The derivation of a battery electric vehicle (BEV) architecture represents a challenging task for car manufacturers. For the early development of combustion engine architectures, the required design ...parameters can be derived from the analysis of previously-built model series. Regarding BEV architectures, the manufacturers do not yet have a reference series of vehicles on the basis of which they can derive the essential design parameters. Therefore, these parameters are mainly estimated at high cost in the early development phase. To avoid cost-intensive changes in the further course of development it is crucial to choose the right set of design parameters. For this reason, the aim of this paper is the identification of a minimum set of design parameters, derived from the current state-of-the-art of vehicle development by a structured literature comparison. We group the results according to our definition of vehicle architecture and discuss each identified parameter to explain its relevance. The sum of all parameters presented in this paper builds a minimum set of design parameters, which can be employed as a guideline for the definition of BEV architectures in the early development stage.
BACKGROUNDPreliminary evidence indicates that the addition of low-dose total body irradiation (TBI) (2-4 Gy) to reduced intensity conditioning may reduce the rate of relapse in allogeneic stem cell ...transplants. In very high-risk patients receiving combination haploidentical single-unit cord blood transplants, we have added 4 Gy TBI to the widely used fludarabine, melphalan conditioning regimen, in hopes of reducing relapse and decreasing graft rejection.
METHODSWe retrospectively reviewed the posttransplant outcomes of patients who underwent haplocord stem cell transplant between May 2013 and March 2015 and who received fludarabine 30 mg/m day (D)−7 to −3, melphalan 140 mg/m D−2, and 2 Gy TBI D−4 and −3.
RESULTSAll 25 patients achieved primary neutrophil engraftment after a median of 12 days. The median time to platelet engraftment was 27 days. The cumulative incidence of nonrelapse mortality was 16% by D+100 and 33% by 1 year. The cumulative incidence of grade III to IV acute graft-versus-host disease was 36% by D+100. The CIR was 13% by D+100 and 29% by 1 year. The estimated 1-year overall survival and progression-free survival were 40% and 37%, respectively. In a subgroup analysis, we compared the outcome of 13 acute myeloid leukemia patients receiving this conditioning regimen with age and disease risk index–matched acute myeloid leukemia patients receiving fludarabine-melphalan without TBI. The TBI group had lower incidence of relapse at 1 year (15% vs 54%, P = 0.05).
CONCLUSIONSOverall, combination fludarabine-melphalan with low-dose TBI after haplocord stem cell transplant assures good engraftment and leads to acceptable toxicity and disease control in the setting of high risk, heavily pretreated patients. These findings warrant further investigation at a larger-scale, prospective level.
Common cancer mutations of p53 tend either to lower the stability or distort the core domain of the protein or weaken its DNA binding affinity. We have previously analyzed in vitro the effects of ...mutations on the core domain of p53. Here, we extend those measurements to full-length p53, using either the wild-type protein or a biologically active superstable construct that is more amenable to accurate biophysical measurements to assess the possibilities of rescuing different types of mutations by anticancer drugs. The tetrameric full-length proteins had similar apparent melting temperatures to those of the individual domains, and the structural mutations lowered the melting temperature by similar amounts. The thermodynamic stability of tetrameric p53 is thus dictated by its core domain. We determined that the common contact mutation R273H weakened binding to the gadd45 recognition sequence by ∼700-1000 times. Many mutants that have lowered melting temperatures should be good drug targets, although the common R273H mutant binds response elements too weakly for simple rescue.
