julilili42/papers huggingface dataset:
On the Migration of Protogiant Solid Cores
2006-11-16

The increase of computational resources has recently allowed high resolution,\\nthree dimensional calculations of planets embedded in gaseous protoplanetary\\ndisks. They provide estimates of the planet migration timescale that can be\\ncompared to analytical predictions. While these predictions can result in\\nextremely short migration timescales for cores of a few Earth masses, recent\\nnumerical calculations have given an unexpected outcome: the torque acting on\\nplanets with masses between 5 M_Earth and 20 M_Earth is considerably smaller\\nthan the analytic, linear estimate. These findings motivated the present work,\\nwhich investigates existence and origin of this discrepancy or ``offset'', as\\nwe shall call it, by means of two and three dimensional numerical calculations.\\nWe show that the offset is indeed physical and arises from the coorbital\\ncorotation torque, since (i) it scales with the disk vortensity gradient, (ii)\\nits asymptotic value depends on the disk viscosity, (iii) it is associated to\\nan excess of the horseshoe zone width. We show that the offset corresponds to\\nthe onset of non-linearities of the flow around the planet, which alter the\\nstreamline topology as the planet mass increases: at low mass the flow\\nnon-linearities are confined to the planet's Bondi sphere whereas at larger\\nmass the streamlines display a classical picture reminiscent of the restricted\\nthree body problem, with a prograde circumplanetary disk inside a ``Roche\\nlobe''. This behavior is of particular importance for the sub-critical solid\\ncores (M &lt;~ 15 M_Earth) in thin (H/r &lt;~0.06) protoplanetary disks. Their\\nmigration could be significantly slowed down, or reversed, in disks with\\nshallow surface density profiles.\\n
Microevolution of Cytochrome bd Oxidase in Staphylococci and Its Implication in Resistance to Respiratory Toxins Released by Pseudomonas
2006-11-16

ABSTRACT Pseudomonas aeruginosa and Staphylococcus aureus are opportunistic pathogens and frequently coinfect the lungs of cystic fibrosis patients. P. aeruginosa secretes an arsenal of small respiratory inhibitors, like pyocyanin, hydrogen cyanide, or quinoline N-oxides, that may act against the commensal flora as well as host cells. Here, we show that with respect to their susceptibility to these respiratory inhibitors, staphylococcal species can be divided into two groups: the sensitive group, comprised of pathogenic species such as S. aureus and S. epidermidis , and the resistant group, represented by nonpathogenic species such as S. carnosus , S. piscifermentans , and S. gallinarum . The resistance in the latter group of species was due to cydAB genes that encode a pyocyanin- and cyanide-insensitive cytochrome bd quinol oxidase. By exchanging cydB in S. aureus with the S. carnosus -specific cydB , we could demonstrate that CydB determines resistance. The resistant or sensitive phenotype was based on structural alterations in CydB, which is part of CydAB, the cytochrome bd quinol oxidase. CydB represents a prime example of both microevolution and the asymmetric pattern of evolutionary change.
The Ligand of Glucocorticoid-Induced TNF Receptor Is Expressed on Human Macrophages and Stimulates Proinflammatory and Anti-Tumor Effector Functions.
2006-11-16

Abstract Macrophages are involved in inflammatory and anti-tumor responses by antigen presentation, release of immunoregulatory cytokines and cellular cytotoxicity. Among the molecules influencing macrophage functions are many members of the TNF superfamily. The TNF receptor family member Glucocorticoid-induced TNF Receptor (GITR) costimulates effector T cells, modulates apoptosis and nuclear factor kappa B and abrogates suppression of murine but not human regulatory T cells. Expression of its cognate ligand GITRL has, in humans, been detected in dendritic cells and various healthy nonlymphoid tissues. Up to now, nothing is known regarding the function of human GITRL, while in mice, reverse signaling through GITRL has been shown to influence the activation and survival of macrophages. Here we report for the first time that GITRL is expressed in human macrophages as determined by FACS and RT-PCR analysis. Reverse signaling through GITRL using a recombinant GITR-Ig fusion protein differentially affects expression of costimulatory molecules like CD80, CD86 and B7-H1, death ligands like TNF, CD178 and TRAIL as well as MHC class I and II on the macrophage surface. Furthermore, stimulation of GITRL enhances phagocytosis and respiratory burst of macrophages as determined by analysis of ingestion of PE-labeled polystyrene microspheres and oxidation of dichlor-fluorescein diacetate, respectively by FACS. Interaction of GITRL with its receptor also leads to significantly increased production of proinflammatory cytokines like TNF, IL-6 and IL-8 as determined by ELISA. In addition, stimulation of GITRL significantly increases the killing of various human tumor cell lines by macrophages as determined by cytotoxicity assays. Taken together, our data demonstrate that GITRL plays an important role in the stimulation of macrophage-mediated inflammatory responses and immune responses against tumors.
Treatment of Patients up to 60 Years with High Risk AML: Final Results of the AML SHG-Hannover 01/99 Trial.
2006-11-16

