AbstractA general approach for calibration of resistance factors for load and resistance factor design (LRFD) of pullout and tensile failure internal limit states of soil nail walls is presented. The ...calibration of resistance factor values includes the influence of nominal load and nominal resistance model type and accuracy (method bias), bias dependencies, uncertainty in nominal load and resistance values, and possible cross-correlation (dependency) between nominal load and resistance terms. The current default Federal Highway Administration simplified method and an improved version are used to compute maximum nail loads under operational (in-service) conditions. Nail pullout capacity is calculated using the effective stress method adopted in Hong Kong and a more accurate modified version. Resistance factors are calibrated for a range of load factors and target reliability indexes. Example design outcomes for internal limit states of a soil nail wall using different load and resistance model combinations are presented. The benefit of using the more accurate improved load and resistance models for soil nail wall pullout design is demonstrated by a reduction in total length of soil nails.
We evaluated the therapeutic effects of the histone deacetylase inhibitor PXD101 alone and in combination with conventional chemotherapy in treating thyroid cancer.
We studied eight cell lines from ...four types of thyroid cancer (papillary, follicular, anaplastic and medullary). The cytotoxicity of PXD101 alone and in combination with three conventional chemotherapeutic agents (doxorubicin, paclitaxel and docetaxel) was measured using LDH assay. Western blot assessed expression of acetylation of histone H3, histone H4 and tubulin, proteins associated with apoptosis, RAS/RAF/ERK and PI3K/AKT/mTOR signaling pathways, DNA damage and repair. Apoptosis and intracellular reactive oxygen species (ROS) were measured by flow cytometry. Mice bearing flank anaplastic thyroid cancers (ATC) were daily treated with intraperitoneal injection of PXD101 for 5 days per week. PXD101 effectively inhibited thyroid cancer cell proliferation in a dose-dependent manner. PXD101 induced ROS accumulation and inhibited RAS/RAF/ERK and PI3K/mTOR pathways in sensitive cells. Double-stranded DNA damage and apoptosis were induced by PXD101 in both sensitive and resistant cell lines. PXD101 retarded growth of 8505C ATC xenograft tumors with promising safety. Combination therapy of PXD101with doxorubicin and paclitaxel demonstrated synergistic effects against four ATC lines in vitro.
PXD101 represses thyroid cancer proliferation and has synergistic effects in combination with doxorubicin and paclitaxel in treating ATC. These findings support clinical trials using PXD101 for patients with this dismal disease.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Medulloblastoma is a malignant childhood brain tumour comprising four discrete subgroups. Here, to identify mutations that drive medulloblastoma, we sequenced the entire genomes of 37 tumours and ...matched normal blood. One-hundred and thirty-six genes harbouring somatic mutations in this discovery set were sequenced in an additional 56 medulloblastomas. Recurrent mutations were detected in 41 genes not yet implicated in medulloblastoma; several target distinct components of the epigenetic machinery in different disease subgroups, such as regulators of H3K27 and H3K4 trimethylation in subgroups 3 and 4 (for example, KDM6A and ZMYM3), and CTNNB1-associated chromatin re-modellers in WNT-subgroup tumours (for example, SMARCA4 and CREBBP). Modelling of mutations in mouse lower rhombic lip progenitors that generate WNT-subgroup tumours identified genes that maintain this cell lineage (DDX3X), as well as mutated genes that initiate (CDH1) or cooperate (PIK3CA) in tumorigenesis. These data provide important new insights into the pathogenesis of medulloblastoma subgroups and highlight targets for therapeutic development.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
AbstractA rigorous probabilistic-based approach for load and resistance factor design (LRFD) calibration of internal stability tensile rupture and pullout limit states for geogrid reinforced ...mechanically stabilized earth (MSE) walls is presented. Load and resistance factors are provided for different combinations of the load model with pullout model and the tensile strength model used in current practice. The load models are the AASHTO Simplified Method and the Simplified Stiffness Method. Resistance factors are tabulated for use in LRFD foundation practice in Canada which rewards designers with larger resistance factors for greater project level of understanding. Resistance factors are also provided that are amenable to US practice where the notion of level of understanding is not explicitly considered in LRFD practice. The paper demonstrates the application of the load and resistance factors for tensile rupture and pullout internal stability limit states using a design example and shows the reduction in required reinforcement strength using the Simplified Stiffness Method. The paper is of value to practitioners and LRFD code writers in the United States and Canada for future revisions of design specifications in their jurisdictions.
Proteasome inhibition with bortezomib is a validated approach to the treatment of multiple myeloma, but drug resistance often emerges and limits its utility in the retreatment setting. To begin to ...identify some of the mechanisms involved, we developed bortezomib-resistant myeloma cell lines that, unlike previously reported models, showed no β5 subunit mutations. Instead, up-regulation of the insulin-like growth factor (IGF)–1 axis was identified, with increased autocrine and paracrine secretion of IGF-1, leading to increased activation of the IGF-1 receptor (IGF-1R). Exogenous IGF-1 reduced cellular sensitivity to bortezomib, whereas pharmacologic or small hairpin RNA–mediated IGF-1R suppression enhanced bortezomib sensitivity in cell lines and patient samples. In vitro studies with OSI-906, a clinically relevant dual IGF-1R and insulin receptor inhibitor, showed it acted synergistically with bortezomib, and potently resensitized bortezomib-resistant cell lines and patient samples to bor-tezomib. Importantly, OSI-906 in combination with bortezomib also overcame bor-tezomib resistance in an in vivo model of myeloma. Taken together, these data support the hypothesis that signaling through the IGF-1/IGF-1R axis contributes to acquired bortezomib resistance, and provide a rationale for combining bortezomib with IGF-1R inhibitors like OSI-906 to overcome or possibly prevent the emergence of bortezomib-refractory disease in the clinic.
