More than 30 years ago it was discovered that permeability glycoprotein (P-gp) can cause drug resistance. Over the following decades numerous studies showed that high expression of P-gp is associated ...with poor prognosis in acute myeloid leukemia in adults and that it causes multidrug resistance via ATP-dependent drug efflux. It was hoped that an inhibition of P-gp could sensitize resistant leukemic cells to chemotherapy and thus improve treatment results. Today we know that the family of ATP-binding cassette transporters (ABC transporters) comprises 48 different proteins. Some of them seem to be able to cause drug resistance as well as P-gp. This review focuses on emerging data on the clinical relevance of other ABC transporters, such as BCRP, MRP3, and ABCA3. When Heracles fought the ancient Hydra, he had to fight all the heads at ones but only one head was vital for the beast. Can we block all the relevant ABC transporters at once? Is there one transporter that is more important than the others?
As 3D printing has increased in popularity, it has become more important to understand the properties and characteristics of the parts being produced. The material properties of 3D printed parts are ...not equivalent to the bulk properties of the materials used to print them. The nature of 3D printing, with varying raster and build orientations, results in anisotropy of the printed parts. This paper presents the experimental techniques and results for the mechanical characterization of acrylonitrile butadiene styrene (ABS) and polycarbonate (PC) 3D printed parts to determine the anisotropy of their shear properties. Because of the anisotropy, tensile material properties cannot be used to determine shear properties. Iosipescu shear specimens were manufactured at various print raster (+45/−45, +30/−60, +15/−75, and 0/90) and build orientations (flat, on-edge, and up-right) to determine the directional properties of both ABS and PC samples. Ten samples of each raster were subjected to loading in a universal testing machine while making use of 2D digital image correlation (DIC) to measure full-field strain on both sides of the specimen. Results for both the ABS and PC materials show that there were measurable differences in the modulus of rigidity between build orientations and significant differences in shear strength. The ABS samples exhibited strong anisotropy as a function of build orientation while the PC samples exhibited strong anisotropy as a function of raster orientation.
GnpIS is a data repository for plant phenomics that stores whole field and greenhouse experimental data including environment measures. It allows long-term access to datasets following the FAIR ...principles: Findable, Accessible, Interoperable, and Reusable, by using a flexible and original approach. It is based on a generic and ontology driven data model and an innovative software architecture that uncouples data integration, storage, and querying. It takes advantage of international standards including the Crop Ontology, MIAPPE, and the Breeding API. GnpIS allows handling data for a wide range of species and experiment types, including multiannual perennial plants experimental network or annual plant trials with either raw data,
direct measures, or computed traits. It also ensures the integration and the interoperability among phenotyping datasets and with genotyping data. This is achieved through a careful curation and annotation of the key resources conducted in close collaboration with the communities providing data. Our repository follows the Open Science data publication principles by ensuring citability of each dataset. Finally, GnpIS compliance with international standards enables its interoperability with other data repositories hence allowing data links between phenotype and other data types. GnpIS can therefore contribute to emerging international federations of information systems.
Breast cancer resistance protein (BCRP), also known as mitoxantrone resistance protein (MRX) or placenta ABC protein (ABC-P), is the second member of the ABCG subfamily of ABC transport proteins ...(gene symbol ABCG2). Transfection and enforced expression of BCRP in drug-sensitive cells confers resistance to mitoxantrone, doxorubicin, daunorubicin and topotecan. In this study the expression of BCRP gene was measured using TaqMan real-time PCR in 59 children with newly diagnosed AML. Nine patients were also analyzed in relapse. The median of BCRP gene expression was more than 10 times higher in patients who did not achieve remission after the first phase of chemotherapy (n = 24) as compared to patients who did achieve remission at this stage (n = 21; P = 0.012). In first relapse the expression of the BCRP gene was higher than at diagnosis (P = 0.038). Although high levels of BCRP gene expression were more frequent in subtypes of AML with a favorable prognosis, we found that within both risk groups (high and low risk), patients who expressed high levels of BCRP had a worse prognosis (P = 0.023). Our results strongly suggest that the expression of the BCRP gene reduces the response to chemotherapy in AML and that BCRP expression is higher at the time of relapse.
