julilili42/papers huggingface dataset:
The Role of Activation-Induced C-Type Lectin (AICL) in NK Cell Reactivity against Acute Leukemia
2008-11-16

Abstract Studies of haploidentical stem cell transplantation (SCT) demonstrate that NK cells play an important role in immunosurveillance of leukemia and indicate that acute lymphoblastic leukemias (ALL) are less susceptible to NK cell reactivity than acute myeloid leukemia (AML). The molecular mechanisms mediating NK cell reactivity against leukemia cells, especially those responsible for the differential susceptibility of AML and ALL to NK cell immunosurveillance, are yet largely unclear. Recently we have identified AICL as a myeloid-specific ligand for the activating NK cell receptor NKp80 (Welte et al., Nat. Immunol.2006, 7:1334). Here we studied the role of AICL and NKp80 in NK cell reactivity against acute leukemia. Substantial levels of AICL were expressed on blasts in 23 cases (40%) of 57 AML patients studied, while no AICL expression was detected on leukemic cells of 21 investigated ALL patients. Healthy CD34+ cells did also not express AICL, which suggests that AICL may be a marker for a malignant phenotype of myeloid hematopoietic precursor cells. Expression in AML was not restricted to a specific French-American-British (FAB) subtype, but was significantly associated with myelomonocytic differentiation (FAB M4 and M5). No correlation with a particular cytogenetic abnormality or expression levels of HLA class I was observed. Inhibition of AICL-NKp80 interaction by blocking NKp80 (Fab’)2 fragments significantly diminished both cellular cytotoxicity (&amp;gt;60% reduction, E:T ratio 40:1) and IFN-γ production (&amp;gt;60% reduction) of NK cells in cocultures with AICL-positive AML cells demonstrating that AICL expression renders AML blasts susceptible to NK cell reactivity. On NK cells of AML patients, expression of NKp80 was found to be significantly reduced compared to healthy donors. Cocultures of AICL- and control-transfectants with NK cells revealed that NKp80 expression is downregulated after interacting with its ligand, which provides a functional explanation how leukemia cells may evade NKp80-mediated NK cell immunosurveillance. Taken together, our data indicate that AICL-NKp80 interaction substantially contributes to NK cell reactivity against AML but not against ALL, which may explain the differential susceptibility of AML and ALL to NK cell reactivity. Our data further support the notion that NK cells play an important role in the pathophysiology of acute leukemia and provide useful information for therapeutic approaches in AML which, like e.g. haploidentical stem cell transplantation, rely on a sufficient NK cell response.
The Role of CD137 and Its Ligand in Chronic Lymphocytic Leukemia (CLL)
2008-11-16

Abstract Tumor immunosurveillance is dependent on the reciprocal interaction between tumor cells and anti-tumor immunity mediated e.g. by NK cells. This has led to the concept of tumor immunoediting, which incorporates the multitude of mechanisms underlying this dual tumor- and immune-sculpting interaction. Various members of the TNF/TNFR family modulate differentiation, proliferation, activation, and death of both tumor and immune effector cells. Very recently the TNFR family member CD137 has been shown to be induced on NK cells by Fc receptor triggering indicating that not only the Fab region but also the Fc part of a given antibody may be responsible for effects attributed to CD137 modulation (Lin et al., Blood2008, 112: 699). Thus we here studied the role of human CD137 and its cognate counterpart, the CD137 ligand (CD137L) in the interaction of CLL with NK cells. High levels of CD137L expression were detected on B-CLL cells in all investigated patients (n=40). Incubation of CLL cells in the presence of an immobilized CD137-Ig fusionprotein significantly induced the release of the immunoregulatory cytokine TNF demonstrating that CLL-expressed CD137L was capable to transduce bidirectional signals. Furthermore, we found that NK cells of CLL patients displayed substantial CD137 expression. While being absent on resting NK cells, CD137 expression was upregulated on the CD56dimCD16+ but not the CD56brightCD16− NK cell subset of healthy donors upon activation e.g. with IL-2 or IL-15. In addition, CD137 was also induced on NK cells after incubation in supernatants of PBMC of CLL patients. Surprisingly, disruption of CD137-CD137L interaction in cocultures of allogenic NK cells with patient CLL cells by blocking CD137 antibody caused a significant increase in NK cell cytotoxicity. The observed inhibitory effect of CD137L on NK cell reactivity was confirmed in cytotoxicity assays using CD137L-transfectants with mock-transfectants as control. Furthermore, blocking CD137-CD137L interaction also substantially enhanced Rituximab-induced antibody dependent cellular cytotoxicity in an allogenic setting. Importantly, CD137 blockade also substantially enhanced CD107a expression as a surrogate marker for granule mobilization on autologous NK cells within PBMC of B-CLL patients, and this effect was observed both in the absence and more pronounced in the presence of Rituximab. Thus, expression of functional CD137L by CLL cells impairs anti-tumor immunity by diminishing both direct and antibody-dependent cellular cytotoxicity of allogenic and autologous NK cells. Modulation of the CD137-CD137L system might therefore be a suitable therapeutic approach in strategies like antibody therapy which rely on a sufficient NK cell anti-tumor response.
Targeting CDK4 in Mantle Cell Lymphoma (MCL) Cell Lines by Specific Lentiviral shRNA Mediated Knockdown Has Profound Effects on Cell Growth and Cell Cycle but Minimal Effects on Apoptosis.
2008-11-16