Abstract In this prospective multicenter trial, we treated 520 patients with AML ≤60 years (414 with de novo and 106 with secondary AML). Patients with CBF-leukemias [t(8;21) or inv(16)] or normal karyotype and good response (GR) to induction I (≤5% blasts in day 15 BM) were considered standard risk (SR), all other patients as high risk (HR). Patients with t(15;17) were excluded. Induction course I consisted of standard dose araC, idarubicine and etoposide (IVA-I). Patients with GR to IVA-I continued with IVA-II on day 21. In patients with bad response (BR; &amp;gt;5% BM blasts on day 15), the second cycle consisted of either IVA-II or FlAG/Ida. Double induction was followed by early consolidation with intermediate dose araC. As late consolidation, HR patients with an HLA-matched sibling were scheduled for a matched related donor (MRD) transplantation; patients without a family donor should undergo autologous peripheral blood stem cell transplantation (autoPBSCT). PBSC were mobilized after early consolidation. An interim analysis showed superior results for allogeneic transplants compared to patients who had undergone autoPBSCT. Therefore, since 2003 all HR patients without a sibling donor were scheduled for matched unrelated donor (MUD) transplantation. 147 of 249 HR patients (59%) achieved complete remission. 33 (13%) of the HR patients died during induction. After 75 months, overall survival (OS) was significantly worse for HR patients (24%) than for SR patients (53%). For HR patients, there was no difference in OS and relapse-free survival (RFS) between patients classified as HR because of BR to IVA-1 (n = 83), unfavourable karyotype (n = 87) or both characteristics (n = 79). RFS was neither different between HR patients with de novo or secondary AML nor between HR patients with normal karyotype, complex karyotype or other high risk cytogenetics. Regarding late consolidation, the “as treated” analysis revealed that OS and RFS was significantly better after an MRD transplantation (n=41, OS 67%, RFS 62%) than after autoPBSCT (n=27, OS 14%, RFS 7%). Patients who received a MUD transplantation (n=32) showed a significantly better RFS (52%) than after autoPBSCT. RFS and OS after MUD transplantation did not differ significantly from MRD transplants. OS of patients after autoPBSCT was not significantly different from patients who received no transplant at all after entering CR. Of the 69 HR patients who did not enter CR after induction, 44 received an MRD or MUD transplantation. 15 of these patients (35%) are alive in CR. In conclusion, HR patients as defined in our study do not benefit from an autologous PBSCT and an allogeneic MRD or MUD transplantation should be performed. Moreover, allogeneic transplants are a viable salvage option for HR patients not entering CR.
Identification and Characterization of T Cell Epitopes Deduced from RGS5, a Novel Broadly Expressed Tumor Antigen.
2006-11-16

