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  • 1
    Publication Date: 2018-06-20
    Description: Activating JAK2 point mutations are implicated in the pathogenesis of myeloid and lymphoid malignancies, including high-risk B-cell acute lymphoblastic leukemia (B-ALL). In preclinical studies, treatment of JAK2 mutant leukemias with type I JAK2 inhibitors (e.g., Food and Drug Administration [FDA]-approved ruxolitinib) provided limited single-agent responses, possibly due to paradoxical JAK2 Y1007/1008 hyperphosphorylation induced by these agents. To determine the importance of mutant JAK2 in B-ALL initiation and maintenance, we developed unique genetically engineered mouse models of B-ALL driven by overexpressed Crlf2 and mutant Jak2, recapitulating the genetic aberrations found in human B-ALL. While expression of mutant Jak2 was necessary for leukemia induction, neither its continued expression nor enzymatic activity was required to maintain leukemia survival and rapid proliferation. CRLF2/JAK2 mutant B-ALLs with sustained depletion or pharmacological inhibition of JAK2 exhibited enhanced expression of c-Myc and prominent up-regulation of c-Myc target genes. Combined indirect targeting of c-Myc using the BET bromodomain inhibitor JQ1 and direct targeting of JAK2 with ruxolitinib potently killed JAK2 mutant B-ALLs.
    Print ISSN: 0890-9369
    Topics: Biology
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  • 2
    Publication Date: 2018-05-01
    Description: Aim: To compare toxicity, response, and survival outcomes of patients with hepatic metastases from breast cancer who underwent transarterial chemoembolization (TACE) or radioembolization (TARE). Materials and Methods: A retrospective review was carried out of all patients who underwent TACE or TARE for liver-dominant breast cancer metastases between January 2006 and March 2016 at an academic medical center in the United States. Results: Seventeen patients in the TACE group and 30 patients in the TARE group received 32 TACE and 49 TARE treatments, respectively. Median follow-up was 9 months. Both groups had similar background variables. More all-grade adverse events were seen in the TACE group (71% vs. 44%; p=0.02). Median overall survival in the TACE group was 4.6 months compared to 12.9 months in the TARE group (p=0.2349). Treatment type was not an independent prognostic factor. Conclusion: TARE is better tolerated than TACE for the treatment of liver-dominant breast cancer metastasis. There was a trend towards improved survival with TARE; however, it did not approach statistical significance. Larger studies are needed to validate these findings.
    Print ISSN: 0250-7005
    Electronic ISSN: 1791-7530
    Topics: Medicine
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  • 3
    Publication Date: 2018-09-15
    Description: Purpose: To determine the safety, pharmacokinetics, and recommended phase II dose of an antibody–drug conjugate (ADC) targeting ectonucleotide phosphodiesterases-pyrophosphatase 3 (ENPP3) conjugated to monomethyl auristatin F (MMAF) in subjects with advanced metastatic renal cell carcinoma (mRCC). Patients and Methods: Two phase I studies were conducted sequentially with 2 ADCs considered equivalent, hybridoma-derived AGS-16M8F and Chinese hamster ovary–derived AGS-16C3F. AGS-16M8F was administered intravenously every 3 weeks at 5 dose levels ranging from 0.6 to 4.8 mg/kg until unacceptable toxicity or progression. The study was terminated before reaching the MTD. A second study with AGS-16C3F started with the AGS-16M8F bridging dose of 4.8 mg/kg given every 3 weeks. Results: The AGS-16M8F study ( n = 26) closed before reaching the MTD. The median duration of treatment was 12 weeks (1.7–83 weeks). One subject had durable partial response (PR; 83 weeks) and 1 subject had prolonged stable disease (48 weeks). In the AGS-16C3F study ( n = 34), the protocol-defined MTD was 3.6 mg/kg, but this was not tolerated in multiple doses. Reversible keratopathy was dose limiting and required multiple dose deescalations. The 1.8 mg/kg dose was determined to be safe and was associated with clinically relevant signs of antitumor response. Three of 13 subjects at 1.8 mg/kg had durable PRs (range, 100–143 weeks). Eight subjects at 2.7 mg/kg and 1.8 mg/kg had disease control 〉37 weeks (37.5–141 weeks). Conclusions: AGS-16C3F was tolerated and had durable antitumor activity at 1.8 mg/kg every 3 weeks. Clin Cancer Res; 24(18); 4399–406. ©2018 AACR .
