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  • 1
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    Particle nucleation in the tropical boundary layer and its coupling to marine sulfur sources (1998)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 1998-10-02
    Description: New particle formation in a tropical marine boundary layer setting was characterized during NASA's Pacific Exploratory Mission-Tropics A program. It represents the clearest demonstration to date of aerosol nucleation and growth being linked to the natural marine sulfur cycle. This conclusion was based on real-time observations of dimethylsulfide, sulfur dioxide, sulfuric acid (gas), hydroxide, ozone, temperature, relative humidity, aerosol size and number distribution, and total aerosol surface area. Classic binary nucleation theory predicts no nucleation under the observed marine boundary layer conditions.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Clarke -- Davis -- Kapustin -- Eisele -- Chen -- Paluch I -- Lenschow -- Bandy -- Thornton -- Moore -- Mauldin -- Tanner -- Litchy -- Carroll -- Collins -- Albercook -- New York, N.Y. -- Science. 1998 Oct 2;282(5386):89-92.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉A. D. Clarke, V. N. Kapustin, K. Moore, M. Litchy, School of Ocean and Earth Science and Technology, University of Hawaii, Honolulu, HI, USA. D. Davis, F. Eisele, G. Chen, School of Earth and Atmospheric Sciences, Georgia Institute of Technology, Atl.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/9756483" target="_blank"〉PubMed〈/a〉
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 2
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    Peripherally applied Abeta-containing inoculates induce cerebral beta-amyloidosis (2010)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2010-10-23
    Description: The intracerebral injection of beta-amyloid-containing brain extracts can induce cerebral beta-amyloidosis and associated pathologies in susceptible hosts. We found that intraperitoneal inoculation with beta-amyloid-rich extracts induced beta-amyloidosis in the brains of beta-amyloid precursor protein transgenic mice after prolonged incubation times.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3233904/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3233904/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Eisele, Yvonne S -- Obermuller, Ulrike -- Heilbronner, Gotz -- Baumann, Frank -- Kaeser, Stephan A -- Wolburg, Hartwig -- Walker, Lary C -- Staufenbiel, Matthias -- Heikenwalder, Mathias -- Jucker, Mathias -- P51 RR000165/RR/NCRR NIH HHS/ -- P51 RR000165-51/RR/NCRR NIH HHS/ -- RR-00165/RR/NCRR NIH HHS/ -- New York, N.Y. -- Science. 2010 Nov 12;330(6006):980-2. doi: 10.1126/science.1194516. Epub 2010 Oct 21.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Cellular Neurology, Hertie-Institute for Clinical Brain Research, University of Tubingen, D-72076 Tubingen, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/20966215" target="_blank"〉PubMed〈/a〉
    Keywords: Alzheimer Disease/metabolism/pathology ; Amyloid beta-Peptides/administration & dosage/*chemistry/metabolism ; Animals ; Brain/blood supply/*pathology ; Brain Chemistry ; Cerebral Amyloid Angiopathy/metabolism/pathology ; Female ; Injections, Intraperitoneal ; Mice ; Mice, Transgenic ; Plaque, Amyloid/pathology ; Prions/chemistry/metabolism ; Protein Folding ; Time Factors
    Print ISSN: 0036-8075
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  • 3
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    An Intercomparison of Tropospheric OH Measurements at Fritz Peak Observatory, Colorado (1992)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 1992-05-22
    Description: The hydroxyl radical (OH) controls the lifetimes and therefore the concentrations of many important chemical species in Earth's lower atmosphere including several greenhouse and ozone-depleting species. Two completely different measurement techniques were used in an informal intercomparison to determine tropospheric OH concentrations at Fritz Peak concentrations by chemical analysis; the other used spectroscopic absorption on a long path. The intercomparison showed that ambient OH concentrations can now be measured with sufficient sensitivity to provide a test for photochemical models, with the derived OH concentrations agreeing well under both polluted and clean atmospheric conditions. Concentrations of OH on all days were significantly lower than model predictions, perhaps indicating the presence of an unknown scavenger. The change in OH concentration from early morning to noon on a clear day was found to be only a factor of 2.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mount, G H -- Eisele, F L -- New York, N.Y. -- Science. 1992 May 22;256(5060):1187-90.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/17795214" target="_blank"〉PubMed〈/a〉