Abstract Identification of tumor-associated antigens (TAA) has resulted in the development of therapeutic vaccines for the treatment of cancer. We applied an integrated functional genomics approach to identify TAA in malignant tissues of patients with renal cell carcinoma (RCC). A comparative DNA chip analysis of tumor and the corresponding non-malignant tissue from patients with RCC followed by sequencing of peptides bound to the HLA-class I molecules by mass spectrometry was applied to identify novel TAA in RCC. To confirm the immunogenicity of identified epitopes cytotoxic T lymphocytes (CTL) were generated using dendritic cells (DC). Utilizing this approach, two peptides derived from RGS5 binding to either HLA-A*02 or 03 were identified. The key function of regulators of G protein-signalling (RGS) is to bind to G protein α subunits and to stimulate their intrinsic GTPase activity. The hydrolysis of guanosine triphosphate (GTP) to guanosine diphosphate (GDP) thereby is accelerated and the inactive heterotrimer more rapidly restored. Thus, RGS proteins inhibit the biological activity of G proteins. Interestingly, it was recently shown that RGS5 is overexpressed in pericytes of newly developing tumor vessels, indicating that RGS5 plays an important role during tumor angiogenesis. Using RT-PCR analysis we found that RGS5 is expressed on a broad variety of tumor cells including RCC, colorectal, breast and ovarian cancer, malignant melanoma and multiple myeloma as well as in acute and chronic leukemias making this protein an interesting candidate for the development of vaccination strategies to target the tumor cells and the tumor vessels. CTL that were induced using the RGS5 peptides lysed autologous DC pulsed with the cognate peptide or transfected with in vitro transcribed RGS5 RNA as well as HLA-matched tumor cell lines. The specificity and HLA restriction was confirmed using blocking monoclonal antibodies and in cold-target inhibition assays. We next utilized DC transfected with RGS5 RNA to generate specific CTL. Using this approach we confirmed the processing and presentation of the identified peptides by malignant cells. These CTL lysed tumor cells in an antigen specific manner while sparing non-malignant cells. To analyze the induction of RGS5 specific CTL in an autologous setting in patients with malignant diseases, we used blood samples from a patient with acute myeloid leukemia (AML) in complete remission after chemotherapy and were able to generate specific CTL capable of recognizing autologous AML blasts while sparing non-malignant cells. Our results demonstrate that RGS5 is a novel tumor rejection antigen expressed in a wide range of malignancies that can be applied to target malignant cells and tumor angiogenesis.
New Pinostilbene Analogues Overcome Anthracycline Resistance in Acute Lymphoplastic Leukemia Ex Vivo.
2006-11-16

Abstract Anthracylines play a very important role in the treatment of acute lymphoblastic leukemia (ALL) and relapsed ALL in childhood, however resistance to anthracyclines leads to a poor prognosis. In the present study, we have synthesized two new pinostilbene analogues, i.e. trans-3,4′-dihydroxy-5-methoxystilbene and (E)-resveratrol 4′-O-ß-D-glucopyranoside, which are able to overcome anthracycline resistance in childhood acute lymphoblastic leukemia (ALL) ex vivo and induce apoptosis in established leukemia cell lines via mitochondrial pathway. Apoptosis induction has been investigated by flowcytometric measurement of DNA-fragmentation [LC 50: 10 μM for (1) and (2)], mitochondrial membrane potential reduction and phosphatedylserin-staining on cell membrane surface. Cell death by necrosis could be excluded by a lactatdehydrogenase-release assay. For the first time we analysed the antileukemic and chemopreventive potentials of the pinostilbene analogues (1) and (2) ex vivo in a significant number of primary lymphoblasts of patients suffering from childhood ALL. Patients: Primary lymphoblasts isolated from 22 children with de novo ALL (median: 6.8 years; range 0,6–16.9 years) and relapsed ALL (median:7.2 years) were tested for ex vivo drug response with the anthracyclines daunorubicin (10 μmol/l) and doxorubicin (10 μmol/l) and two new pinostilbene analogues (1) and (2) (10μmol/l), according to their LC50 values in established cell lines. We could demonstrate in these primary cells that the pinostilbenes (1) and (2) were even more effective as compared with the anthracyclines. Out of 22 patients 14 were female (14 de novo ALL) and 8 were male (6 de novo ALL, 2 relapsed ALL). Within these cell populations following immunologic subgroups were found: c-ALL, pre-B-ALL, pro-B-ALL, T-ALL and pre-T-ALL. Results: Daunorubicin induced apoptosis in 6 out of 22 lymphoblast populations (response rate 27,3 %). A similar response rate was observed after treatment with doxorubicin: only 5 of 22 lymphoblast populations responded (22,7%). Nevertheless, far higher response rates were observed for (1) with 11/15 (73,3 %; p&lt;0.005) and for (2) with 15/17 (88,2%; p&lt;0.0002, all p-values by t-test). Interestingly, treatment of daunorubicin-resistant lymphoblasts resulted in significant apoptosis induction in 6 out of 10 cell populations after treatment with compound (1) (response rate 60 %) and in 6/6 after treatment with compound (2) (response rate 100%). Furthermore, pinostilbene (2) showed significant synergistic activity with daunorubicin in 2 of 3 lymphoblast populations. We clearly demonstrated that the ex vivo treatment of lymphoblasts from children with de novo and relapsed ALL with the new pinostilbenes (1) and (2) induced significantly higher response rates than daunorubicin or doxorubicin treatment. In conclusion, the high ex vivo sensitivity of anthracycline resistant leukemia cells to pinostilbene treatment reveals the great proapoptotic and chemopreventive potential of this new class of antileukemic agents.
HD12 Randomised Trial Comparing 8 Dose-Escalated Cycles of BEACOPP with 4 Escalated and 4 Baseline Cycles in Patients with Advanced Stage Hodgkin Lymphoma (HL): An Analysis of the German Hodgkin Lymphoma Study Group (GHSG), University of Cologne, D-50924 Cologne, Germany.
2006-11-16