Abstract Introduction: The hallmark of MCL is overexpression of cyclin D1 due to the t(11;14). Cyclin D1 accelerates the transition of lymphoma cells from G1 to S phase by binding the cyclin-dependent kinase 4 (CDK4), and inactivating the retinoblastoma protein. Due to the importance of cyclin D1-CDK4 complexes in the control of the cell cycle, CDK4 has become a novel and attractive therapeutic target in MCL. Flavopiridol is a pharmacologically derived CDK inhibitor, which is in phase II trial in relapsed MCL patients. The aim of this study was to investigate the effects of silencing CDK4 expression in MCL using highly specific CDK4-shRNA, and compare the results with known effects of flavopiridol and other CDK inhibitors. Material and methods: A highly efficient CDK4-shRNA was identified using a LacZ-cyclin D1 fusion gene reporter system in HEK293T cells. This shRNA was cloned into a lentiviral transfer vector carrying GFP as a reporter gene, which enables the detection of infected cells by FACS analysis. Four MCL cell lines were analyzed (Granta 519, Jeko-1, Rec-1, Z-138), using appropriate controls. Western Blot analysis and qRT-PCR were performed to quantify the knockdown effect. The effect of CDK4 knockdown on proliferation, cell cycle, and viability was analyzed by MTT assay and FACS analysis. Results: In MCL cell lines with high CDK4 levels (Jeko-1, Rec-1, Z-138), profound effects on cell growth and cell cycle were observed with only minor effects in apoptosis. The cells showed 40% growth retardation compared to control cells after seven days of infection. Additionally, a clear shift from the S phase to the G1 phase in the cell cycle was observed as compared to control cells (S phase decreased by 23% and G1 increased by 28%). In contrast, only minimal apoptosis was induced (11% increase compared to control cells). CDK4-shRNA infected cells showed a strong induction of cyclin D2 mRNA (5,6 fold on average). Additionally, Granta 519 and Z-138 cell lines showed an increase in CDK6 mRNA. The expression of cyclin D1 mRNA and protein and cyclin E protein remained unchanged or was slightly induced. No changes were observed in the protein expression of cyclin D3, p27Kip1 and CDK2. Conclusions: Our data showed that the specific CDK4 downregulation induces important growth retardation but not significant apoptosis. The reported effects after Flavopiridol treatment including downregulation of cyclin D1 and D3, as well as the induction of apoptosis, were not observed after specific CDK4 knockdown, and indicate CDK4-independent effects of this CDK inhibitor. Taken together, targeting specifically CDK4 alone is likely to have less effect on MCL than broader kinase inhibitors like Flavopiridol, used either as a single drug or in combination with conventional chemotherapy.
Influence of Genetic Polymorphisms of VKORC1 and CYP2C9 in Patients on Phenprocoumon Steady-State Dose Requirements
2008-11-16