Alternative donor transplantation with the haplo-cord platform allows the use of a lower-dose single umbilical cord blood unit (CBU) by co-infusion of third-party CD34
-selected cells from a ...haploidentical relative, which provides early transient engraftment while awaiting durable CBU engraftment. In our experience, ~15% of patients lack a suitable haploidentical donor. Here we report 26 patients who underwent haplo-cord transplant using CD34
-selected partially matched unrelated donor grafts. Twenty-four were conditioned with fludarabine/melphalan +/- low-dose TBI (n = 16). Twenty-five received ATG and all received posttransplant tacrolimus and mycophenolate mofetil. Median time to neutrophil and platelet recovery was 11 and 18 days. CBU engraftment, with CD33 and CD3 >5% cord chimerism in the myeloid/lymphoid compartment by day +60, occurred in 20 of 24 patients (83%). Incidence of grade 2-4 acute graft-versus-host disease (GVHD) was 27% at day +100, and chronic GVHD was 4% at 1 year. Overall survival at 1 year was 54%. For patients in need of an alternative transplant who lack a haploidentical donor, haplo-cord transplantation using CD34
-selected partially matched unrelated donor grafts results in rapid engraftment with no increased rate of cord graft failure or GVHD.
Cancer-testis antigens (CTA) comprise a family of proteins, which are physiologically expressed in adult human tissues solely in testicular germ cells and occasionally placenta. However, CTA ...expression has been reported in various malignancies. CTAs have been identified by their ability to elicit autologous cellular and or serological immune responses, and are considered potential targets for cancer immunotherapy. The breast differentiation antigen NY-BR-1, expressed specifically in normal and malignant breast tissue, has also immunogenic properties. Here we evaluated the expression patterns of CTAs and NY-BR-1 in breast cancer in correlation to clinico-pathological parameters in order to determine their possible impact as prognostic factors.
The reactivity pattern of various mAbs (6C1, MA454, M3H67, 57B, E978, GAGE #26 and NY-BR-1 #5) were assessed by immunohistochemistry in a tissue micro array series of 210 randomly selected primary invasive breast cancers in order to study the diversity of different CTAs (e.g. MAGE-A, NY-ESO-1, GAGE) and NY-BR-1. These expression data were correlated to clinico-pathological parameters and outcome data including disease-free and overall survival.
Expression of at least one CTA was detectable in the cytoplasm of tumor cells in 37.2% of the cases. NY-BR-1 expression was found in 46.6% of tumors, respectively. Overall, CTA expression seemed to be linked to adverse prognosis and M3H67 immunoreactivity specifically was significantly correlated to shorter overall and disease-free survival (p=0.000 and 0.024, respectively).
Our findings suggest that M3H67 immunoreactivity could serve as potential prognostic marker in primary breast cancer patients. The exclusive expression of CTAs in tumor tissues as well as the frequent expression of NY-BR-1 could define new targets for specific breast cancer therapies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Umbilical cord blood stem cell transplants are commonly used in adults lacking HLA-identical donors. Delays in hematopoietic recovery contribute to mortality and morbidity. To hasten recovery, we ...used co-infusion of progenitor cells from a partially matched related donor and from an umbilical cord blood graft (haplo-cord transplant). Here we compared the outcomes of haplo-cord and double-cord transplants. A total of 97 adults underwent reduced intensity conditioning followed by haplo-cord transplant and 193 patients received reduced intensity conditioning followed by double umbilical cord blood transplantation. Patients in the haplo-cord group were more often from minority groups and had more advanced malignancy. Haplo-cord recipients received fludarabine-melphalan-anti-thymocyte globulin. Double umbilical cord blood recipients received fludarabine-cyclophosphamide and low-dose total body irradiation. In a multivariate analysis, haplo-cord had faster neutrophil (HR=1.42, P=0.007) and platelet (HR=2.54, P<0.0001) recovery, lower risk of grade II-IV acute graft-versus-host disease (HR=0.26, P<0.0001) and chronic graft-versus-host disease (HR=0.06, P<0.0001). Haplo-cord was associated with decreased risk of relapse (HR 0.48, P=0.001). Graft-versus-host disease-free, relapse-free survival was superior with haplo-cord (HR 0.63, P=0.002) but not overall survival (HR=0.97, P=0.85). Haplo-cord transplantation using fludarabine-melphalan-thymoglobulin conditioning hastens hematopoietic recovery with a lower risk of relapse relative to double umbilical cord blood transplantation using the commonly used fludarabine-cyclophosphamide-low-dose total body irradiation conditioning. Graft-versus-host disease-free and relapse-free survival is significantly improved. Haplo-cord is a readily available graft source that improves outcomes and access to transplant for those lacking HLA-matched donors. Trials registered at clinicaltrials.gov identifiers 00943800 and 01810588.