Abstract The preceding trial HD9 had shown a significant superiority for escalated BEACOPP (EB) for failure-free survival (FFTF) and overall survival (OS) over COPP/ABVD or baseline BEACOPP (BB) (each 8 cycles). HD12 aimed to de-escalate chemotherapy by comparing 8 cycles EB with 4 cycles EB plus 4 cycles BB, with or without consolidatory 30 Gy radiation (RT) to initial bulky and residual disease. A total of 1661 patients aged 16–65 with HL in stage IIB (large mediastinal mass and/or E-lesions) or stage III-IV were randomised from 9/1999-1/2003 according to a factorial design between: 8EB + RT, 8EB no RT, 4EB+4BB + RT, 4EB+4BB no RT. A central diagnostic panel reviewed CT images after completion of chemotherapy independent of randomisation arm, and prescribed RT in selected cases. In the fifth analysis of HD12 (5/2006), 94% of all 1593 eligible randomised patients were evaluable, including 1498 for the chemotherapy comparison and 1449 for the radiotherapy comparison. Patient characteristics were very similar for all 4 arms. Radiation was given in arms with planned RT in 65%, in arms with no planned RT in 10%. 93% of all patients reached a complete remission, 2.2% suffered early progression, 4.6% relapsed and 8.2% died with a median folllow-up time of 48 months. Death due to acute toxicity was 3.2% (sepsis, cardiac, pulmonary, infection), with 21 such deaths in the 8EB arms and 27 in the 4EB+4BB arms. Secondary neoplasias were observed in 55 patients (3.7%): 14 AML/MDS, 12 NHL and 29 solid tumors/others. Four-year Kaplan-Meier estimates for arm pairs according to the factorial design were: 4 year rates, %(95% CI) 8EB vs. 4EB+4BB with RT vs. without RT FFTF 88(86–91) 86(83–89) 91(89–93) 88(86–91) OS 93(91–95) 91(89–93) No significant differences were observed when comparing treatments according to the sequential analysis plan (N.B. 10% received RT in arms ‘without RT’). The final analysis, scheduled when 80% of patients have 5 years follow-up, must be awaited before final conclusions can be drawn.
A Phase II Immunochemotherapy Study with Alemtuzumab, Fludarabine, Cyclophosphamide, and Doxorubicin (Campath-FCD) in Peripheral T-Cell Lymphomas.
2006-11-16