Abstract The variants of the (Vitamin-K epoxid reductase subcomplex 1) VKORC1 and of cytochrome P450 2C9 (CYP2C9) genes are know to influence the steady state dose of the vitamin-K antagonist (VKA) phenprocoumon during oral anticoagulant therapy. We have analysed in detail the influence of the VCORC1 1173CC and 1173CT variants in combination with the CYP2C9 variants on the steady state dose of phenprocoumon. The weekly phenprocoumon dosage was calculated after a 3 to 6 months of stable anticoagulation by the international normalized ratio (INR) which had to be in a range from 2 to 3 in 114 patients. VKORC1 1173CC, CT, TT and CYP2C9*1/*1, *1/*2, *1/*3, *2/*2, *2/*3 and *3/*3 genotypes were determined using direct DNA sequencing and realtime PCR. Patients carrying VKORC1 1173CT and CYP2C9*1/*1 genotypes required a 33% lower steady state dose of phenprocoumon compared to VKORC1 1173CC and CYP2C9*1/*1 genotypes (p=0.0001). Patients with VKORC1 1173CC in combination with CYP2C9*1/*2, *1/*3 needed 10% and 34% lower steady state dose of phenprocoumon compared to the combination with CYP2C9*1/*1, respectively (p=0.0001). Patients carrying VKORC1 1173CT needed lower doses of phenprocoumon in combination with CYP2C9*1/*1 (−32%), *1/*2 (−29%), or *1/*3 (−33%), and VKORC1 1173TT in combination with CYP2C9*1/*3 (−44%) compared to VKORC1 1173CC combined with CYP2C9*1/*1 (all p&amp;lt;0.001). CYP2C9 variants did not influence the dose of carriers of VKORC1 1173CT gene. Both genotypes together influenced the phenprocoumon maintenance dosage in this naturalistic study design. Genotyping for CYP2C9 and VCORC1 therefore might be a suitable tool for dose individualization in patients at oral anticoagulant drug therapy.
Crystalline Intermediates during Polycondensation Reactions in the C–N–Cl System – The Paddle‐Wheel Molecule N(C6N7Cl2)3
2008-11-17

Abstract Solid state metathesis reactions between cyanuric chloride and C–N–H or alkali metal–(B–)C–N compounds, respectively, were carried out in the temperature range between 150 °C to 500 °C, studying intermediate stages of reactions and targeting the formation of carbon nitride materials by elimination of HCl or alkali metal chlorides. Although cyanuric chloride was reacted with quite a number of different reaction partners such as melamine, cyanamide, lithium nitride, lithium or sodium carbodiimide, lithium nitridoborate or sodium dicyandiamide, always the same intermediate compounds appeared in the reactions mixtures. Colorless, needle‐shaped crystals of the tertiary amine N(C 3 N 3 Cl 2 ) 3 ( 1 ) were obtained at temperatures around 200–250 °C. Temperatures as high as 400 °C yielded yellow, plate‐like crystals of the heptazine compound C 6 N 7 Cl 3 ( 2 ). At even higher temperatures, the reaction products were of poorer crystallinity, but evidence of the formation of another crystalline intermediate was given by X‐ray powder diffraction and electron diffraction experiments. This third intermediate is assumed to be a tertiary amine, quite similar to 1 , however, having heptazine ligands instead of triazine ligands and is assigned with the formula N(C 6 N 7 Cl 2 ) 3 ( 3 ). Theoretical calculations were performed for the structures and the vibrational spectra of 1 and 3 . Theoretical calculations and a structure refinement based of X‐ray powder diffraction data yielded a plausible structural model for compound 3 .
Perceptual and Computational Categories in Art
2008-11-17

The categorization of art (paintings, literature) into distinct styles such as expressionism, or surrealism has had a profound influence on how art is presented, marketed, analyzed, and historicized. Here, we present results from several perceptual experiments with the goal of determining whether such categories also have a perceptual foundation. Following experimental methods from perceptual psychology on category formation, naive, non-expert participants were asked to sort printouts of artworks from different art periods into categories. Converting these data into similarity data and running a multi-dimensional scaling (MDS) analysis, we found distinct perceptual categories which did in some cases correspond to canonical art periods. Initial results from a comparison with several computational algorithms for image analysis and scene categorization are also reported.
Structure of neutron stars in tensor-vector-scalar theory
2008-11-18

Bekenstein's tensor-vector-scalar (TeVeS) theory has had considerable success in explaining various phenomena without the need for dark matter. However, it is difficult to observationally discern the differences between TeVeS and predictions made within the Lambda-cold dark matter concordance model. This implies that alternative tests are required that independently verify which theory is correct. For this we turn to the strong-field regime of TeVeS. In particular, we solve the spherically symmetric equations of hydrostatic equilibrium for a perfect fluid with a realistic equation of state to build models of neutron stars in TeVeS. We show that causality within the neutron star is only maintained for certain cosmological values of the scalar field, which allows us to put constraints on this value independently of cosmological observations. We also discuss in detail the internal structure of neutron stars and how each of the free parameters in the theory affects the overall size and mass of the neutron stars. In particular, the radii of neutron stars in TeVeS can significantly differ from those in general relativity for certain values of the vector field coupling, which allows us to also place extra constraints on this parameter. Finally, we discuss future observations of neutron stars using both the electromagnetic and gravitational wave spectrums that will allow for tests of the appropriate theory of gravity.
Efficient shRNA delivery into B and T lymphoma cells using lentiviral vector-mediated transfer
2008-11-18