A standardized, sensitive and universal method for minimal residual disease (MRD) detection in acute myeloid leukemia (AML) is still pending. Although hyperexpression of Wilms' tumor (WT1) gene ...transcript has been frequently proposed as an MRD marker in AML, wide comparability of the various methods used for evaluating WT1 expression has not been given. We established and standardized a multicenter approach for quantifying WT1 expression by quantitative reverse transcriptase PCR (qRT-PCR), on the basis of a primer/probe set combination at exons 6 and 7. In a series of quality-control rounds, we analyzed 69 childhood AML samples and 47 normal bone marrow (BM) samples from 4 participating centers. Differences in the individual WT1 expressions levels ranged within <0.5 log of the mean in 82% of the cases. In AML samples, the median WT1/1E+04 Abelson (ABL) expression was 3.5E+03 compared with that of 2.3E+01 in healthy BM samples. As 11.5% of childhood AML samples in this cohort harbored WT1 mutations in exon 7, the effect of mutations on WT1 expression has been investigated, showing that mutated cases expressed significantly higher WT1 levels than wild-type cases. Hence, our approach showed high reproducibility and applicability, even in patients with WT1 mutations; therefore, it can be widely used for the quantitation of WT1 expression in future clinical trials.
Infants <1 year of age have a high prevalence of prognostically unfavorable leukemias and a presumed susceptibility to treatment-related toxicities. A total of 125 infants with acute myeloid leukemia ...(AML) were treated in studies AML-BFM-98 (n = 59) and -2004 (n = 66). Treatment regimens of both studies were comparable, consisting of intensive induction followed by four courses (mainly high-dose cytarabine and anthracyclines). Allogeneic-hematopoietic stem-cell-transplantation (allo-HSCT) in 1st remission was optional for high-risk (HR) patients. Most infants (120/125=96%) were HR patients according to morphological, cytogenetic/molecular genetic and response criteria. Five-year overall survival was 66 ± 4%, and improved from 61 ± 6% in study-98 to 75 ± 6% in study-2004 (P(logrank) 0.14) and event-free survival rates were 44 ± 6% and 51 ± 6% (P(logrank) 0.66), respectively. Results in HR infants were similar to those of older HR children (1-<2- or 2-<10-year olds, P(logrank) 0.90 for survival). Survival rates of HSCT in 1st remission, initial partial response and after relapse were high (13/14, 2/8 and 20/30 patients, respectively). The latter contributes to excellent 5-year survival after relapse (50±8%). Despite more severe infections and pulmonary toxicities in infants, treatment-related death rate was identical to that of older children (3%). Our data indicate that intensive frontline and relapse AML treatment is feasible in infants, toxicities are manageable, and outcome is favorable.
Recent studies with very small numbers of patients showed that in some cases of childhood acute lymphoblastic leukemia (ALL), preleukemic cells are detectable on Guthrie cards that were used for ...newborn screening. We present here the largest series of ALL patients (n=32) in whom Guthrie cards were analyzed for the presence of preleukemic cells. Rearranged immunoglobulin heavy-chain genes were used as a marker for leukemic clones. We combined our set of patients with 17 previously published cases. Preleukemic cells were detected in 31 of all 49 patients (63%). Positive screening cards were not associated with patient's age at diagnosis but were almost always found in patients with hyperdiploidy (10/11; 91%; P=0.04). High birth weight is an established risk factor for childhood ALL. Positive screening cards were strongly associated with low birth weight (P=0.01). In conclusion, the majority of childhood B-precursor ALL arise prior to birth. In the search for causes of childhood leukemia we should concentrate on prenatal factors as well as postnatal factors. Our results suggest that autologous cord bloods could be a poor choice as the source of stem cells for transplantation in leukemia, which may contain preleukemic cells. Pending the development of suitable methods, childhood leukemia is a potentially screenable disease.
Noninvasive ventilation (NIV) may be superior to conventional therapy in immunocompromised children with respiratory failure.
Mortality, success rate, prognostic factors and side effects of NIV for ...acute respiratory failure (ARF) were investigated retrospectively in 41 in children with primary immunodeficiency, after stem cell transplantation or chemotherapy for oncologic disease.
In 11/41 (27%) children invasive ventilation was avoided and patients were discharged from ICU. In children with NIV failure ICU-mortality was 19/30 (63%). 8/11 (72%) children with NIV success had recurrence of ARF after 27 days. Only 4/11 (36%) children with first episode NIV success and 8/30 (27%) with NIV failure survived to hospital discharge. Lower FiO2, SpO2/FiO2 and blood culture positive bacterial sepsis were predictive for NIV success, while fungal sepsis or culture negative ARF were predictive for NIV failure. We observed catecholamine treatment in 14/41 (34%), pneumothorax in 2/41 (5%), mediastinal emphysema in 3/41 (7%), a life threatening nasopharyngeal hemorrhage and need for resuscitation during intubation in 5/41 (12%) NIV-episodes.
The prognosis of ARF in immunocompromised children remains guarded independent of initial success or failure of NIV due to a high rate of recurrent ARF. Reversible causes like bacterial sepsis had a higher NIV response rate. Relevant side effects of NIV were observed.
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