Abstract The majority of entities of peripheral (mature) T-cell lymphomas (PTCL) have an unfavourable prognosis as compared to aggressive B-cell lymphomas. This difference has become even more pronounced since the introduction of CD20 antibodies in B-cell lymphoma therapy. The purpose of the present study was to investigate the feasibility and efficacy of the combination of the monoclonal antibody alemtuzumab with chemotherapy consisting of fludarabine, cyclophosphamide and doxorubicin in PTCL. Patients were treated with alemtuzumab 3, 10, 30, 30 mg, days 1–4, fludarabine 25 mg/m2 days 2–4, cyclophosphamide 600 mg/m2 day 3, and doxorubicin 50 mg/m2 day 4. Initially, patients with primary diagnosis, with first relapse, or with primary refractory disease were included. Excluded were patients with primary cutaneous T-cell lymphomas and ALK-positive large cell anaplastic T-cell lymphomas. So far, 37 patients have been included and 30 are evaluable for response and toxicity: 13 patients with PTCL-unspecified, 9 with angioimmunoblastic lymphoma, two with ALK negative anaplastic large cell lymphoma, two with enteropathy-associated T-cell lymphoma, two with nasal-type NK-/T-cell lymphoma, one with an NK-cell lymphoma, and one with a T-PLL. 19/30 patients were enrolled with primary diagnosis of PTCL and 11/30 patients with relapse or refractory disease. The median age was 56 years (range 21–77); 69% of the patients had an intermediate high or high prognostic score according to the international prognostic index. In patients with primary diagnosis the remission rate was 63% (12/19; CR 58%, PR 5%), four patients were primary progressive, and three patients dropped out because of treatment associated complications. Of the 12 responding patients 10 are in ongoing remission at 2+, 2+, 3+, 6+, 12+, 14+, 26+, 27+, 38+, and 39+ months, respectively. Two patients relapsed after being in CR for 23 and 34 months, respectively. In the group of relapsed or refractory patients three CR and two PR (45% overall response) were observed. The main toxicity was leukocytopenia (65% grade III and IV of all evaluable treatment cycles), other grade III and IV toxicities included anemia (17%), thrombocytopenia (35%), infections (16%), pruritus/skin reactions (11%), nausea/emesis (6%), mucositis (4%), and cardiac toxicity (4%, two patients with relapsed disease after pre-treatment with CHOP-like regimens developed severe heart failure and died). 12 (40%) patients reactivated CMV, however, 10 without developing CMV-related disease. In conclusion, the combination is an effective first-line regimen for peripheral T-cell lymphoma, however, regarding the general outcome a longer follow-up period of a larger patient population is required. Because the results were not convincing in relapsed and refractory disease and because of two heart failures in this group, the study was closed for relapsed and refractory patients, but is ongoing for first-line treatment of peripheral T-cell lymphomas.
Bortezomib Once Weekly Is Well Tolerated as Maintenance Therapy after Less Than a Complete Response to High-Dose Melphalan in Patients with Multiple Myeloma.
2006-11-16

Abstract Background: Despite intensive treatment strategies in multiple myeloma (MM) consisting of one or two cycles of high-dose melphalan (HD-Mel) with autologous stem cell support only a minority of patients (pts) achieves molecular complete remission leading to an event free survival (EFS) of eight to ten years. The median EFS for all patients following HD-Mel, however, is no more than 30 to 35 months. Several agents have been evaluated as a part of maintenance strategies in order to eradicate minimal residual disease and thus extending the period until salvage treatment is required. Interferon alpha, that has been most widely used in this setting showed a significant prolongation of EFS and a trend to better overall survival in a large meta-analysis. Bortezomib (VELCADE® [Vel]), a proteasome inhibitor, has substantial anti-myeloma activity in relapsed and refractory disease and was shown to induce exceptional response rates, including consistently high CR rates in up-front treatment. Patients and methods: We decided to set up a phase II trial in patients up to 70 years with less than CR (SD, PR, or VGPR) after one or two cycles of HD-Mel using a less dose-intense schedule than the standard protocol for monotherapy. The first eleven pts were to receive four cycles of Vel 1.0 mg/m2 once weekly for four weeks followed by a two-week rest period. Since no dose limiting toxicity occurred, the dose was increased as per protocol to 1.3 mg/m2 for the subsequent pts. Results: Up to now, 20 subjects were included with a median age of 60.5 (range, 46 – 69) years, 3 of whom had previously received single, and 17 tandem HD-Mel. Two cases of moderately severe herpes zoster prompted us to generally administer acyclovir prophylaxis throughout the treatment. Five pts experienced symptoms of peripheral neuropathy all of which were of grade I. WBC nadir occurred during cycles 2 and 3 with a median of 3.7 × 109/l while median PLT and HB values did not decline below normal values. Three patients progressed while on the study and received salvage treatment while all other patients enrolled completed all four scheduled cycles of treatment. To date, two patients showed improvement of response by conversion of VGPR into CR with confirmed negative immunofixation. Conclusion: We are currently continuing patient accrual on the once-weekly 1.3 mg/m2 schedule since treatment is considered to be safe. Data on the efficacy (i.e. median EFS, OS as compared to historic controls on interferon alpha), however, will require significantly longer follow up.