RNA interference is a powerful tool for the functional analysis of proteins by specific gene knockdown. In this study, we devised a rapid and efficient way to screen suitable siRNA sequences and subsequently employ them for specific gene knockdown in usually hard-to-transfect lymphoid cell lines, using a self-inactivating lentiviral vector. Two proteins with different half-lives were chosen, cyclin D1 and STAT3. A specific lacZ reporter fusion assay was used to identify highly effective siRNA sequences. Only siRNA molecules with more than 85% of knockdown efficiency were selected for the generation of lentiviral transfer vectors. Transduction rates of 75-99% were achieved in the lymphoma cell lines Granta 519 (mantle cell lymphoma), Karpas 299, and SUDHL-1 (anaplastic large T cell lymphoma), as demonstrated by green fluorescent protein expression in fluorescence-activated cell sorting analysis. The high level of transduction efficiency allows RNA interference studies to be performed on transduced cells without further manipulation, such as cell sorting or cloning. The LacZ reporter system together with the lentivirus technology is a very important tool in the hematology field, which enables experiments in lymphoid cells that were not possible before.
Novel Algorithm for More Accurate Calculation of Renal Function in Adults with Cancer
2008-11-18

Background: Cytotoxic agents have a narrow therapeutic window. A high percentage of some of them is renally excreted in unchanged form. Accurate assessment of an individual's glomerular filtration rate (GFR) helps to predict the pharmacokinetic behavior of those drugs more precisely. GFR calculations, however, have their limitations. Objective: To establish a more accurate calculation of renal function over a broad range of constitutive GFR values. Methods: Patients with cancer were included in the analysis. Serum levels of cystatin C, creatinine, urea, albumin, and β-trace protein were measured, and GFR was calculated by 8 mathematical formulas. The results were compared with creatinine clearance (CrCI) calculated from timed urine specimens. Results: One hundred two patients were evaluated: median age, 57.5 years (range 20–91); females, 52; males, 50; and mean urinary CrCI, 77.0 mL/min. The bias (mean percentage error) was -2% and the precision (mean absolute percentage error) was 23% for the Modification of Diet in Renal Disease (MDRD) estimation of GFR. All equations significantly overestimated CrCI in patients with measured clearance less than 50 mL/min (p &lt;0.05), with the exception of the modified Salazar-Corcoran formula. All equations underestimated CrCI in patients with measured clearance greater than 100 mL/min. The Wright formula was the least biased and most precise (–5%, 16%, respectively). In patients with measured CrCI 50–100 mL/min, the MDRD calculation had a bias of -4% and a precision of 17%. The Jelliffe and Larsson equations were associated with significant sex bias (p &lt;0.05). Conclusions: These observations suggest that individual GFR values over a broad range cannot be calculated accurately enough with only one selected formula. It may be useful to classify renal function of patients with cancer according to the novel algorithm by using MDRD first and then to subsequently calculate GFR in higher and lower ranges with the Wright and modified Salazar-Corcoran formulas, respectively. This algorithm should be validated using larger numbers of patients.
Adiponectin Oligomers and Ectopic Fat in Liver and Skeletal Muscle in Humans
2008-11-18

We aimed at determining which circulating forms of the adipokine adiponectin that increases lipid oxidation in liver and skeletal muscle are related to ectopic fat in these depots in humans. Plasma total‐, high‐molecular weight (HMW)‐, middle‐molecular weight (MMW)‐, and low‐molecular weight (LMW) adiponectin were quantified by an enzyme‐linked immunosorbent assay. Their relationships with liver‐ and intramyocellular fat, measured using 1 H magnetic resonance spectroscopy, were investigated in 54 whites without type 2 diabetes. Liver fat, adjusted for gender, age, and total body fat, was associated only with HMW adiponectin ( r = −0.35, P = 0.012), but not with total‐, MMW‐, or LMW adiponectin. In addition, subjects with fatty liver (liver fat ≥5.56%, n = 15) had significantly lower HMW‐ ( P = 0.04), but not total‐, MMW‐, or LMW adiponectin levels, compared to controls ( n = 39). Similarly, intramyocellular fat correlated only with HMW ( r = −0.32, P = 0.039), but not with the other circulating forms of adiponectin. These data indicate that, among circulating forms of adiponectin, HMW is strongly related to ectopic fat, thus possibly representing the form of adiponectin regulating lipid oxidation in liver and skeletal muscle.
Familial thrombocytosis caused by the novel germ‐line mutation p.Pro106Leu in the MPL gene
2008-11-19

