of dual cyclooxygenase (COX)/5-lipoxygenase (LOX) inhibitors as anticancer agents in colon cancer treatment. Here, we report, for the first time, that the dual COX/5-LOX inhibitor licofelone triggers apoptosis in a dose- and time-dependent manner in HCA-7 colon cancer cells. Induction of apoptosis was related to the recruitment of the intrinsic mitochondrial apoptotic pathway, as shown by loss in mitochondrial membrane potential, cytochrome c release, caspase-9 and 3 activation and poly-(ADP-ribose)polymerase-1 cleavage. Moreover, licofelone induced the cleavage of the full-length p21(Bax) into p18(Bax), a more potent inducer of the apoptotic process than the uncleaved form. Pre-treatment of HCA-7 cells with the pan-caspase inhibitor z-VAD-fmk significantly blocked licofelone-induced apoptosis, confirming that this process occurred primarily in a caspase-dependent pathway. We also present evidences that licofelone was able to affect the arachidonic acid (AA) cascade, as it blocked the activity of 5-LOX and COX enzymes, and it induced, through the phosphorylation of cytoplasmic phospholipase A(2) (cPLA(2)), the release of unesterified AA from HCA-7 membrane phospholipids. However, apoptosis induction was not related to the ability of licofelone to affect the AA cascade, since neither exogenous prostaglandin E(2) and leukotriene B(4) addition, nor pharmacological inhibition of cPLA(2), was able to rescue HCA-7 cells from apoptosis. Even if further studies are needed to clarify the mechanism of licofelone-induced apoptosis, this study suggests that this drug, as well as similar dual COX/5-LOX inhibitors, may represent a novel and promising approach in colon cancer treatment.
Cytomegalovirus hyperimmunoglobulin: mechanisms in allo‐immune responsein vitro
2007-11-21

Abstract Background Cytomegalovirus hyperimmunoglobulin (CMVIg) containing drugs are routinely administered in cardiac transplantation for prophylaxis against CMV disease. Yet little is known about their influence on transplant relevant immune functions. The aim of this study was to evaluate the effect of CMVIg on cellular immunity in in vitro experiments and to define their role in tolerance inducing mechanisms. Materials and methods/results CMVIg reduces proliferation in mixed lymphocyte reactions and anti‐CD3 blastogenesis assays and is related to decreased production of immune modulating cytokines interleukin (IL)‐2, interferonr (IFNγ), IL‐10. This antiproliferative effect is associated with a cell‐cycle arrest in the G0/G1 phase and induction of apoptosis in CD8+ and natural killer cells. Co‐incubation with CMVIg causes down‐regulation of cell bound immunoglobulin and FcγRIII surface expression on natural killer cells and leads to attenuation of antibody dependent cellular cytotoxicity effector functions. Conclusions We conclude that CMVIg induces immunological features on leukocytes in vitro that are known to be related to tolerance induction. Our observations extend the current concept of CMVIg as passive CMV prophylaxis to a therapeutic drug compound capable of reducing allogeneic immune response.
Color terms in ancient Egyptian and Coptic
2007-11-21

The examination of the ancient Egyptian-Coptic color terms, their grammatical identification, their range of usage, and their etymologies permit the following conclusions: There are four BCTs, all verbs, ‘black,’ ‘white,’ ‘red’ and ‘green,’ as traditionally translated. The focus of ‘red’ is in the red range and not in the middle of the red-with-yellow range. The focus of ‘green’ lies in the green range and not in the middle of the green-with-blue range nor in the pale green range. In the final, Coptic, stage, the partition of the red range into ‘deep red’ and ‘light-red’ must be assumed. The traditional written language allowed additional place for further verbal color terms, but these never entered the colloquial language as BCTs. Among these alternatives, the use of ‘lapis lazuli-colored, blue’ is strikingly common; that of ‘charcoal-like, black’ and ‘golden’ is less common. Egyptian did not develop a BCT for either blue or yellow. Basically Egyptian-Coptic remained at B&amp;K Stage IIIa.
Combined microslit electrokinetic measurements and reflectometric interference spectroscopy to study protein adsorption processes
2007-11-21

Streaming potential/current measurements for the characterization of charge formation processes at solid/liquid interfaces were combined with reflectometric interference spectroscopy. The simultaneous determination of electrosurface characteristics and the optical thickness of interfacial layers provides information on structural variations of adsorbed or covalently bound polymers and on charge dependent adsorption and desorption phenomena at solid/liquid interfaces. To demonstrate the potentialities of this extended approach for biointerfacial studies the authors report a series of experiments on the adsorption of the plasma protein fibrinogen at poly(octadecene-alt-maleic acid) thin films.