48 research outputs found

    Cephalosporin-resistant Pneumococci and Sickle Cell Disease

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    Increasingly resistant bacteria in sickle cell disease patients indicate need to evaluate extendedspectrum cephalosporin therapy

    Metabolic compensation activates pro-survival mTORC1 signaling upon 3-phosphoglycerate dehydrogenase inhibition in osteosarcoma

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    Osteosarcoma is the most common pediatric and adult primary malignant bone cancer. Curative regimens target the folate pathway, downstream of serine metabolism, with high-dose methotrexate. Here, the rate-limiting enzyme in the biosynthesis of serine from glucose, 3-phosphoglycerate dehydrogenase (PHGDH), is examined, and an inverse correlation between PHGDH expression and relapse-free and overall survival in osteosarcoma patients is found. PHGDH inhibition in osteosarcoma cell lines attenuated cellular proliferation without causing cell death, prompting a robust metabolic analysis to characterize pro-survival compensation. Using metabolomic and lipidomic profiling, cellular response to PHGDH inhibition is identified as accumulation of unsaturated lipids, branched chain amino acids, and methionine cycle intermediates, leading to activation of pro-survival mammalian target of rapamycin complex 1 (mTORC1) signaling. Increased mTORC1 activation sensitizes cells to mTORC1 pathway inhibition, resulting in significant, synergistic cell death in vitro and in vivo. Identifying a therapeutic combination for PHGDH-high cancers offers preclinical justification for a dual metabolism-based combination therapy for osteosarcoma

    Height at diagnosis and birth-weight as risk factors for osteosarcoma

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    OBJECTIVES: Osteosarcoma typically occurs during puberty. Studies of the association between height and/or birth-weight and osteosarcoma are conflicting. Therefore, we conducted a large pooled analysis of height and birth-weight in osteosarcoma. METHODS: Patient data from seven studies of height and three of birth-weight were obtained, resulting in 1,067 cases with height and 434 cases with birth-weight data. We compared cases to the 2000 US National Center for Health Statistics Growth Charts by simulating 1,000 age- and gender-matched controls per case. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for associations between height or birth-weight and risk of osteosarcoma for each study were estimated using logistic regression. All of the case data were combined for an aggregate analysis. RESULTS: Compared to average birth-weight subjects (2,665-4,045 g), individuals with high birth-weight (≥ 4,046 g) had an increased osteosarcoma risk (OR 1.35, 95% CI 1.01-1.79). Taller than average (51st - 89th percentile) and very tall individuals (≥ 90th percentile) had an increased risk of osteosarcoma (OR 1.35, 95% CI 1.18-1.54 and OR 2.60, 95% CI 2.19-3.07, respectively; P (trend) < 0.0001). CONCLUSIONS: This is the largest analysis of height at diagnosis and birth-weight in relation to osteosarcoma. It suggests that rapid bone growth during puberty and in utero contributes to OS etiology

    A Phase I Trial of the MET/ALK/ROS1 Inhibitor Crizotinib Combined with the VEGF Inhibitor Pazopanib in Patients with Advanced Solid Malignancies

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    Background: Crizotinib inhibits ALK, MET and ROS1 tyrosine kinases but the development of resistance to monotherapy is an issue. The anti-angiogenic properties of pazopanib could overcome crizotinib drug resistance. Additionally, the anti-angiogenic properties of crizotinib could augment the clinical efficacy of pazopanib. Methods: We evaluated the safety and responses in patients with advanced solid tumors treated with crizotinib and pazopanib. Results: Eighty-two patients (median age 53 years, range 18-78 years) were enrolled. The median number of prior systemic therapies was 3 (range, 0-8). We were able to dose escalate to dose level 8 (crizotinib 250 mg twice daily and pazopanib 800 mg daily) with no MTD identified. Grade 3 or 4 toxicities were seen in 32% of patients with the highest prevalence being fatigue (n=9, 11%), diarrhea (n=6, 7%), vomiting (n=3, 4%), anemia (n=2, 2%) and ALT increased (n=2, 2%). Of the 82 patients, 61 (74%) had measurable disease by RECISTv1.1 and reached first restaging (6 weeks). Partial response (PR) was observed in 6/61 (10%) patients, and stable disease (SD) lasting ≥6 months was observed in 10/61 patients (16%) (total = 16/61 (26%) of patients with SD ≥6 months/PR). Conclusion: Dose level 6 (crizotinib 200 mg twice daily and pazopanib 600 mg daily) was the most tolerable dosing of the combination and can be used in future studies. We also observed moderate clinical activity in patients with advanced solid tumors that had received numerous prior therapies

    Tumor biology, biomarkers, and liquid biopsy in pediatric renal tumors

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    The expansion of knowledge regarding driver mutations for Wilms tumor (WT) and malignant rhabdoid tumor of the kidney (MRT) and various translocations for other pediatric renal tumors opens up new possibilities for diagnosis and treatment. In addition, there are growing data surrounding prognostic factors that can be used to stratify WT treatment to improve outcomes. Here, we review the molecular landscape of WT and other pediatric renal tumors as well as WT prognostic factors. We also review incorporation of circulating tumor DNA/liquid biopsies to leverage this molecular landscape, with potential use in the future for distinguishing renal tumors at the time of diagnosis and elucidating intratumor heterogeneity, which is not well evaluated with standard biopsies. Incorporation of liquid biopsies will require longitudinal collection of multiple biospecimens. Further preclinical research, identification and validation of biomarkers, molecular studies, and data sharing among investigators are crucial to inform therapeutic strategies that improve patient outcomes
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