Due to their post-transcriptional regulatory impact on gene expression, microRNAs (miRNA, miRs) influence decisively cellular processes of differentiation, proliferation and apoptosis. In oncogenic ...pathways various miRNAs exert either oncogenic or tumor suppressor activities in a stage-specific manner. Dysregulation of miRNA expression pattern has been associated with several human cancers including endometrial cancer (EC). In the present study, expression profile alterations of EC associated secreted miRNAs were determined under the microenvironmental stress situations hypoxia and acidosis occurring in tumor progression and metastasis. The potential influence of hypoxia and acidosis vs. control conditions on the expression levels of 24 EC-relevant miRNA types was quantitatively accessed via real-time PCR in three established EC in vitro models. Expression data were analyzed statistically. In vitro application of hypoxia resulted in downregulation of miR-15a, miR-20a, miR-20b and miR-128-1 in Ishikawa cells (type I EC) and upregulation of miR-21 in EFE-184 cells (type I EC). Acidosis triggered upregulation of tumor promoting miR-125b in AN3-CA cell (type II EC), whereas in Ishikawa cells (type I EC) miRNAs with tumor suppressive function were found altered in divergent directions, both up- (let-7a) and down- (miR-22) regulated. Our current findings emphasize the functional importance of secreted miRNAs in the immediate response of EC cells to exogenic stress situations such as the typical tumor epiphenomena hypoxia and acidosis. Focusing on the specific potential of secreted, thus circulating miRNA molecules, alterations in expression levels not only influence intracellular gene expression and signaling cascades, but also transfer the induction of (tumor)biological cellular changes to adjacent cells.
Background: Breast cancer is the most common type of cancer worldwide. Cyclin-dependent kinase inhibition is one of the backbones of metastatic breast cancer therapy. However, there are a significant ...number of therapy failures. This study evaluates the biomarker potential of microRNAs for the prediction of a therapy response under cyclin-dependent kinase inhibition. Methods: This study comprises the analysis of intracellular and extracellular microRNA-expression-level alterations of 56 microRNAs under palbociclib mono as well as combination therapy with letrozole. Breast cancer cell lines BT-474, MCF-7 and HS-578T were analyzed using qPCR. Results: A palbociclib-induced microRNA signature could be detected intracellularly as well as extracellularly. Intracellular miR-10a, miR-15b, miR-21, miR-23a and miR-23c were constantly regulated in all three cell lines, whereas let-7b, let-7d, miR-15a, miR-17, miR-18a, miR-20a, miR-191 and miR301a_3p were regulated only in hormone-receptor-positive cells. Extracellular miR-100, miR-10b and miR-182 were constantly regulated across all cell lines, whereas miR-17 was regulated only in hormone-receptor-positive cells. Conclusions: Because they are secreted and significantly upregulated in the microenvironment of tumor cells, miRs-100, -10b and -182 are promising circulating biomarkers that can be used to predict or detect therapy responses under CDK inhibition. MiR-10a, miR-15b, miR-21, miR-23a and miR-23c are potential tissue-based biomarkers.
BCL6 encodes a transcription factor that represses genes necessary for the terminal differentiation of lymphocytes within germinal centers, and the misregulated expression of this factor is strongly ...implicated in several types of B cell lymphoma. The homodimeric BTB domain of BCL6 (also known as the POZ domain) is required for the repression activity of the protein and interacts directly with the SMRT and N-CoR corepressors that are found within large multiprotein histone deacetylase-containing complexes. We have identified a 17 residue fragment from SMRT that binds to the BCL6 BTB domain, and determined the crystal structure of the complex to 2.2 Å. Two SMRT fragments bind symmetrically to the BCL6 BTB homodimer and, in combination with biochemical and in vivo data, the structure provides insight into the basis of transcriptional repression by this critical B cell lymphoma protein.
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