Hematologic malignances are more common and often higher risk in older patients. Allogeneic hematopoietic cell transplantation (alloHCT) best enables long-term disease control for patients with poor ...risk or relapsed/refractory hematologic malignancies such as acute myeloid leukemia, myelodysplastic syndromes, or myelofibrosis. Rates of alloHCT among older patients, while still relatively low compared with younger patients, have risen sharply over the past decade. Accumulating evidence supports alloHCT for patients ≥60 years of age relative to non-HCT therapies based on improved overall and disease-free survival. However, a significant proportion of older adults have limitations characterized by geriatric assessment. A systematic process to evaluate and optimize older patients may improve decision making, transplant outcomes, and alloHCT access. We present case-based studies to illustrate a stepwise and rational approach to proper older patient evaluation, pretransplant optimization, and posttransplant care with attention to important geriatric issues and quality of life.
Vehicle traffic loading appears to contribute significantly to long-term settlement beneath highways, airport runways, and metro lines in China. Wheel loading imposes cycles in both the magnitude and ...direction of the principal stresses acting on the soils beneath pavement or rail-track structures. Conventional cyclic triaxial (CT) testing, which is not capable of imposing such stress paths, may underestimate how heavy traffic loading affects any underlying soft clay layers. A hollow cylinder apparatus (HCA) can simulate such traffic loading stress paths more accurately, including rotation of the principal stress directions. This paper presents a systematic experimental study of cyclic HCA (CHCA) tests on K
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-consolidated saturated soft clay involving cyclic variations in both vertical and torsional shear stresses, along with a parallel programme of CT tests, considering the undrained response of saturated samples of intact soft clay. It is shown that when applied above certain critical cyclic stress ratios, principal stress rotation accelerates excess pore-water pressure and permanent strain development. Corresponding changes are also seen in the resilient modulus and damping ratio trends. The discrepancies between the behaviour of CHCA and equivalent CT tests grow as the cyclic stress ratios increase.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Long-lived humoral immunity is manifested by the ability of bone marrow plasma cells (PCs) to survive for extended periods of time. Recent studies have underscored the importance of BLyS and APRIL as ...factors that can support the survival of B lineage lymphocytes. We show that BLyS can sustain PC survival in vitro, and this survival can be further enhanced by interleukin 6. Selective up-regulation of Mcl-1 in PCs by BLyS suggests that this alpha-apoptotic gene product may play an important role in PC survival. Blockade of BLyS, via transmembrane activator and cyclophilin ligand interactor-immunoglobulin treatment, inhibited PC survival in vitro and in vivo. Heightened expression of B cell maturation antigen (BCMA), and lowered expression of transmembrane activator and cyclophilin ligand interactor and BAFF receptor in PCs relative to resting B cells suggests a vital role of BCMA in PC survival. Affirmation of the importance of BCMA in PC survival was provided by studies in BCMA-/- mice in which the survival of long-lived bone marrow PCs was impaired compared with wild-type controls. These findings offer new insights into the molecular basis for the long-term survival of PCs.
Objective To evaluate the efficacy and safety of ganciclovir therapy in neonates with congenital cytomegalovirus (CMV) disease.
Study design Neonates with symptomatic CMV disease involving the ...central nervous system were randomly assigned to receive 6 weeks of intravenous ganciclovir versus no treatment. The primary end point was improved brainstem-evoked response (BSER) between baseline and 6-month follow-up (or, for patients with normal baseline hearing, normal BSER at both time points).
Results From 1991 to 1999, 100 patients were enrolled. Of these, 42 patients had both a baseline and 6-month follow-up BSER audiometric examination and thus were evaluable for the primary end point. Twenty-one (84%) of 25 ganciclovir recipients had improved hearing or maintained normal hearing between baseline and 6 months versus 10 (59%) of 17 control patients (P=.06). None (0%) of 25 ganciclovir recipients had worsening in hearing between baseline and 6 months versus 7 (41%) of 17 control patients (P<.01). A total of 43 patients had a BSER at both baseline and at 1 year or beyond. Five (21%) of 24 ganciclovir recipients had worsening of hearing between baseline and ≥1 year versus 13 (68%) of 19 control patients (P<.01). A total of 89 patients had absolute neutrophil counts determined during the course of the study; 29 (63%) of 46 ganciclovir-treated patients had grade 3 or 4 neutropenia during treatment versus 9 (21%) of 43 control patients (P<.01).
Conclusions Ganciclovir therapy begun in the neonatal period in symptomatically infected infants with CMV infection involving the central nervous system prevents hearing deterioration at 6 months and may prevent hearing deterioration at ≥1 year. Almost two thirds of treated infants have significant neutropenia during therapy.
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