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  • 4
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    Donor Cell Myeloma: A Unique Case (2018)
    American Society of Hematology
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    Publication Date: 2018-11-29
    Description: Leukemia relapse occurring in donor cells, so called donor cell leukemia (DCL) after allogeneic hematopoietic stem cell transplantation has been previously reported in the literature. Some authors have suggested that the development of DCL is perhaps a more common occurrence than traditionally thought. Donor cell myeloma (DCM) seems to be less frequent than DCL. This 46-year old male when first seen in 2000 was diagnosed with stage IIIa multiple myeloma. A monoclonal IgA kappa spike was recorded at diagnosis. Treatment with melphalan and prednisone was delivered every four to six weeks for a total of 22 courses. Fourty months after the initial diagnosis, an M2 acute myelogenous leukemia was identified. Treatment with chemotherapy resulted in complete remission. Matched UCB cells were localized at the London Cord Blood Bank. The UCB belonged to a male product of a white western European mother and a black Nigerian father who was a carrier of hemoglobin S. Hemoglobins A, F and S were detected in the UCB, consonant with sickle cell trait. The patient was allografted employing the "Mexican" NST conditioning regimen, granulocyte count recovered to more than 0.5 x 109/L on day 14, with the platelet count never dropping below 20 x 109/L. On day +40, the polymorphic microsatellite markers revealed mixed chimerism. The hemoglobin S gene was identified on day +20 and on day +60, full chimerism was shown. Cyclosporine A was stopped on day +350. The patient returned 170 months after the transplant with low back pain and the bone marrow aspiration disclosed 80% abnormal plasma cells, an IgA kappa monoclonal spike of 3.1 gr/dl, and complete chimerism. Malignant plasma cells were sorted by means of flow cytometry before genetic fingerprinting; cells were stained with an admixture of fluorescent monoclonal antibodies and cells co-expressing dim CD45, bright CD38 and CD56 were sorted out to ≥99% purity. Sorted cells were shown to have donor origin (Figure 1). The patient was treated with thalidomide, dexamethasone and bortezomib and the monoclonal spike disappeared; an autologous stem cell transplant is planned. Most people consider that the development of a malignancy in the cells of the donor is a rare event and very few prospective studies have analyzed the real prevalence of this phenomenon. Prospectively, we have found that 7% (95% CI 2.9 to 13.6%) of patients with leukemic activity after an allogeneic graft do have a donor cell-derived leukemia; this figure contrasts with those described elsewhere in non-prospective studies. A major problem in the analysis of donor cell derived malignancies is that demonstration of the donor cell origin of malignant activity. In this case, the demonstration of DNA of the donor in the fluorescence-activated sorted malignant plasma cells is indicative of the origin of the myeloma cells. Interestingly, the immunoglobulin type produced by the initial myeloma cells is the same as that of the donor-cell myeloma; Despite being two myelomas producing the same immunoglobulin subtype, both should be considered as de novomalignancies and as such, treated; we have previously shown that donor cell leukemias do have a response when treated as de novo, non-secondary leukemias. To our best knowledge, this is the second report of DCM following allogeneic HSCT. Prior to this case, Kim et al reported a DCM after an allogeneic transplant in a patient with refractory anemia with ringed sideroblasts. Previously, two cases have been reported of donor-origin MM, but they occurred in patients who underwent solid organ transplantation of the kidney and heart-lung. Kumar et alreported a case of DCM developing after unrelated allogeneic HSCT in the both donor and recipient but they did not conducted a comprehensive molecular cytogenetic study. In the case published by Maestas et al, an abnormal proliferation of plasma cells was identified in the donor, thus making possible that a malignant plasma cell clone was already present in the donor stem cells. In summary, we have clearly shown that this patient has had three different malignancies: 1) De novomultiple myeloma, 2) Secondary acute myelogenous leukemia and 3) De novodonor cell-derived multiple myeloma. The mechanisms involved in these episodes could be useful to better understand tumorigenesis. Disclosures No relevant conflicts of interest to declare.