    Print ISSN: 1078-0432
    Electronic ISSN: 1557-3265
    Topics: Medicine
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  • 4
    Publication Date: 2018-04-20
    Description: Objective There is some evidence that lung function and chronic kidney disease (CKD) may be related. We evaluated the impact of lung function on the development of CKD in a large-scale longitudinal study. Method Retrospective longitudinal analyses were conducted among subjects who participated in comprehensive health check-ups at least four times during 7 years (between 2006 and 2012). We investigated the development of CKD during the follow-up period according to lung function status. Results Ten thousand one hundred and twenty-eight individuals (mean age =51.2 years) without CKD at baseline were enrolled. During the mean follow-up of 5 years (58.5±14.4 months), 167 of the 10 128 subjects (1.6%) developed CKD. Multivariable Cox proportional hazards analyses adjusting for age, sex, body mass index, systolic blood pressure, fasting glucose, estimated glomerular filtration rate, uric acid, triglycerides, serum albumin, and the presence of diabetes and hypertension revealed that a decrease of 10% in the forced expiratory volume in 1s (FEV 1 )/forced vital capacity (FVC) ratio was associated with a 35% increase in the development of CKD during the follow-up. The incidence of CKD was higher in those with an FEV 1 /FVC ratio 〈0.8 compared with those with FEV 1 /FVC ratio ≥0.8 (HR=1.454; 95% CI 1.042 to 2.028, p=0.028). Conclusions Limited airflow as measured by the FEV 1 /FVC ratio was associated with an increased risk of CKD.
    Keywords: Open access, Renal medicine
    Electronic ISSN: 2044-6055
    Topics: Medicine
    Published by BMJ Publishing
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  • 5
    Publication Date: 2018-01-30
    Description: BACKGROUND: Noninvasive prenatal testing (NIPT) uses cell-free DNA (cfDNA) as an analyte to detect copy-number alterations in the fetal genome. Because maternal and fetal cfDNA contributions are comingled, changes in the maternal genome can manifest as abnormal NIPT results. Circulating tumor DNA (ctDNA) present in cases of maternal neoplasia has the potential to distort the NIPT readout to a degree that prevents interpretation, resulting in a nonreportable test result for fetal aneuploidy. METHODS: NIPT cases that showed a distortion from normal euploid genomic representation were communicated to the caregiving physician as nonreportable for fetal aneuploidy. Follow-up information was subsequently collected for these cases. More than 450000 pregnant patients who submitted samples for clinical laboratory testing 〉3 years are summarized. Additionally, in-depth analysis was performed for 〉79000 research-consented samples. RESULTS: In total, 55 nonreportable NIPT cases with altered genomic profiles were cataloged. Of these, 43 had additional information available to enable follow-up. A maternal neoplasm was confirmed in 40 of these cases: 18 malignant, 20 benign uterine fibroids, and 2 with radiological confirmation but without pathological classification. CONCLUSIONS: In a population of pregnant women who submitted a blood sample for cfDNA testing, an abnormal genomic profile not consistent with fetal abnormalities was detected in about 10 out of 100000 cases. A subset of these observations (18 of 43; 41.9%) was attributed to maternal malignant neoplasms. These observational results suggest the need for a controlled trial to evaluate the potential of using cfDNA as an early biomarker of cancer.
    Keywords: Molecular Diagnostics and Genetics
    Print ISSN: 0009-9147
    Electronic ISSN: 1530-8561
    Topics: Medicine
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