Summary Familial thrombosis (FT) has been described as a rare autosomal‐dominant disorder, mostly caused by activating mutations of the thrombopoietin gene ( THPO ). Other cases of FT have been linked to one of two different germline mutations in the myeloproliferative leukaemia virus oncogene gene ( MPL ), which codes for the thrombopoietin receptor MPL. We studied an Arab family with two siblings with severe thrombocytosis by linkage analysis and obtained evidence for linkage to MPL . Sequencing revealed homozygosity for the novel MPL germline mutation p.Pro106Leu (c.317C &gt; T) in the two siblings. Subsequently, homozygosity for p.Pro106Leu was identified in six further FT patients from three other Arab families. Of 18 heterozygous carriers, 14 had normal platelet counts, while four had mild thrombocytosis. Strong support for association of the novel MPL mutation p.Pro106Leu with development of familial thrombocytosis has been obtained. Overall, p.Pro106Leu was absent on 386 alleles of 193 healthy German controls and present on 14 of 426 alleles (3·3%) of 213 unrelated Arabs, which was statistically significantly different ( P &lt; 0·001, Fisher’s exact test). We assume that p.Pro106Leu is a frequent MPL mutation in the Arab population, leading to severe thrombocytosis in homozygotes and occasionally to mild thrombocytosis in heterozygotes. In the families described the mode of inheritance could be regarded as autosomal‐recessive with possible mild heterozygote manifestation rather than autosomal‐dominant with high penetrance as usually seen in FT.
Diagnostic and Interventional MRI of the Sacroiliac Joints Using a 1.5-T Open-Bore Magnet: A One-Stop-Shopping Approach
2008-11-19

We accept the hypothesis that combined diagnostic and interventional MRI of the sacroiliac joints can be performed efficiently and effectively for comprehensive diagnosis and therapy of lower back pain originating from the sacroiliac joints.
Late Cretaceous blueschist facies metamorphism in southern Thrace (Turkey) and its geodynamic implications
2008-11-19

Abstract A blueschist facies tectonic sliver, 9 km long and 1 km wide, crops out within the Miocene clastic rocks bounded by the strands of the North Anatolian Fault zone in southern Thrace, NW Turkey. Two types of blueschist facies rock assemblages occur in the sliver: (i) A serpentinite body with numerous dykes of incipient blueschist facies metadiabase (ii) a well‐foliated and thoroughly recrystallized rock assemblage consisting of blueschist, marble and metachert. Both are partially enveloped by an Upper Eocene wildflysch, which includes olistoliths of serpentinite–metadiabase, Upper Cretaceous and Palaeogene pelagic limestone, Upper Eocene reefal limestone, radiolarian chert, quartzite and minor greenschist. Field relations in combination with the bore core data suggest that the tectonic sliver forms a positive flower structure within the Miocene clastic rocks in a transpressional strike–slip setting, and represents an uplifted part of the pre‐Eocene basement. The blueschists are represented by lawsonite–glaucophane‐bearing assemblages equilibrated at 270–310 °C and ∼0.8 GPa. The metadiabase dykes in the serpentinite, on the other hand, are represented by pumpellyite–glaucophane–lawsonite‐assemblages that most probably equilibrated below 290 °C and at 0.75 GPa. One metadiabase olistolith in the Upper Eocene flysch sequence contains the mineral assemblage epidote + pumpellyite + glaucophane, recording P–T conditions of 290–350 °C and 0.65–0.78 GPa, indicative of slightly lower depths and different thermal setting. Timing of the blueschist facies metamorphism is constrained to c. 86 Ma (Coniacian/Santonian) by Rb–Sr phengite–whole rock and incremental 40 Ar– 39 Ar phengite dating on blueschists. The activity of the strike–slip fault post‐dates the blueschist facies metamorphism and exhumation, and is only responsible for the present outcrop pattern and post‐Miocene exhumation (∼2 km). The high‐ P/T metamorphic rocks of southern Thrace and the Biga Peninsula are located to the southeast of the Circum Rhodope Belt and indicate Late Cretaceous subduction and accretion under the northern continent, i.e. the Rhodope Massif, enveloped by the Circum Rhodope Belt. The Late Cretaceous is therefore a time of continued accretionary growth of this continental domain.