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  • 5
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    Indirect Comparison Using Individual Patient Level Data Comparing Efficacy and Safety of a Daratumumab Monotherapy Vs. EU Approved Comparator Therapies in Patients with Multiple Myeloma (2018)
    American Society of Hematology
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    Publication Date: 2018-11-29
    Description: Introduction. Efficacy and safety of daratumumab monotherapy (DARA mono) in relapsed/refractory multiple myeloma (rrMM) has been shown in the single-arm phase I/II trial GEN501 and the single-arm phase II trial SIRIUS (1, 2). Since then, several indirect treatment comparisons of DARA mono versus comparator therapies have been published showing consistent results with an overall survival benefit for DARA mono (3, 4, 5, 6). This analysis compares efficacy and for the first time also safety of DARA mono data versus an international historic control group, adjusting for differences in patient populations based on individual patient level data (IPD). Methods. IPD from the SIRIUS trial and from the International Myeloma Foundation (IMF)-cohort (7), a retrospective, multicenter cohort, were compared using a multivariate Cox proportional hazards model, on the endpoints of efficacy (overall survival (OS)) and safety (discontinuation due to adverse events (DISCONAE)). The IMF-cohort included patients with rrMM who received at least three prior lines of therapy, were refractory to both an immunomodulator (IMiD) and a proteasome inhibitor (PI), and were exposed to an alkylating agent. An inclusion criterion for the historic control group in this analysis was treatment with EU approved regimens. Baseline covariates adjusted for in the regression model included age, gender, prior lines of therapy, albumin, beta-2 microglobulin, prior exposure to pomalidomide and carfilzomib, and PI/IMiD refractory status. Several sensitivity analyses were run, including multiple imputation of missing values. Results. Data from 106 patients treated with DARA mono (16 mg/kg) were available from SIRIUS; 258 patients from the IMF chart review fulfilled the inclusion criteria; most frequent treatment regimens contained pomalidomide plus dexamethasone (PomDex) (n=172), bortezomib (n=31), carfilzomib (n=21), cyclophosphamide (n=14) and lenalidomide (n=9). The adjusted HR for OS was 0.41 [0.25, 0.69], p
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  • 6
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    Improving the Treatment Outcome of Acute Promyelocytic Leukemia in Developing Countries through International Cooperative Network. Report On the International Consortium On Acute Promyelocytic Leukemia Study Group. (2009)
    American Society of Hematology
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    Publication Date: 2009-11-20
    Description: Abstract 6 Acute promyelocytic leukemia (APL) is a curable disease, and contemporary treatment based on the combination of all-trans retinoic acid (ATRA) with anthracyclines results in overall survival (OS) rates of around 90% at five years. Unfortunately, the treatment outcome of patients with APL in developing countries is significantly less. A recent Brazilian study had reported an OS of 53% with a first 5-days mortality of 13.4%. The International Consortium on Acute Promyelocytic Leukemia (IC-APL) is an initiative of the International Members Committee of the ASH and the project aims to reduce this gap through the establishment of international network, which was launched in Brazil, México and Uruguay. All patients with a suspected diagnosis of APL were immediately started on ATRA, while bone marrow samples were shipped to a national central lab where genetic verification of the diagnosis was performed. Results of the immunofluorescence for PML was obtained within hours and upon confirmation of the diagnosis, patients were enrolled in a protocol identical to the PETHEMA-LPA 2005, except for the replacement of idarubicin by daunorubicin. Supportive care aimed at maintaining platelet counts above 30,000/μl and fibrinogen levels above 150 mg/dl. In each country, cases were discussed every other week through internet and whenever needed international experts were involved. As of June 2009, 102 (70 Brazil, 25 Mexico, 7 Uruguay) APL patients were enrolled. The median age was 34 y (range: 9–72y) with 55 males (54%).The median white blood cell counts (WBC) at baseline was 3.6×109 /L(range: 0.2–149.7). The distribution of the relapse risk score at diagnosis according to PETHEMA-GIMEMA criteria was 14 low (14%), 54 intermediate (53%) and 34 high risk(33%) respectively. The incidence of low risk APL appeared lower than the values reported in developed countries. Of 102, 97 patients have toxicity and response data available. Of these 97, 12 (12.3%)experienced at least three symptoms/signs of differentiation syndrome (DS) and 77 (79%) patients achieved a complete remission (CR). Twenty-three deaths occurred and the cause of deaths included 9 hemorrhage, 8 infection, 2 DS . The 7 and 30 day mortality rates were 8% and 19.6%, respectively, and the one- year overall survival was 75% (95%CI:68%–84%). The median follow-up time among survivors was 14 months (range: 1.3–35). Among 77 patients who achieved CR, the 1-year OS and disease-free survival from the date of CR was 95% (95% CI: 89%–100%). Only one patient relapsed. For patients surviving a minimum of 30 days the outcome was similar to that reported by the twin PETHEMA-LPA 2005 protocol in European patients. Prognostic factors for overall survival were examined using log-rank test as well as multivariate Cox models. Factors predicting OS were a high relapse risk score at baseline (1-year OS: 59% for high, 87% for intermediate, 91% for low, p=0.0007) and age. The 1-year OS was 85% for age
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  • 7
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    Polyclonal Free Light Chain Elevation and Mortality In the German Heinz Nixdorf Recall Study (2010)
    American Society of Hematology
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    Publication Date: 2010-11-19
    Description: Abstract 3903 Abnormalities of the κ:λ free light chain (FLC) ratio can detect monoclonal FLC elevations and are a valuable tool in the diagnosis and follow-up of plasma cell dyscrasias. However, due to their generation in active cells of the immune system and their renal metabolism, polyclonal FLC elevations might also provide valuable hints to other pathologic conditions. Recent reports suggest e.g. a role in predicting outcome in chronic viral infectious diseases. In a previous study, we screened the cohort of the German Heinz Nixdorf Recall Study for monoclonal gammopathies by combined serum protein electrophoresis and screening immunofixation (Eisele et al. EHA 2010, Abstract #0949) and also measured FLC concentration by nephelometric immunoassays (FREELITE, The Binding Site, UK) in all available samples. We here report our first preliminary results of the analysis of polyclonal FLC elevation with regard to all-cause mortality in the Heinz Nixdorf Recall cohort. The Heinz Nixdorf Recall Study cohort comprises 4814 men and women from 3 large adjacent cities in Germany. Subjects were randomly selected from statutory lists of residence and gave informed consent. We screened serum samples from the baseline examination which took place from 2000 until 2003. After exclusion of samples with monoclonal FLC elevation, laboratory results together with clinical information of 4350 study subjects (2180 male, 2170 female) were available for analysis. We used summated FLC (total FLC, tFLC) as a measure for polyclonal elevation. tFLC ranged from 2.7 to 275 mg/l with a median of 30.2 mg/l. High levels of tFLC were associated with high-sensitive CRP (hsCRP) and chronic kidney disease (CKD). Both quintiles of tFLC and CKD stage were associated with shorter survival in univariate analysis. Using the median as cutoff, tFLC still separated groups with different survival within CKD stages 0 and 1. tFLC remained an independent predictor of survival in multivariable cox regression analysis adjusted for sex, age, hsCRP and CKD stage (HR 1.13 (95%CI 1.03 – 1.24 per quintile, p=0.0068). For the 274 deaths that occurred during a median observational time of 5 years we had information available from death certificates. Causes of death were categorized into cardiopulmonary, infectious, cancer, and other. The number of deaths increased from the lowest to the highest tFLC quintile (34 vs. 98), however we found no associations of tFLC with categorized causes of death. Polyclonal FLC measurements are affected by a variety of health conditions and may thus be subject to fluctuations over time. We are currently measuring FLC in the 5-year follow-up samples of the Heinz Nixdorf Recall study. This will provide us with a more precise estimate of polyclonal FLC elevation and will help us to further define their role in predicting mortality. These results will also be reported at the conference. Disclosures: Eisele: Celgene: Research Funding. Dürig:Celgene: Research Funding.
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  • 8
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    Prevalence of Monoclonal Gammopathy of Undetermined Significance (MGUS) and Light-Chain MGUS (LCMGUS) In a Metropolitan Area In Germany (2010)
    American Society of Hematology
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    Publication Date: 2010-11-19
    Description: Abstract 4037 Background: We utilized the biobank of the ongoing population-based, prospective Heinz Nixdorf Recall Study to determine the prevalence of monoclonal gammopathy of undetermined significance (MGUS) and a recently defined entity – light-chain MGUS (LCMGUS) – in the densely populated Ruhr area in Germany. Methods: The Heinz Nixdorf Recall study cohort comprises 4814 men and women from 3 large adjacent cities in Germany. Subjects were randomly selected from statutory lists of residence and gave informed consent. We screened serum samples from the baseline examination which took place from 2000 until 2003. Standard serum electrophoresis (SPE) was combined with parallel screening immunofixation electrophoresis (scIFE) using pentavalent antisera (Hydragel 12 IF, Penta-Kit, Sebia, Fulda, Germany). Where a monoclonal band was visible or suspected, confirmatory IFE followed. Free light-chain (FLC) κ and λ measurements were performed on a Dade Behring BNII automated nephelometer (Siemens, Germany) utilizing a commercially available kit (FREELITE, The Binding Site Ltd, Birmingham, UK). Definition of MGUS cases was based on common criteria including monoclonal protein concentration, laboratory results, and disease history. LCMGUS cases were defined as an abnormal FLC ratio, an increase in the FLC that caused the abnormal ratio and no detectable intact immunoglobulin (Dispenzieri et al. Lancet 2010: 1721-8). Age-standardization of prevalences was performed by direct standardization to the U.S. population 2000. Results: 165 MGUS cases were identified in a total of 4708 screened samples, translating into a prevalence of 3.5% (95% CI, 3.0 – 4.1). The median age of MGUS cases was 63 years (range 47 – 75), 103 (62%) were of male gender, and prevalence increased with age. The age-standardized prevalence was 3.9% (95% CI 3.2 – 4.5) which was significantly higher (p
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  • 9
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    Inherited genetic susceptibility to monoclonal gammopathy of unknown significance (2014)
    American Society of Hematology
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    Publication Date: 2014-04-17
    Description: Key Points Inherited genetic variation increases risk to developing multiple myeloma through predisposition to MGUS. Loci identified that increase risk of developing MGUS include 2p23.3, 3p22.1, 3q26.2, 6p21.33, 7p15.3, 17p11.2, and 22q13.1.
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  • 10
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    Clonal Abundance Determines The Prognostic Relevance Of a NOTCH1 Mutation In Chronic Lymphocytic Leukemia (2013)
    American Society of Hematology
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    Publication Date: 2013-11-15
    Description: Introduction The transmembrane receptor NOTCH1 operates as a ligand-activated transcription factor controlling developmental processes, proliferation and apoptosis. In the context of cancer, activating NOTCH1 mutations are the most frequent oncogenic events in T-cell acute lymphoblastic leukemia and have been implicated in chronic lymphocytic leukemia (CLL) as well. The most prevalent CLL NOTCH1 mutation (N1ΔCT) leads to a truncation of the protein (p.P2515Rfs*4) and has been associated with impaired overall survival (OS). Here, we applied three different methods to study the N1ΔCT prevalence and subclone size in a cohort of n=275 CLL patients. Methods Presence of the N1ΔCT mutation was analyzed using newly established restriction fragment length polymorphism (RFLP) and allele-specific PCR (AS-PCR) methodologies. A novel real-time PCR (qRT-PCR) assay was used to precisely quantify the N1ΔCT allele frequency. Presence of the N1ΔCT mutation was confirmed by conventional Sanger sequencing. Results Using RFLP analysis we detected the N1ΔCT mutation in n=17 CLL patients. In parallel, we used a more sensitive AS-PCR and identified n=12 additional N1ΔCT-mutated cases resulting in a total N1ΔCT mutation rate of 10.5% (n=29/275) in our cohort. The OS of RFLP-positive patients (RFLP+) was significantly shorter than the OS of N1ΔCT-unmutated patients (wt) (mean OS; RFLP+, 87 months vs. wt, 218 months; p=0.017). In contrast, OS of AS-PCR-positive cases (AS-PCR+) did not differ significantly from the OS of wt patients (mean OS; AS-PCR+, 175 months vs. wt, 218 months; p=0.42). These data prompted us to design a quantitative real-time PCR (qRT-PCR) assay, which is capable of precisely quantifying the size of the N1ΔCT-mutated subclones (allele frequency, %) in our CLL cohort. As expected, significantly different allele frequencies between RFLP+ (mean±SEM 27.1±3.4%), AS-PCR+ (3.7±0.6%) and wt patients (0.6±0.04%) were revealed by qRT-PCR (p
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